Mcl-1参与HBx和游离脂肪酸诱导细胞凋亡的作用机制研究
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摘要
第一部分Mcl-1参与HBx诱导细胞凋亡的作用机制研究
研究背景和目的
持续HBV感染是病毒引起的包括慢性肝炎、肝硬化等在内的慢性肝病的主要原因,并与肝细胞癌(HCC)的发生发展密切相关,在我国HBV感染是HCC最主要的病因。在HBV病毒所编码的蛋白中,HBx蛋白是HBV非结构基因编码的多功能病毒调控蛋白,参与HBV的感染、复制等一系列致病过程,并对肝细胞的增殖、凋亡、代谢、应激、迁移等多种生物学功能具有广泛而复杂的影响,被认为是HBV诱导肝癌发生过程中最主要的决定因素之一,而其确切致病机理仍有待进一步阐明。越来越多的证据表明凋亡是HBV病毒诱发慢性肝病的重要介质,相关研究发现HBx可以增强肝细胞对凋亡信号的敏感性。这些证据提示我们HBx可能通过促进肝细胞凋亡实现其诱发肝癌的作用,而HBx促进肝细胞凋亡的具体机制目前尚无定论。
Bcl-2家族是细胞内调节凋亡与存活的最重要的一类蛋白家族,家族成员同时包括抗凋亡和促凋亡分子。其中Mcl-1(Myeloid cell leukemia-1),中文译为髓细胞淋巴瘤-1,是Bcl-2家族中重要的抗凋亡成员。目前发现Mcl-1广泛表达于各类组织细胞,参与胚胎发育、造血干细胞内稳态的维持,以及细胞凋亡的动态调控。但是,Mcl-1是否参与HBx诱导肝细胞凋亡并在其中发挥重要作用目前国内外均未见有系统报道。
本研究从细胞和转基因动物水平观察HBx的表达对氧化应激信号诱导的肝细胞凋亡敏感性的影响,同时观察在此过程中Mcl-1表达水平的改变,明确HBx在何种水平、以何种方式调节Mcl-1的表达;再结合腺病毒介导的过表达技术,阐明Mcl-1在HBx诱导细胞凋亡中的作用;并结合临床HBV阳性肝癌患者的肝组织样本从组织水平明确HBx与Mcl-1表达的相关性。
实验方法
1.构建HBx和Mcl-1过表达及干扰质粒、包装表达HBx、Mcl-1和干扰Mcl-1的腺病毒、筛选建立HBx稳定细胞系;
2.通过流式细胞技术观察瞬时表达和稳定表达HBx的细胞系对氧化应激信号敏感性的变化;
3.通过双荧光素酶报告基因实验、RT-PCR和real-time PCR技术以及Westernblot方法分别观察表达HBx的细胞系在氧化应激信号暴露下对Mcl-1启动子转录活性、转录水平及其蛋白质水平的影响;
4.使用通路特异性抑制剂实验开展HBx对Mcl-1表达调节的机制研究;
5.运用荧光TUNEL法和流式细胞技术验证抑制相关信号通路和过表达Mcl-1在HBx诱导的细胞凋亡中的作用;
6.建立HBx转基因小鼠肝氧化应激刺激模型,运用组织TUNEL、Western blot方法从体内水平验证HBx对Mcl-1蛋白水平及肝脏细胞凋亡的影响;
7.免疫组化结合Western blot方法观察HBV阳性肝癌患者癌组织中HBx与Mcl-1表达的相关性。
结果
1.HBx明显增强细胞对氧化应激信号诱导凋亡的敏感性,在此过程中伴随Mcl-1蛋白水平的下调;且HBx能剂量依赖性的及时间依赖性的下调Mcl-1蛋白,并不受细胞系的影响;
2.HBx下调Mcl-1蛋白主要发生在翻译后水平;
3.过表达Mcl-1显著抑制HBx的促凋亡作用;
4.HBx主要通过诱导细胞内ROS显著增加,激活caspas-3进而加速降解Mcl-1蛋白实现其促凋亡作用的;
5.HBx转基因小鼠肝脏缺血再灌注处理后肝组织中Mcl-1蛋白水平下降,同时伴随肝细胞凋亡明显增加;
6.HBV阳性肝癌患者癌组织中Mcl-1与HBx的表达水平存在负相关。
结论
本研究发现HBx增强肝细胞对氧化应激信号诱导凋亡的敏感性主要通过显著增加胞内ROS,活化caspas-3进而加速Mcl-1蛋白降解来实现。提示ROS/caspase-3/Mcl-1途径在HBx促肝细胞凋亡的过程中可能发挥重要作用。
第二部分Mcl-1参与游离脂肪酸诱导细胞凋亡的作用机制研究
研究背景和目的
大量研究表明非酒精性脂肪肝是与肥胖、Ⅱ型糖尿病、高脂血症以及代谢综合征等疾病病程进展密切相关的代谢性疾病。近年来由于生活方式、饮食结构等的改变,非酒精性脂肪肝的发病率不断增加,目前已成为全世界范围内最常见的肝脏疾病,越来越受到人们的重视。然而,由于非酒精性脂肪肝的病因非常复杂,导致至今仍不清楚其确切的发病机制,因而也缺乏有效的治疗手段。
游离脂肪酸是肝脏甘油三脂的主要来源,目前认为游离脂肪酸是引起肝脏脂毒性的重要介质,并在非酒精性脂肪肝的发病和病程进展中具有重要作用。研究发现,非酒精性脂肪肝病理学的重要特点是肝脏细胞凋亡显著增加。然而,对于游离脂肪酸如何诱导肝细胞发生凋亡的具体机制目前不十分清楚,仍有待进一步研究。
近年来研究表明,Bcl-2家族中的Mcl-1作为其家族中一个重要的抗凋亡成员,在肝细胞的生存与凋亡的调控中发挥重要作用,然而Mcl-1是否参与游离脂肪酸诱导肝细胞凋亡并在其中发挥重要作用目前国内外未见相关报道。
本实验首先观察游离脂肪酸诱导肝细胞凋亡过程中Mcl-1表达的改变,然后结合腺病毒介导的过表达及干扰技术,明确Mcl-1在游离脂肪酸诱导的细胞凋亡中的作用,并进一步阐明游离脂肪酸调节Mcl-1表达的分子机制。
实验方法
1.构建干扰Mcl-1的腺病毒;
2.通过检测caspase活性和Western blot技术明确游离脂肪酸对凋亡的影响;
3.Western blot实验检测游离脂肪酸诱导细胞凋亡过程中Mcl-1蛋白水平的改变;
4.real-time PCR技术检测游离脂肪酸对Mcl-1转录水平的影响;
5.运用腺病毒介导的过表达和干扰技术明确Mcl-1在游离脂肪酸诱导的细胞凋亡中的生物学功能;
6.结合通路抑制剂实验开展游离脂肪酸对Mcl-1表达调控的信号通路研究。
结果
1.游离脂肪酸中的软脂酸可明显诱导肝细胞发生凋亡;
2.软脂酸诱导的细胞凋亡过程中Mcl-1的蛋白水平显著下调;
3.软脂酸诱导的肝细胞凋亡主要是由Mcl-1所介导的;
4.软脂酸主要在翻译后水平促进Mcl-1蛋白通过泛素—蛋白酶体途径降解;
5.抗氧化剂和caspase抑制剂均无法阻断软脂酸诱导的Mcl-1的下降;
6.JNK通路介导软脂酸对Mcl-1的负向调节。
结论
本研究发现软脂酸诱导肝细胞凋亡过程中Mcl-1的蛋白水平显著下调,并进一步明确软脂酸诱导肝细胞凋亡主要是通过激活JNK通路、促进Mcl-1下调实现的,提示JNK/Mcl-1途径在软脂酸诱导的肝细胞脂性凋亡过程中具有重要作用。本研究为深入理解非酒精性脂肪肝发病机制提供新的线索,并为该病的治疗提供新的潜在靶点和策略。
Background & Aims:Many studies provide strong evidence of the critical role of hepatitis B virus X(HBx) in human hepatocarcinogenesis.Although the association of HBx with apoptosis has been widely investigated,the exact role of HBx in modulating apoptotic process remains controversial.Here,we examined whether HBx exerts its apoptosis- promoting effects via dysregulation of Mcl-1 expression.
Methods:Apoptotic cell death and the expression of Bcl-2 family proteins were determined in HBx-expressing hepatic cell lines and HBx transgenic mice. Immunohistochemistry and immunoblotting were performed to evaluate the expression of Mcl-1 in hepatocellular carcinoma(HCC) samples with or without hepatitis B virus(HBV) infection.
Results:Ectopic expression of HBx rendered cell susceptible to death signals in response to cisplatin,which relied on the loss of Mcl-1.Caspase-3 inhibitors,but not JNK,P38,GSK-3βor proteasome inhibitors,effectively abrogated HBx-enhanced Mcl-1 degradation as well as cell apoptosis.Antioxidant treatment demonstrated that reactive oxygen species(ROS) triggered caspase-3-mediated Mcl-1 turnover in this model.Moreover,HBx sensitized cells to ROS-induced apoptotic killing also through activating caspase-3/Mcl-1 signaling.This pathway may be a general signal,as it was also observed in HBx transgenic mice in which HBx-primed Mcl-1 degradation and hepatocyte apoptosis were enhanced during liver ischemia/reperfusion(I/R),and was further supported by immunohistochemical and immunoblot data in HBV-related HCCs.
Conclusions:We suggested that ROS/caspase-3/Mcl-1 pathway plays a dominant role in HBx-promoted cell apoptosis,which may shed a new light on the molecular mechanism of HBx-mediated hepatocarcinogenesis.
Background & Aims:Non-alcoholic fatty liver disease(NAFLD) is the most common liver disease and affects millions of people worldwide.Elevated serum free fatty acids(FFAs) and hepatocyte lipoapoptosis are features of non-alcoholic fatty liver disease.It is well established that free fatty acid(FFA)-induced lipotoxicity plays a pivotal role in the pathogenesis of NAFLD.However,the mechanism by which FFAs mediate lipoapoptosis remains unclear.Here,we explored whether the antiapoptotic Bcl-2 family member Mcl-1 plays a role in FFAs-mediated hepatocyte lipoapoptosis.
Methods:Multiple hepatocyte cell lines were treated in culture with monounsaturated fatty acids and saturated fatty acids.Apoptotic cell death,caspase activity and the expression of antiapoptotic Bcl-2 family members were determined using Western blot and caspase activity assay.
Results:Apoptosis was greater during exposure to palmitic acid versus oleic acid. Protein levels of Mcl-1,but not Bcl-xL or Bcl-2 were decreased during palmitic acid-induced apoptosis in a time-dependent manner.Mcl-1 overexpression dramatically prevented palmitic acid-induced apoptosis.Conversely,Mcl-1 downregulation further enhanced palmitic acid toxicity.Neither antioxidant nor pancaspase inhibitor was able to abrogated palmitic acid-enhanced Mcl-1 downregulation.Importantly,JNK activation was enhanced during exposure to palmitic acid and Inhibition of JNK,pharmacologically,effectively blocked hepatocyte lipoapoptosis triggered by palmitic acid.
Conclusions:We suggested that JNK/Mcl-1 pathway plays a major role in palmitic acid-mediated hepatocyte lipoapoptosis,which may provide novel insights into the pathogenesis of NAFLD.
研究背景和目的
持续HBV感染是病毒引起的包括慢性肝炎、肝硬化等在内的慢性肝病的主要原因,并与肝细胞癌(HCC)的发生发展密切相关,在我国HBV感染是HCC最主要的病因。在HBV病毒所编码的蛋白中,HBx蛋白是HBV非结构基因编码的多功能病毒调控蛋白,参与HBV的感染、复制等一系列致病过程,并对肝细胞的增殖、凋亡、代谢、应激、迁移等多种生物学功能具有广泛而复杂的影响,被认为是HBV诱导肝癌发生过程中最主要的决定因素之一,而其确切致病机理仍有待进一步阐明。越来越多的证据表明凋亡是HBV病毒诱发慢性肝病的重要介质,相关研究发现HBx可以增强肝细胞对凋亡信号的敏感性。这些证据提示我们HBx可能通过促进肝细胞凋亡实现其诱发肝癌的作用,而HBx促进肝细胞凋亡的具体机制目前尚无定论。
Bcl-2家族是细胞内调节凋亡与存活的最重要的一类蛋白家族,家族成员同时包括抗凋亡和促凋亡分子。其中Mcl-1(Myeloid cell leukemia-1),中文译为髓细胞淋巴瘤-1,是Bcl-2家族中重要的抗凋亡成员。目前发现Mcl-1广泛表达于各类组织细胞,参与胚胎发育、造血干细胞内稳态的维持,以及细胞凋亡的动态调控。但是,Mcl-1是否参与HBx诱导肝细胞凋亡并在其中发挥重要作用目前国内外均未见有系统报道。
本研究从细胞和转基因动物水平观察HBx的表达对氧化应激信号诱导的肝细胞凋亡敏感性的影响,同时观察在此过程中Mcl-1表达水平的改变,明确HBx在何种水平、以何种方式调节Mcl-1的表达;再结合腺病毒介导的过表达技术,阐明Mcl-1在HBx诱导细胞凋亡中的作用;并结合临床HBV阳性肝癌患者的肝组织样本从组织水平明确HBx与Mcl-1表达的相关性。
实验方法
1.构建HBx和Mcl-1过表达及干扰质粒、包装表达HBx、Mcl-1和干扰Mcl-1的腺病毒、筛选建立HBx稳定细胞系;
2.通过流式细胞技术观察瞬时表达和稳定表达HBx的细胞系对氧化应激信号敏感性的变化;
3.通过双荧光素酶报告基因实验、RT-PCR和real-time PCR技术以及Westernblot方法分别观察表达HBx的细胞系在氧化应激信号暴露下对Mcl-1启动子转录活性、转录水平及其蛋白质水平的影响;
4.使用通路特异性抑制剂实验开展HBx对Mcl-1表达调节的机制研究;
5.运用荧光TUNEL法和流式细胞技术验证抑制相关信号通路和过表达Mcl-1在HBx诱导的细胞凋亡中的作用;
6.建立HBx转基因小鼠肝氧化应激刺激模型,运用组织TUNEL、Western blot方法从体内水平验证HBx对Mcl-1蛋白水平及肝脏细胞凋亡的影响;
7.免疫组化结合Western blot方法观察HBV阳性肝癌患者癌组织中HBx与Mcl-1表达的相关性。
结果
1.HBx明显增强细胞对氧化应激信号诱导凋亡的敏感性,在此过程中伴随Mcl-1蛋白水平的下调;且HBx能剂量依赖性的及时间依赖性的下调Mcl-1蛋白,并不受细胞系的影响;
2.HBx下调Mcl-1蛋白主要发生在翻译后水平;
3.过表达Mcl-1显著抑制HBx的促凋亡作用;
4.HBx主要通过诱导细胞内ROS显著增加,激活caspas-3进而加速降解Mcl-1蛋白实现其促凋亡作用的;
5.HBx转基因小鼠肝脏缺血再灌注处理后肝组织中Mcl-1蛋白水平下降,同时伴随肝细胞凋亡明显增加;
6.HBV阳性肝癌患者癌组织中Mcl-1与HBx的表达水平存在负相关。
结论
本研究发现HBx增强肝细胞对氧化应激信号诱导凋亡的敏感性主要通过显著增加胞内ROS,活化caspas-3进而加速Mcl-1蛋白降解来实现。提示ROS/caspase-3/Mcl-1途径在HBx促肝细胞凋亡的过程中可能发挥重要作用。
第二部分Mcl-1参与游离脂肪酸诱导细胞凋亡的作用机制研究
研究背景和目的
大量研究表明非酒精性脂肪肝是与肥胖、Ⅱ型糖尿病、高脂血症以及代谢综合征等疾病病程进展密切相关的代谢性疾病。近年来由于生活方式、饮食结构等的改变,非酒精性脂肪肝的发病率不断增加,目前已成为全世界范围内最常见的肝脏疾病,越来越受到人们的重视。然而,由于非酒精性脂肪肝的病因非常复杂,导致至今仍不清楚其确切的发病机制,因而也缺乏有效的治疗手段。
游离脂肪酸是肝脏甘油三脂的主要来源,目前认为游离脂肪酸是引起肝脏脂毒性的重要介质,并在非酒精性脂肪肝的发病和病程进展中具有重要作用。研究发现,非酒精性脂肪肝病理学的重要特点是肝脏细胞凋亡显著增加。然而,对于游离脂肪酸如何诱导肝细胞发生凋亡的具体机制目前不十分清楚,仍有待进一步研究。
近年来研究表明,Bcl-2家族中的Mcl-1作为其家族中一个重要的抗凋亡成员,在肝细胞的生存与凋亡的调控中发挥重要作用,然而Mcl-1是否参与游离脂肪酸诱导肝细胞凋亡并在其中发挥重要作用目前国内外未见相关报道。
本实验首先观察游离脂肪酸诱导肝细胞凋亡过程中Mcl-1表达的改变,然后结合腺病毒介导的过表达及干扰技术,明确Mcl-1在游离脂肪酸诱导的细胞凋亡中的作用,并进一步阐明游离脂肪酸调节Mcl-1表达的分子机制。
实验方法
1.构建干扰Mcl-1的腺病毒;
2.通过检测caspase活性和Western blot技术明确游离脂肪酸对凋亡的影响;
3.Western blot实验检测游离脂肪酸诱导细胞凋亡过程中Mcl-1蛋白水平的改变;
4.real-time PCR技术检测游离脂肪酸对Mcl-1转录水平的影响;
5.运用腺病毒介导的过表达和干扰技术明确Mcl-1在游离脂肪酸诱导的细胞凋亡中的生物学功能;
6.结合通路抑制剂实验开展游离脂肪酸对Mcl-1表达调控的信号通路研究。
结果
1.游离脂肪酸中的软脂酸可明显诱导肝细胞发生凋亡;
2.软脂酸诱导的细胞凋亡过程中Mcl-1的蛋白水平显著下调;
3.软脂酸诱导的肝细胞凋亡主要是由Mcl-1所介导的;
4.软脂酸主要在翻译后水平促进Mcl-1蛋白通过泛素—蛋白酶体途径降解;
5.抗氧化剂和caspase抑制剂均无法阻断软脂酸诱导的Mcl-1的下降;
6.JNK通路介导软脂酸对Mcl-1的负向调节。
结论
本研究发现软脂酸诱导肝细胞凋亡过程中Mcl-1的蛋白水平显著下调,并进一步明确软脂酸诱导肝细胞凋亡主要是通过激活JNK通路、促进Mcl-1下调实现的,提示JNK/Mcl-1途径在软脂酸诱导的肝细胞脂性凋亡过程中具有重要作用。本研究为深入理解非酒精性脂肪肝发病机制提供新的线索,并为该病的治疗提供新的潜在靶点和策略。
Background & Aims:Many studies provide strong evidence of the critical role of hepatitis B virus X(HBx) in human hepatocarcinogenesis.Although the association of HBx with apoptosis has been widely investigated,the exact role of HBx in modulating apoptotic process remains controversial.Here,we examined whether HBx exerts its apoptosis- promoting effects via dysregulation of Mcl-1 expression.
Methods:Apoptotic cell death and the expression of Bcl-2 family proteins were determined in HBx-expressing hepatic cell lines and HBx transgenic mice. Immunohistochemistry and immunoblotting were performed to evaluate the expression of Mcl-1 in hepatocellular carcinoma(HCC) samples with or without hepatitis B virus(HBV) infection.
Results:Ectopic expression of HBx rendered cell susceptible to death signals in response to cisplatin,which relied on the loss of Mcl-1.Caspase-3 inhibitors,but not JNK,P38,GSK-3βor proteasome inhibitors,effectively abrogated HBx-enhanced Mcl-1 degradation as well as cell apoptosis.Antioxidant treatment demonstrated that reactive oxygen species(ROS) triggered caspase-3-mediated Mcl-1 turnover in this model.Moreover,HBx sensitized cells to ROS-induced apoptotic killing also through activating caspase-3/Mcl-1 signaling.This pathway may be a general signal,as it was also observed in HBx transgenic mice in which HBx-primed Mcl-1 degradation and hepatocyte apoptosis were enhanced during liver ischemia/reperfusion(I/R),and was further supported by immunohistochemical and immunoblot data in HBV-related HCCs.
Conclusions:We suggested that ROS/caspase-3/Mcl-1 pathway plays a dominant role in HBx-promoted cell apoptosis,which may shed a new light on the molecular mechanism of HBx-mediated hepatocarcinogenesis.
Background & Aims:Non-alcoholic fatty liver disease(NAFLD) is the most common liver disease and affects millions of people worldwide.Elevated serum free fatty acids(FFAs) and hepatocyte lipoapoptosis are features of non-alcoholic fatty liver disease.It is well established that free fatty acid(FFA)-induced lipotoxicity plays a pivotal role in the pathogenesis of NAFLD.However,the mechanism by which FFAs mediate lipoapoptosis remains unclear.Here,we explored whether the antiapoptotic Bcl-2 family member Mcl-1 plays a role in FFAs-mediated hepatocyte lipoapoptosis.
Methods:Multiple hepatocyte cell lines were treated in culture with monounsaturated fatty acids and saturated fatty acids.Apoptotic cell death,caspase activity and the expression of antiapoptotic Bcl-2 family members were determined using Western blot and caspase activity assay.
Results:Apoptosis was greater during exposure to palmitic acid versus oleic acid. Protein levels of Mcl-1,but not Bcl-xL or Bcl-2 were decreased during palmitic acid-induced apoptosis in a time-dependent manner.Mcl-1 overexpression dramatically prevented palmitic acid-induced apoptosis.Conversely,Mcl-1 downregulation further enhanced palmitic acid toxicity.Neither antioxidant nor pancaspase inhibitor was able to abrogated palmitic acid-enhanced Mcl-1 downregulation.Importantly,JNK activation was enhanced during exposure to palmitic acid and Inhibition of JNK,pharmacologically,effectively blocked hepatocyte lipoapoptosis triggered by palmitic acid.
Conclusions:We suggested that JNK/Mcl-1 pathway plays a major role in palmitic acid-mediated hepatocyte lipoapoptosis,which may provide novel insights into the pathogenesis of NAFLD.
引文
1.Feitelson MA,Clayton MM,Reis HM,Wu G,Lu EP.Pharmacotherapy of chronic viral hepatitis and hepatocellular carcinoma.Expert Opin Pharmacother.2008 Sep;9(13):2233-45.
2.Bouchard MJ,Schneider RJ.The enigmatic X gene of hepatitis B virus.J Virol.2004 Dec;78(23):12725-34.
3.Kim CM,Koike K,Saito I,Miyamura T,Jay G.HBx gene of hepatitis B virus induces liver cancer in transgenic mice.Nature 1991 May 23;351(6324):317-20.
4.Kanzler S,Galle PR.Apoptosis and the liver.Semin Cancer Biol.2000 Jun;10(3):173-84.
5.Zhang X,Zhang H,Ye L.Effects of hepatitis B virus X protein on the development of liver cancer.J Lab Clin Med.2006 Feb;147(2):58-66.
6.Grasl-Kraupp B,Ruttkay-Nedecky B,M(?)llauer L,et al.Inherent increase of apoptosis in liver tumors:implications for carcinogenesis and tumor regression.Hepatology 1997 Apr;25(4):906-12.
7.Michels J,Johnson PW,Packham G Mcl-1.Int J Biochem Cell Biol.2005 Feb;37(2):267-71.
8.Sieghart W,Losert D,Strommer S,et al.Mcl-1 overexpression in hepatocellular carcinoma:a potential target for antisense therapy.J Hepatol 2006 Jan;44(1):151-7.
9.Vick B,Weber A,Urbanik T,et al.Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes.Hepatology.2009 Feb;49(2):627-36.
10.Su F,Schneider RJ.Hepatitis B virus HBx protein sensitizes cells to apoptotic killing by tumor necrosis factor alpha.Proc Natl Acad Sci USA.1997 Aug 5;94(16):8744-9.
11.Lee AT,Ren J,Wong ET,et al.The Hepatitis B Virus X Protein Sensitizes HepG2 Cells to UV Light-induced DNA Damage.J Biol Chem 2005 Sep 30;280(39):33525-35.
12.Liang X,Liu Y,Zhang Q,et al.Hepatitis B virus sensitizes hepatocytes to TRAIL-induced apoptosis through Bax.2007 Jan 1;178(1):503-10.
13.Youle RJ,Strasser A.The BCL-2 protein family:opposing activities that mediate cell death.Nat Rev Mol Cell Biol.2008 Jan;9(1):47-59.
14.Elmore LW,Hancock AR,Chang SF,Wang XW,Chang S,Callahan CP,Geller DA,Will H, Harris CC.Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis.Proc Natl Acad Sci U S A.1997 Dec 23;94(26):14707-12.
15.Takehara T,Liu X,Fujimoto J,Friedman SL,Takahashi H.Expression and role of Bcl-xL in human hepatocellular carcinomas.Hepatology.2001 Jul;34(1):55-61.
16.Kobayashi S,Werneburg NW,Bronk SF,Kaufmann SH,Gores GJ.InterIeukin-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells.Gastroenterology.2005 Jun;128(7):2054-65.
17.Isomoto H,Kobayashi S,Werneburg NW,Bronk SF,Guicciardi ME,Frank DA,Gores GJ.Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells.Hepatology.2005 Dec;42(6):1329-38.
18.Opferman JT.Unraveling MCL-1 degradation.Cell Death Differ.2006 Aug;13(8):1260-2.
19.Domina AM,Vrana JA,Gregory MA,Hann SR,Craig RW.MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells,and at additional sites with cytotoxic okadaic acid or taxol.Oncogene.2004 Jul 8;23(31):5301-15.
20.Derouet M,Thomas L,Cross A,Moots RJ,Edwards SW.Granulocyte macrophage colony-stimulating factor signaling and proteasome inhibition delay neutrophil apoptosis by increasing the stability of Mcl-1.J Biol Chem.2004 Jun 25;279(26):26915-21.
21.Han Y,Amin HM,Franko B,Frantz C,Shi X,Lai R.Loss of SHPl enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma.Blood.2006 Oct 15;108(8):2796-803.
22.Inoshita S,Takeda K,Hatai T,Terada Y,Sano M,Hata J,Umezawa A,Ichijo H.Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress.J Biol Chem.2002 Nov 15;277(46):43730-4.
23.Derouet M,Thomas L,Moulding DA,Akgul C,Cross A,Moots RJ,Edwards SW.Sodium salicylate promotes neutrophil apoptosis by stimulating caspase-dependent turnover of Mcl-1.J Immunol.2006 Jan 15;176(2):957-65.
24.Ding Q,He X,Xia W,Hsu JM,Chen CT,Li LY,Lee DF,Yang JY,Xie X,Liu JC,Hung MC.Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer.Cancer Res.2007 May 15;67(10):4564-71.
25.Michels J,O'Neill JW,Dallman CL,Mouzakiti A,Habens F,Brimmell M,Zhang KY,Craig RW,Marcusson EG,Johnson PW,Packham G Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage.Oncogene.2004 Jun 17;23(28):4818-27.
26.Herrant M,Jacquel A,Marchetti S,et al.Cleavage of Mcl-1 by caspases impaired its ability to counteract Bim-induced apoptosis.Oncogene.2004 Oct 14;23(47):7863-73.
27.Pan J,Quintas-Cardama A,Manshouri T,Giles FJ,Lamb P,Tefferi A,Cortes J,Kantarjian H,Verstovsek S.The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-alpha-expressing cells through caspase-3-mediated cleavage of Mcl-1.Leukemia.2007 Jul;21(7):1395-404.
28.Jiang M,Wei Q,Pabla N,Dong G,Wang CY,Yang T,Smith SB,Dong Z.Effects of hydroxyl radical scavenging on cisplatin-induced p53 activation,tubular cell apoptosis and nephrotoxicity.Biochem Pharmacol.2007 May 1;73(9):1499-510.
29.Ding WX,Shen HM,Ong CN.Critical role of reactive oxygen species and mitochondrial permeability transition in microcystin-induced rapid apoptosis in rat hepatocytes.Hepatology.2000 Sep;32(3):547-55.
30.Wang Y,Cui F,Lv Y,Li C,Xu X,Deng C,Wang D,Sun Y,Hu G,Lang Z,Huang C,Yang X.HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice.Hepatology.2004 Feb;39(2):318-24.
31.Tsung A,Sahai R,Tanaka H,Nakao A,Fink MP,Lotze MT,Yang H,Li J,Tracey KJ,Geller DA,Billiar TR.The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion.J Exp Med.2005 Apr 4;201(7):1135-43.
32.Jiingst C,Cheng B,Gehrke R,et al.Oxidative Damage Is Increased in Human Liver Tissue Adjacent to Hepatocellular Carcinoma.Hepatology 2004 Jun;39(6):1663-72.
33.Arbuthnot P,Kew M.Hepatitis B virus and hepatocellular carcinoma.Int J Exp Pathol.2001 Apr;82(2):77-100.
34.Mevorach D,Zhou JL,Song X,Elkon KB.Systemic exposure to irradiated apoptotic cells induces autoantibody production.J Exp Med.1998 Jul 20;188(2):387-92.
35.Kim HS,Han MS,Chung KW,Kim S,Kim E,Kim MJ,Jang E,Lee HA,Youn J,Akira S,Lee MS.Toll-like receptor 2 senses beta-cell death and contributes to the initiation of autoimmune diabetes.Immunity.2007 Aug;27(2):321-33.
36.Coussens LM,Werb Z.Inflammation and cancer.Nature.2002 Dec 19-26;420(6917):860-7.
37.Murakami S.Hepatitis B virus X protein:a multifunctional viral regulator.J Gastroenterol.2001 Oct;36(10):651-60.
38.Kim WH,Hong F,Jaruga B,Zhang ZS,Fan SJ,Liang TJ,Gao B.Hepatitis B virus X protein sensitizes primary mouse hepatocytes to ethanol-and TNF-alpha-induced apoptosis by a caspase-3-dependent mechanism.Cell Mol Immunol.2005 Feb;2(l):40-8.
39.Terradillos O,de La Coste A,Pollicino T,Neuveut C,Sitterlin D,Lecoeur H,Gougeon ML,Kahn A,Buendia MA.The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver.Oncogene.2002 Jan 17;21(3):377-86.
40.Shirakata Y,Koike K.Hepatitis B Virus X Protein Induces Cell Death by Causing Loss of Mitochondrial Membrane Potential.2003 Jun 13;278(24):22071-8.
41.Chirillo P,Pagano S,Natoli G,Puri PL,Burgio VL,Balsano C,Levrero M.The hepatitis B virus X gene induces p53-mediated programmed cell death.Proc Natl Acad Sci U S A.1997 Jul 22;94(15):8162-7.
42.Yoo YG,Lee MO.Hepatitis B virus X protein induces expression of Fas ligand gene through enhancing transcriptional activity of early growth response factor.J Biol Chem.2004 Aug 27;279(35):36242-9.
43.Chami M,Ferrari D,Nicotera P,Paterlini-Brechot P,Rizzuto R.Caspase-dependent alterations of Ca2+ signaling in the induction of apoptosis by hepatitis B virus X protein.J Biol Chem.2003 Aug 22;278(34):31745-55.
44.Miao J,Chen GG,Chun SY,Lai PP.Hepatitis B virus X protein induces apoptosis in hepatoma cells through inhibiting Bcl-xL expression.Cancer Lett.2006 May 8;236(1):115-24.
45.Waris G,Huh KW,Siddiqui A.Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-kappa B via oxidative stress.Mol Cell Biol.2001 Nov;21(22):7721-30.
46.Allen RG,and Tresini M.Oxidative stress and gene regulation.Free Radic.Biol.Med 2000 Feb 1;28(3):463-99.
47.Lim SO,Gu JM,Kim MS,et al.Epigenetic changes induced by reactive oxygen species in
hepatocellular carcinoma:methylation of the E-cadherin promoter.Gastroenterology 2008 Dec;135(6):2128-40,2140.e1-8.
48.Sakurai T,He G,Matsuzawa A,et al.Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis.Cancer Cell 2008 Aug 12;14(2):156-65.
49.Toyokuni S.Novel aspects of oxidative stress-associated carcinogenesis.Antioxid Redox Signal.2006 Jul-Aug;8(7-8):1373-7.
50.Tien Kuo M,Savaraj N.Roles of reactive oxygen species in hepatocarcinogenesis and drug resistance gene expression in liver cancers.Mol Carcinog.2006 Sep;45(9):701-9.
1.Adams LA,Lindor KD.Nonalcoholic fatty liver disease.Ann Epidemiol.2007 Nov;17(11):863-9.
2.Malhi H,Bronk SF,Werneburg NW,Gores GJ.Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis.J Biol Chem.2006 Apr 28;281(17):12093-101.
3.Utzschneider KM,Kahn SE.Review:The role of insulin resistance in nonalcoholic fatty liver disease.J Clin Endocrinol Metab.2006 Dec;91(12):4753-61.
4.Malhi H,Gores GJ.Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease.Semin Liver Dis.2008 Nov;28(4):360-9.
5.Nehra V,Angulo P,Buchman AL,Lindor KD.Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis.Dig Dis Sci.2001 Nov;46(11):2347-52.
6.Vick B,Weber A,Urbanik T,et al.Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes.Hepatology.2009 Feb;49(2):627-36.
7.Barreyro FJ,Kobayashi S,Bronk SF,Werneburg NW,Malhi H,Gores GJ.Transcriptional regulation of Bim by FoxO3A mediates hepatocyte lipoapoptosis.J Biol Chem.2007 Sep 14;282(37):27141-54.
8.Malhi H,Barreyro FJ,Isomoto H,Bronk SF,Gores GJ.Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity.Gut.2007 Aug;56(8):1124-31.
9.Youle RJ,Strasser A.The BCL-2 protein family:opposing activities that mediate cell death.Nat Rev Mol Cell Biol.2008 Jan;9(1):47-59.
10.Takehara T,Liu X,Fujimoto J,Friedman SL,Takahashi H.Expression and role of Bcl-xL in human hepatocellular carcinomas.Hepatology.2001 Jul;34(1):55-61.
11.Opferman JT.Unraveling MCL-1 degradation.Cell Death Differ.2006 Aug;13(8):1260-2.
12.Browning JD,Horton JD.Molecular mediators of hepatic steatosis and liver injury.J Clin Invest.2004 Jul;114(2):147-52.
13.Michels J,O'Neill JW,Dallman CL,Mouzakiti A,Habens F,Brimmell M,Zhang KY,Craig RW,Marcusson EG,Johnson PW,Packham G Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage. Oncogene.2004 Jun 17;23(28):4818-27.
14.Herrant M,Jacquel A,Marchetti S,et al.Cleavage of Mcl-1 by caspases impaired its ability to counteract Bim-induced apoptosis.Oncogene.2004 Oct 14;23(47):7863-73.
15.Pan J,Quintas-Cardama A,Manshouri T,Giles FJ,Lamb P,Tefferi A,Cortes J,Kantarjian H,Verstovsek S.The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human IP1L1-PDGFR-alpha-expressing cells through caspase-3-mediated cleavage of Mcl-1.Leukemia.2007 Jul;21(7):1395-404.
16.Inoshita S,Takeda K,Hatai T,Terada Y,Sano M,Hata J,Umezawa A,Ichijo H.Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress.J Biol Chem.2002 Nov 15;277(46):43730-4.
17.Mehta K,Van Thiel DH,Shah N,Mobarhan S.Nonalcoholic fatty liver disease:pathogenesis and the role of antioxidants.Nutr Rev.2002 Sep;60(9):289-93.
18.Li Z,Berk M,Mclntyre TM,Gores GJ,Feldstein AE.The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity.Hepatology.2008 May;47(5):1495-503.
19.Yang SQ,Lin HZ,Mandal AK,Huang J,Diehl AM.Disrupted signaling and inhibited regeneration in obese mice with fatty livers:implications for nonalcoholic fatty liver disease pathophysiology.Hepatology.2001 Oct;34(4 Pt 1):694-706.
20.Li Z,Yang S,Lin H,Huang J,Watkins PA,Moser AB,Desimone C,Song XY,Diehl AM.Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.Hepatology.2003 Feb;37(2):343-50.
21.Dhanasekaran DN,Reddy EP.JNK signaling in apoptosis.Oncogene.2008 Oct 20;27(48):6245-51.
22.Wang Y,Ausman LM,Russell RM,Greenberg AS,Wang XD.Increased apoptosis in high-fat diet-induced nonalcoholic steatohepatitis in rats is associated with c-Jun NH2-terminal kinase activation and elevated proapoptotic Bax.J Nutr.2008 Oct;138(10):1866-71.
23.Kane to H,Matsuoka TA,Katakami N,Kawamori D,Miyatsuka T,Yoshiuchi K,Yasuda T,Sakamoto K,Yamasaki Y,Matsuhisa M.Oxidative stress and the JNK pathway are involved in the development of type 1 and type 2 diabetes.Curr Mol Med.2007 Nov;7(7):674-86.
24.Boden G,Duan X,Homko C,Molina EJ,Song W,Perez O,Cheung P,Merali S.Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals.Diabetes.2008 Sep;57(9):2438-44.
25.Schattenberg JM,Singh R,Wang Y,Lefkowitch JH,Rigoli RM,Scherer PE,Czaja MJ.JNKl but not JNK2 promotes the development of steatohepatitis in mice.Hepatology.2006 Jan;43(1):163-72.
26.Singh R,Wang Y,Xiang Y,Tanaka KE,Gaarde WA,Czaja MJ.Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance.Hepatology.2009 Jan;49(1):87-96.
27.Nanji AA.Role of different dietary fatty acids in the pathogenesis of experimental alcoholic liver disease.Alcohol.2004 Aug;34(1):21-5.
1.Feitelson MA,Clayton MM,Reis HM,Wu G,Lu EP.Pharmacotherapy of chronic viral hepatitis and hepatocellular carcinoma.Expert Opin Pharmacother.2008 Sep;9(13):2233-45.
2.Bouchard MJ,Schneider RJ.The enigmatic X gene of hepatitis B virus.J Virol.2004 Dec;78(23):12725-34.
3.Guo WT,Wang J,Tarn G,Yen TS,Ou JS.Leaky transcription termination produces larger and smaller than genome size hepatitis B virus X gene transcripts.Virology.1991 Apr;181(2):630-6.
4.Colgrove R,Simon G,Ganem D.Transcriptional activation of homologous and heterologous genes by the hepatitis B virus X gene product in cells permissive for viral replication.J Virol.1989 Sep;63(9):4019-26.
5.Kodama K,Ogasawara N,Yoshikawa H and Murakami S.Nucleotide sequence of a cloned woodchuck hepatitis virus genome:evolutional relationship between hepadnaviruses.J Virol.1985 Dec;56(3):978-86.
6.Urban S,Hildt E,Eckerskorn C,Sirma H,Kekule A,Hofschneider PH.Isolation and molecular characterization of hepatitis B virus X-protein from a baculovirus expression system.Hepatology.1997 Oct;26(4):1045-53.
7.Lin MH,Lo SC.Dimerization of hepatitis B viral X protein synthesized in a cell-free system.Biochem Biophys Res Commun.1989 Oct 16;164(1):14-21.
8.Schek N,Bartenschlager R,Kuhn C,Schaller H.Phosphorylation and rapid turnover of hepatitis B virus X-protein expressed in HepG2 cells from a recombinant vaccinia virus.Oncogene.1991 Oct;6(10):1735-44.
9.Summers J,O'Connell A,Millman I.Genome of hepatitis B virus:restriction enzyme cleavage and structure of DNA extracted from Dane particles.Proc Natl Acad Sci U S A.1975 Nov;72(11):4597-601.
10.Murakami S,Cheong JH,Kaneko S.Human hepatitis virus X gene encodes a regulatory domain that represses transactivation of X protein.J Biol Chem.1994 May 27;269(21):15118-23.
11.Dandri M,Petersen J,Stockert RJ,Harris TM,Rogler CE.Metabolic labeling of woodchuck hepatitis B virus X protein in naturally infected hepatocytes reveals a bimodal half-life and association with the nuclear framework.J Virol.1998 Nov;72(11):9359-64.
12.Doria M,Klein N,Lucito R,Schneider RJ.The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors.EMBO J.1995 Oct 2;14(19):4747-57.
13.Henkler F,Hoare J,Waseem N,Goldin RD,McGarvey MJ,Koshy R,King JA.Intracellular localization of the hepatitis B virus HBx protein.J Gen Virol.2001 Apr;82(Pt 4):871-82.
14.Forgues M,Marrogi AJ,SpiUare EA,Wu CG,Yang Q,Yoshida M,Wang XW.Interaction of the hepatitis B virus X protein with the Crml-dependent nuclear export pathway.J Biol Chem.2001 Jun 22;276(25):22797-803.
15.Kumar V,Jayasuryan N,Kumar R.A truncated mutant(residues 58-140)of the hepatitis B virus X protein retains transactivation function.Proc Natl Acad Sci U S A.1996 May 28;93(11):5647-52.
16.Nijhara R,Jana SS,Goswami SK,Rana A,Majumdar SS,Kumar V,Sarkar DP.Sustained activation of mitogen-activated protein kinases and activator protein 1 by the hepatitis B virus X protein in mouse hepatocytes in vivo.J Virol.2001 Nov;75(21):10348-58.
17.Lucito R,Schneider RJ.Hepatitis B virus X protein activates transcription factor NF-kappa B without a requirement for protein kinase C.J Virol.1992 Feb;66(2):983-91.
18.Maguire HF,Hoeffler JP,Siddiqui A.HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions.Science.1991 May 10;252(5007):842-4.
19.Aufiero B,Schneider RJ.The hepatitis B virus X-gene product trans-activates both RNA polymerase Ⅱ and Ⅲ promoters.EMBO J.1990 Feb;9(2):497-504.
20.Wang HD,Trivedi A,Johnson DL.Regulation of RNA polymerase I-dependent promoters by the hepatitis B virus X protein via activated Ras and TATA-binding protein.Mol Cell Biol.1998 Dec;18(12):7086-94.
21.Murakami S.Hepatitis B virus X protein:a multifunctional viral regulator.J Gastroenterol.2001 Oct;36(10):651-60.
22.Tarn C,Lee S,Hu Y,Ashendel C,Andrisani OM.Hepatitis B virus X protein differentially activates RAS-RAF-MAPK and JNK pathways in X-transforming versus non-transforming AML12 hepatocytes.J Biol Chem.2001 Sep 14;276(37):34671-80.
23.Shih WL,Kuo ML,Chuang SE,Cheng AL,Doong SL.Hepatitis B virus X protein inhibits transforming growth factor-beta-induced apoptosis through the activation of phosphatidylinositol 3-kinase pathway.J Biol Chem.2000 Aug 18;275(33):25858-64.
24.Lee YI,Kang-Park S,Do SI,Lee YI.The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade.J Biol Chem.2001 May 18;276(20):16969-77.
25.Mansour SJ,Matten WT,Hermann AS,Candia JM,Rong S,Fukasawa K,Vande Woude GF,Ahri NG Transformation of mammalian cells by constitutively active MAP kinase kinase.Science.1994 Aug 12;265(5174):966-70.
26.Cougot D,Wu Y,Cairo S,Caramel J,Renard CA,Levy L,Buendia MA,Neuveut C.The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription.J Biol Chem.2007 Feb 16;282(7):4277-87.
27.Wang WH,Gregori G,Hullinger RL,Andrisani OM.Sustained activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase pathways by hepatitis B virus X protein mediates apoptosis via induction of Fas/FasL and tumor necrosis factor(TNF)receptor 1/TNF-alpha expression.Mol Cell Biol.2004 Dec;24(23):10352-65.
28.Tarn C,Zou L,Hullinger RL,Andrisani OM.Hepatitis B virus X protein activates the p38 mitogen-activated protein kinase pathway in dedifferentiated hepatocytes.J Virol.2002 Oct;76(19):9763-72.
29.Klein NP,Schneider RJ.Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras.Mol Cell Biol.1997 Nov;17(11):6427-36
30.Lee YH,Yun Y.HBx protein of hepatitis B virus activates Jakl-STAT signaling.J Biol Chem.1998 Sep 25;273(39):25510-5.
31.Waris G,Huh KW,Siddiqui A.Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-kappa B via oxidative stress.Mol Cell Biol.2001 Nov;21(22):7721-30.
32.Ruff-Jamison S,Chen K,Cohen S.Epidermal growth factor induces the tyrosine phosphorylation and nuclear translocation of Stat 5 in mouse liver.Proc Natl Acad Sci.1995 May 9;92(10):4215-8.
33.Seto E,Mitchell PJ,Yen TS.Transactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors.Nature.1990 Mar 1;344(6261):72-4.
34.Siddiqui A,Gaynor R,Srinivasan A,Mapoles J,Farr RW.Trans-activation of viral enhancers including long terminal repeat of the human immunodeficiency virus by the hepatitis B virus X protein.Virology.1989 Apr;169(2):479-84.
35.Yun C,Um HR,Jin YH,Wang JH,Lee MO,Park S,Lee JH,Cho H.NF-kappaB activation by hepatitis B virus X(HBx)protein shifts the cellular fate toward survival.Cancer Lett.2002 Oct 8;184(1):97-104.
36.Pan J,Duan LX,Sun BS,Feitelson MA.Hepatitis B virus X protein protects against anti-Fas-mediated apoptosis in human liver cells by inducing NF-kappa B.J Gen Virol.2001 Jan;82(Pt 1):171-82.
37.Yun C,Um HR,Jin YH,Wang JH,Lee MO,Park S,Lee JH,Cho H.NF-kappaB activation by hepatitis B virus X(HBx)protein shifts the cellular fate toward survival.Cancer Lett.2002 Oct 8;184(1):97-104.
38.Diao J,Khine AA,Sarangi F,Hsu E,Iorio C,Tibbies LA,Woodgett JR,Penninger J,Richardson CD.X protein of hepatitis B virus inhibits Fas-mediated apoptosis and is associated with up-regulation of the SAPK/JNK pathway.J Biol Chem.2001 Mar 16;276(11):8328-40.
39.Cha MY,Kim CM,Park YM,Ryu WS.Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells.Hepatology.2004 Jun;39(6):1683-93.
40.Ding Q,Xia W,Liu JC,Yang JY,Lee DF,Xia J,Bartholomeusz G,Li Y,Pan Y,Li Z,Bargou RC,Qin J,Lai CC,Tsai FJ,Tsai CH,Hung MC.Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin.Mol Cell.2005 Jul 22;19(2):159-70.
41.Jung JK,Kwun HJ,Lee JO,Arora P,Jang KL.Hepatitis B virus X protein differentially affects the ubiquitin-mediated proteasomal degradation of beta-catenin depending on the status of cellular p53.J Gen Virol.2007 Aug;88(Pt 8):2144-54.
42.Murata M,Matsuzaki K,Yoshida K,Sekimoto G,Tahashi Y,Mori S,Uemura Y,Sakaida N,Fujisawa J,Seki T,Kobayashi K,Yokote K,Koike K,Okazaki K Hepatitis B virus X protein shifts human hepatic transforming growth factor(TGF)-beta signaling from tumor suppression to oncogenesis in early chronic hepatitis B.Hepatology.2008 Dec 30.[Epub ahead of print]
43.Kanzler S,Galle PR.Apoptosis and the liver.Semin Cancer Biol.2000 Jun;10(3):173-84.
44.Wang XW,Gibson MK,Vermeulen W,Yeh H,Forrester K,Sturzbecher HW,Hoeijmakers JH,Harris CC.Abrogation of p53-induced apoptosis by the hepatitis B virus X gene.Cancer Res.1995 Dec 15;55(24):6012-6.
45.Elmore LW,Hancock AR,Chang SF,Wang XW,Chang S,Callahan CP,Geller DA,Will H,Harris CC.Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis.Proc Natl Acad Sci U S A.1997 Dec 23;94(26):14707-12.
46.Marusawa H,Matsuzawa S,Welsh K,Zou H,Armstrong R,Tamm I,Reed JC.HBXIP functions as a cofactor of survivin in apoptosis suppression.EMBO J.2003 Jun 2;22(11):2729-40.
47.Zhang X,Dong N,Yin L,Cai N,Ma H,You J,Zhang H,Wang H,He R,Ye L.Hepatitis B virus X protein upregulates survivin expression in hepatoma tissues.J Med Virol.2005 Nov;77(3):374-81.
48.Kojima H,Kaita KD,Xu Z,Ou JH,Gong Y,Zhang M,Minuk GY.The absence of up-regulation of telomerase activity during regeneration after partial hepatectomy in hepatitis B virus X gene transgenic mice.J Hepatol.2003 Aug;9(2):262-8.
49.Gottlob K,Fulco M,Levrero M,Graessmann A.The hepatitis B virus HBx protein inhibits caspase 3 activity.J Biol Chem.1998 Dec 11;273(50):33347-53.
50.Chirillo P,Pagano S,Natoli G,Puri PL,Burgio VL,Balsano C,Levrero M.The hepatitis B virus X gene induces p53-mediated programmed cell death.Proc Natl Acad Sci U S A.1997 Jul 22;94(15):8162-7.
51.Shintani Y,Yotsuyanagi H,Moriya K,Fujie H,Tsutsumi T,Kanegae Y,Kimura S,Saito I,Koike K.Induction of apoptosis after switch-on of the hepatitis B virus X gene mediated by the Cre/loxP recombination system.J Gen Virol.1999 Dec;80(Pt 12):3257-65.
52.Terradillos O,Pollicino T,Lecoeur H,Tripodi M,Gougeon ML,Tiollais P,Buendia MA.p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro.Oncogene.1998 Oct 22;17(16):2115-23.
53.Kim H,Lee H,Yun Y X-gene product of hepatitis B virus induces apoptosis in liver cells.J Biol Chem.1998 Jan 2;273(1):381-5.
54.Kim KH,Seong BL.Pro-apoptotic function of HBV X protein is mediated by interaction with c-FLIP and enhancement of death-inducing signal.EMBO J.2003 Mayl;22(9):2104-16.
55.Shirakata Y,Koike K.Hepatitis B Virus X Protein Induces Cell Death by Causing Loss of Mitochondrial Membrane Potential.2003 Jun 13;278(24):22071-8.
56.Yoo YG,Lee MO.Hepatitis B virus X protein induces expression of Fas ligand gene through enhancing transcriptional activity of early growth response factor.J Biol Chem.2004 Aug 27;279(35):36242-9.
57.Chami M,Ferrari D,Nicotera P,Paterlini-Brechot P,Rizzuto R.Caspase-dependent alterations of Ca2+ signaling in the induction of apoptosis by hepatitis B virus X protein.J Biol Chem.2003 Aug 22;278(34):31745-55.
58.Bouchard MJ,Wang LH,Schneider RJ.Calcium signaling by HBx protein in hepatitis B virus DNA replication.Science.2001 Dec 14;294(5550):2376-8.
59.Miao J,Chen GG,Chun SY,Lai PP.Hepatitis B virus X protein induces apoptosis in hepatoma cells through inhibiting Bcl-xL expression.Cancer Lett.2006 May 8;236(1):115-24.
60.Su F,Schneider RJ.Hepatitis B virus HBx protein sensitizes cells to apoptotic killing by tumor necrosis factor alpha.Proc Natl Acad Sci U S A.1997 Aug 5;94(16):8744-9.
61.Terradillos O,de La Coste A,Pollicino T,Neuveut C,Sitterlin D,Lecoeur H,Gougeon ML,Kahn A,Buendia MA.The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver.Oncogene.2002 Jan 17;21(3):377-86.
62.Kim WH,Hong F,Jaruga B,Zhang ZS,Fan SJ,Liang TJ,Gao B.Hepatitis B virus X protein sensitizes primary mouse hepatocytes to ethanol-and TNF-alpha-induced apoptosis by a caspase-3-dependent mechanism.Cell Mol Immunol.2005 Feb;2(1):40-8.
63.Liang X,Liu Y,Zhang Q,et al.Hepatitis B virus sensitizes hepatocytes to TRAIL-induced apoptosis through Bax.2007 Jan 1;178(1):503-10.
64.Lee AT,Ren J,Wong ET,et al.The Hepatitis B Virus X Protein Sensitizes HepG2 Cells to UV Light-induced DNA Damage.J Biol Chem 2005 Sep 30;280(39):33525-35.
65.Kim SY,Kim JK,Kim HJ,Ahn JK Hepatitis B virus X protein sensitizes UV-induced apoptosis by transcriptional transactivation of Fas ligand gene expression.IUBMB Life.2005 Sep;57(9):651-8.
66.Pollicino T,Terradillos 0,Lecoeur H,Gougeon ML,Buendia MA.Pro-apoptotic effect of the hepatitis B virus X gene.Biomed Pharmacother.1998;52(9):363-8.
67.Liu X,Wang L,Zhang S,Lin J,Zhang S,Feitelson MA,Gao H,Zhu M.Mutations in the C-terminus of the X protein of hepatitis B virus regulate Wnt-5a expression in hepatoma Huh7 cells:cDNA microarray and proteomic analyses.Carcinogenesis.2008 Jun;29(6):1207-14.
68.Zhang H,Shan CL,Li N,Zhang X,Zhang XZ,Xu FQ,Zhang S,Qiu LY,Ye LH,Zhang XD.Identification of a natural mutant of HBV X protein truncated 27 amino acids at the COOH terminal and its effect on liver cell proliferation.Acta Pharmacol Sin.2008 Apr;29(4):473-80.
69.Benn J,Schneider RJ.Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls.Proc Natl Acad Sci U S A.1995 Nov 21;92(24):11215-9.
70.Bouchard M,Giannakopoulos S,Wang EH,Tanese N,Schneider RJ.Hepatitis B virus HBx protein activation of cyclin A-cyclin-dependent kinase 2 complexes and Gl transit via a Src kinase pathway.J Virol.2001 May;75(9):4247-57.
71.Park US,Park SK,Lee YI,Park JG,Lee YI.Hepatitis B virus-X protein upregulates the expression of p21wafl/cipl and prolongs G1-->S transition via a p53-independent pathway in human hepatoma cells.Oncogene.2000 Jul 13;19(30):3384-94.
72.Qiao L,Leach K,McKinstry R,Gilfor D,Yacoub A,Park JS,Grant S,Hylemon PB,Fisher PB,Dent P.Hepatitis B virus X protein increases expression of p21(Cip-1/WAF1/MDA6)and p27(Kip-1)in primary mouse hepatocytes,leading to reduced cell cycle progression.Hepatology.2001 Nov;34(5):906-17.
73.Mukherji A,Janbandhu VC,Kumar V.HBx-dependent cell cycle deregulation involves interaction with cyclin E/A-cdk2 complex and destabilization of p27Kipl.Biochem J.2007 Jan l;401(1):247-56.
74.Ahn JY,Chung EY,Kwun HJ,Jang KL.Transcriptional repression of p21(wafl)promoter by hepatitis B virus X protein via a p53-independent pathway.Gene.2001 Sep 5;275(1):163-8.
75.Lee S,Tarn C,Wang WH,Chen S,Hullinger RL,Andrisani OM.Hepatitis B virus X protein differentially regulates cell cycle progression in X-transforming versus nontransforming hepatocyte(AML12)cell lines.J Biol Chem.2002 Mar 8;277(10):8730-40.
76.Madden CR,Finegold MJ,Slagle BL.Hepatitis B virus X protein acts as a tumor promoter in development of diethylnitrosamine-induced preneoplastic lesions.J Virol.2001 Apr;75(8):3851-8.
77.Madden CR,Slagle BL.Stimulation of cellular proliferation by hepatitis B virus X protein.Dis Markers.2001;17(3):153-7.
78.Lara-Pezzi E,Majano PL,Yanez-M6 M,Gomez-Gonzalo M,Carretero M,Moreno-Otero R,Sanchez-Madrid F,Lopez-Cabrera M.Effect of the hepatitis B virus HBx protein on integrin-mediated adhesion to and migration on extracellular matrix.J Hepatol.2001 Mar;34(3):409-15.
79.Lee JO,Kwun HJ,Jung JK,Choi KH,Min DS,Jang KL.Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyl transferase 1.Oncogene.2005 Oct 6;24(44):6617-25.
80.Lara-Pezzi E,Roche S,Andrisani OM,Sanchez-Madrid F,Lopez-Cabrera M.The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner.Oncogene.2001 Jun 7;20(26):3323-31.
81.Lara-Pezzi E,Gomez-Gaviro MV,Galvez BQ Mira E,Iniguez MA,Fresno M,Martinez-A C,Arroyo AG Lopez-Cabrera M.The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression.J Clin Invest.2002 Dec;110(12):1831-8.
82.Chung TW,Lee YC,Kim CH.Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways:involvement of invasive potential.FASEB J.2004 Jul;18(10):1123-5.
83.Yu FL,Liu HJ,Lee JW,Liao MH,Shih WL.Hepatitis B virus X protein promotes cell migration by inducing matrix metalloproteinase-3.J Hepatol.2005 Apr;42(4):520-7.
84.Ou DP,Tao YM,Tang FQ,Yang LY.The hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by upregulation of matrix metalloproteinases.Int J Cancer.2007 Mar 15;120(6):1208-14.
85.Yoo YG Oh SH,Park ES,Cho H,Lee N,Park H,Kim DK,Yu DY,Seong JK,Lee MO.Hepatitis B virus X protein enhances transcriptional activity of hypoxia-inducible factor-1 alpha through activation of mitogen-activated protein kinase pathway.J Biol Chem. 2003 Oct 3;278(40):39076-84.
86.Moon EJ,Jeong CH,Jeong JW,Kim KR,Yu DY,Murakami S,Kim CW,Kim KW.Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor-lalpha.FASEB J.2004 Feb;18(2):382-4.
87.Yoo YG,Na TY,Seo HW,Seong JK,Park CK,Shin YK,Lee MO.Hepatitis B virus X protein induces the expression of MTA1 and HDAC1,which enhances hypoxia signaling in hepatocellular carcinoma cells.Oncogene.2008 May 29;27(24):3405-13.
88.Benn J,Schneider RJ.Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras,Raf,MAP kinase signaling cascade.Proc Natl Acad Sci U S A.1994 Oct 25;91(22):10350-4.
89.Lee TK,Man K,Poon RT,Lo CM,Yuen AP,Ng IO,Ng KT,Leonard W,Fan ST.Signal transducers and activators of transcription 5b activation enhances hepatocellular carcinoma aggressiveness through induction of epithelial-mesenchymal transition.Cancer Res.2006 Oct 15;66(20):9948-56.
90.Jaitovich-Groisman I,Benlimame N,Slagle BL,Perez MH,Alpert L,Song DJ,Fotouhi-Ardakani N,Galipeau J,Alaoui-Jamali MA.Transcriptional regulation of the TFIIH transcription repair components XPB and XPD by the hepatitis B virus x protein in liver cells and transgenic liver tissue.J Biol Chem.2001 Apr 27;276(17):14124-32.
91.Jia L,Wang XW,Harris CC.Hepatitis B virus X protein inhibits nucleotide excision repair.Int J Cancer.1999 Mar 15;80(6):875-9.
92.Nag A,Datta A,Yoo K,Bhattacharyya D,Chakrabortty A,Wang X,Slagle BL,Costa RH,Raychaudhuri P.DDB2 induces nuclear accumulation of the hepatitis B virus X protein independently of binding to DDB1.J Virol.2001 Nov;75(21):10383-92.
93.Forgues M,Difilippantonio MJ,Linke SP,Ried T,Nagashima K,Feden J,Valerie K,Fukasawa K,Wang XW.Involvement of Crml in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles.Mol Cell Biol.2003 Aug;23(15):5282-92.
94.Yun C,Cho H,Kim SJ,Lee JH,Park SY,Chan GK,Cho H.Mitotic aberration coupled with centrosome amplification is induced by hepatitis B virus X oncoprotein via the Ras-mitogen-activated protein/extracellular signal-regulated kinase-mitogen-activated protein pathway.Mol Cancer Res.2004 Mar;2(3):159-69.
95.Kim KH,Shin HJ,Kim K,Choi HM,Rhee SH,Moon HB,Kim HH,Yang US,Yu DY,Cheong J.Hepatitis B virus X protein induces hepatic steatosis via transcriptional activation of SREBP1 and PPARgamma.Gastroenterology.2007 May;132(5):1955-67.
96.Na TY,Shin YK,Roh KJ,Kang SA,Hong 1,Oh SJ,Seong JK,Park CK,Choi YL,Lee MO.Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma.Hepatology.2008 Nov 13.[Epub ahead of print]
97.Martin-Vilchez S,Sanz-Cameno P,Rodriguez-Munoz Y,Majano PL,Molina-Jimenez F,Lopez-Cabrera M,Moreno-Otero R,Lara-Pezzi E.The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells.Hepatology.2008 Jun;47(6):1872-83.
98.Tang H,Da L,Mao Y,Li Y,Li D,Xu Z,Li F,Wang Y,Tiollais P,Li T,Zhao M.Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression.Hepatology.2009 Jan;49(1):60-71.
1.Kozopas KM,Yang T,Buchan HL,Zhou P,Craig RW.MCL1,a gene expressed in programmed myeloid cell differentiation,has sequence similarity to BCL2.Proc Natl Acad Sci U S A.1993 Apr 15;90(8):3516-20.
2.Michels J,Johnson PW,Packham G Mcl-l.Int J Biochem Cell Biol.2005 Feb;37(2):267-71.
3.Youle RJ,Strasser A.The BCL-2 protein family:opposing activities that mediate cell death.Nat Rev Mol Cell Biol.2008 Jan;9(1):47-59.
4.Yang T,Kozopas KM,Craig RW.The intracellular distribution and pattern of expression of Mcl-1 overlap with,but are not identical to,those of Bcl-2.J Cell Biol.1995 Mar;128(6):1173-84.
5.Craig RW.MCL1 provides a window on the role of the BCL2 family in cell proliferation,differentiation and tumorigenesis.Leukemia.2002 Apr;16(4):444-54.
6.Nijhawan D,Fang M,Traer E,Zhong Q,Gao W,Du F,Wang X.Elimination of Mcl-l is required for the initiation of apoptosis following ultraviolet irradiation.Genes Dev.2003 Jun 15;17(12):1475-86.
7.Bae J,Leo CP,Hsu SY,Hsueh AJ.MCL-IS,a splicing variant of the antiapoptotic BCL-2 family member MCL-1,encodes a proapoptotic protein possessing only the BH3 domain.J Biol Chem.2000 Aug 18;275(33):25255-61.
8.Gross A,McDonnell JM,Korsmeyer SJ.BCL-2 family members and the mitochondria in apoptosis.Genes Dev.1999 Aug 1;13(15):1899-911.
9.Krajewski S,Bodrug S,Krajewska M,Shabaik A,Gascoyne R,Berean K and Reed JC.Immunohistochemical analysis of Mcl-l protein in human tissues.Differential regulation of Mcl-1 and Bcl-2 protein production suggests a unique role for Mcl-1 in control of programmed cell death in vivo.Am J Pathol.1995 Jun;146(6):1309-19.
10.Zhuang J,Brady HJ.Emerging role of Mcl-l in actively counteracting BH3-only proteins in apoptosis.Cell Death Differ.2006 Aug;13(8):1263-7.
11.Cuconati A,Mukherjee C,Perez D,White E.DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells.Genes Dev.2003 Dec 1;17(23):2922-32.
12.Gojo I,Zhang B,Fenton RG The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1.Clin Cancer Res.2002 Nov;8(11):3527-38.
13.Zhong Q,Gao W,Du F,Wang X.Mule/ARF-BPl,a BH3-only E3 ubiquitin ligase,catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis.Cell.2005 Jul l;121(7):1085-95.
14.Kim H,Rafiuddin-Shah M,Tu HC,Jeffers JR,Zambetti GP,Hsieh JJ,Cheng EH.Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies.Nat Cell Biol.2006 Dec;8(12):1348-58.
15.Adhikary S,Marinoni F,Hock A,Hulleman E,Popov N,Beier R,Bernard S,Quarto M,Capra M,Goettig S,Kogel U,Scheffner M,Helin K,Eilers M.The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation.Cell.2005 Nov 4;123(3):409-21.
16.Chen D,Kon N,Li M,Zhang W,Qin J,Gu W.ARF-BPl/Mule is a critical mediator of the ARF tumor suppressor.Cell.2005 Jul 1;121(7):1071-83.
17.Liu Z,Oughtred R,Wing SS.Characterization of E3Histone,a novel testis ubiquitin protein ligase which ubiquitinates histones.Mol Cell Biol.2005 Apr;25(7):2819-31.
18.Domina AM,Vrana JA,Gregory MA,Hann SR,Craig RW.MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells,and at additional sites with cytotoxic okadaic acid or taxol.Oncogene.2004 Jul 8;23(31):5301-15.
19.Longo PG,Laurenti L,Gobessi S,Sica S,Leone G,Efremov DG The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells.Blood.2008 Jan 15;111(2):846-55.
20.Kodama Y,Taura K,Miura K,Schnabl B,Osawa Y,Brenner DA.Antiapoptotic Effect of c-Jun N-terminal Kinase-1 through Mcl-1 Stabilization in TNF-induced Hepatocyte Apoptosis.Gastroenterology.2009 Jan 6.[Epub ahead of print]
21.Inoshita S,Takeda K,Hatai T,Terada Y,Sano M,Hata J,Umezawa A,Ichijo H.Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress.J Biol Chem.2002 Nov 15;277(46):43730-4.
22.Maurer U,Charvet C,Wagman AS,Dejardin E,Green DR..Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1.Mol Cell.2006 Mar 17;21(6):749-60.
23.Sitailo LA,Tibudan SS,Denning MR The protein kinase C delta catalytic fragment targets Mcl-l for degradation to trigger apoptosis.J Biol Chem.2006 Oct 6;281(40):29703-10.
24.Michels J,O'Neill JW,Dallman CL,Mouzakiti A,Habens F,Brimmell M,Zhang KY,Craig RW,Marcusson EG,Johnson PW,Packham G Mcl-l is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage.Oncogene.2004 Jun 17;23(28):4818-27.
25.Herrant M,Luciano F,Loubat A,Auberger P.The protective effect of phorbol esters on Fas-mediated apoptosis in T cells.Transcriptional and postranscriptional regulation.Oncogene.2002 Jul 25;21(32):4957-68.
26.Clohessy JG,Zhuang J,Brady HJ.Characterisation of Mcl-l cleavage during apoptosis of haematopoietic cells.Br J Haematol.2004 Jun;125(5):655-65.
27.Herrant M,Jacquel A,Marchetti S,et al.Cleavage of Mcl-l by caspases impaired its ability to counteract Bim-induced apoptosis.Oncogene.2004 Oct 14;23(47):7863-73.
28.Snowden RT,Sun XM,Dyer MJ,Cohen GM.Bisindolylmaleimide IX is a potent inducer of apoptosis in chronic lymphocytic leukaemic cells and activates cleavage of Mcl-l.Leukemia.2003 Oct;17(10):1981-9.
29.Weng C,Li Y,Xu D,Shi Y,Tang H.Specific cleavage of Mcl-l by caspase-3 in tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-induced apoptosis in Jurkat leukemia T cells.J Biol Chem.2005 Mar 18;280(11):10491-500.
30.Opferman JT.Life and death during hematopoietic differentiation.Curr Opin Immunol.2007 Oct;19(5):497-502.
31.Zhou P,Levy NB,Xie H,Qian L,Lee CY,Gascoyne RD,Craig RW.MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes.Blood.2001 Jun 15;97(12):3902-9.
32.Kitada S,Andersen J,Akar S,Zapata JM,Takayama S,Krajewski S,Wang HG,Zhang X,Bullrich F,Croce CM,Rai K,Hines J,Reed JC.Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia:correlations with In vitro and In vivo chemoresponses.Blood.1998 May l;91(9):3379-89.
33.Kaufmann SH,Karp JE,Svingen PA,Krajewski S,Burke PJ,Gore SD,Reed JC.Elevated expression of the apoptotic regulator Mcl-l at the time of leukemic relapse.Blood.1998 Feb 1;91(3):991-1000.
34.Podar K,Gouill SL,Zhang J,Opferman JT,Zorn E,Tai YT,Hideshima T,Amiot M,Chauhan D,Harousseau JL,Anderson KC.A pivotal role for Mcl-l in Bortezomib-induced apoptosis.Oncogene.2008 Jan 31;27(6):721-31.
35.Gomez-Bougie P,Wuilleme-Toumi S,Menoret E,Trichet V,Robillard N,Philippe M,Bataille R,Amiot M.Noxa up-regulation and Mcl-l cleavage are associated to apoptosis induction by bortezomib in multiple myeloma.Cancer Res.2007 Jun l;67(11):5418-24.
36.Zhang B,Gojo I,Fenton RG.Myeloid cell factor-1 is a critical survival factor for multiple myeloma.Blood.2002 Mar 15;99(6):1885-93.
37.Fleischer B,Schulze-Bergkamen H,Schuchmann M,Weber A,Biesterfeld S,Müller M,Krammer PH,Galle PR.Mcl-l is an anti-apoptotic factor for human hepatocellular carcinoma.Int J Oncol.2006 Jan;28(1):25-32.
38.Sieghart W,Losert D,Strommer S,et al.Mcl-l overexpression in hepatocellular carcinoma:a potential target for antisense therapy.J Hepatol.2006 Jan;44(1):151-7.
39.Vick B,Weber A,Urbanik T,et al.Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes.Hepatology.2009 Feb;49(2):627-36.
40.Zhuang J,Brady HJ.Emerging role of Mcl-l in actively counteracting BH3-only proteins in apoptosis.Cell Death Differ.2006 Aug;13(8):1263-7.
41.Opferman JT,Letai A,Beard C,Sorcinelli MD,Ong CC,Korsmeyer SJ.Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1.Nature.2003 Dec 11;426(6967):671-6.
42.Han J,Goldstein LA,Gastman BR,Froelich CJ,Yin XM,Rabinowich H.Degradation of Mcl-l by granzyme B:implications for Bim-mediated mitochondrial apoptotic events.J Biol Chem.2004 May 21;279(21):22020-9.
43.Clohessy JG Zhuang J,de Boer J,Gil-Gomez G,Brady HJ.Mcl-l interacts with truncated Bid and inhibits its induction of cytochrome c release and its role in receptor-mediated apoptosis.J Biol Chem.2006 Mar 3;281(9):5750-9.
44.Villunger A,Michalak EM,Coultas L,Mullauer F,Bock G,Ausserlechner MJ,Adams JM,Strasser A.p53-and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa.Science.2003 Nov 7;302(5647):1036-8.
45.Jeffers JR,Parganas E,Lee Y,Yang C,Wang J,Brennan J,MacLean KH,Han J,Chittenden T,Ihle JN,McKinnon PJ,Cleveland JL,Zambetti GP.Puma is an essential mediator of p53-dependent and-independent apoptotic pathways.Cancer Cell.2003 Oct;4(4):321-8.
46.Shibue T,Takeda K,Oda E,Tanaka H,Murasawa H,Takaoka A,Morishita Y,Akira S,Taniguchi T,Tanaka N.Integral role of Noxa in p53-mediated apoptotic response.Genes Dev.2003 Sep 15;17(18):2233-8.
47.Chen L,Willis SN,Wei A,Smith BJ,Fletcher JI,Hinds MG,Colman PM,Day CL,Adams JM,Huang DC.Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.Mol Cell.2005 Feb 4;17(3):393-403.
48.Kuwana T,Bouchier-Hayes L,Chipuk JE,Bonzon C,Sullivan BA,Green DR,Newmeyer DD.BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly.Mol Cell.2005 Feb18;17(4):525-35.
49.Leu JI,Dumont P,Hafey M,Murphy ME,George DL.Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcll complex.Nat Cell Biol.2004 May;6(5):443-50.
50.Willis SN,Chen L,Dewson G,Wei A,Naik E,Fletcher JI,Adams JM,Huang DC.Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL,but not Bcl-2,until displaced by BH3-only proteins.Genes Dev.2005 Jun l;19(11):1294-305.
51.Rinkenberger JL,Horning S,Klocke B,Roth K,Korsmeyer SJ.Mcl-1 deficiency results in peri-implantation embryonic lethality.Genes Dev.2000 Janl;14(1):23-7.
52.Veis DJ,Sorenson CM,Shutter JR,Korsmeyer SJ.Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis,polycystic kidneys,and hypopigmented hair.Cell.1993 Oct 22;75(2):229-40.
53.Nakayama K,Nakayama K,Negishi I,Kuida K,Shinkai Y,Louie MC,Fields LE,Lucas PJ,Stewart V,Alt FW,et al.Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice.Science.1993 Sep 17;261(5128):1584-8.
54.Opferman JT,Iwasaki H,Ong CC,Suh H,Mizuno S,Akashi K,Korsmeyer SJ.Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells.Science.2005 Feb 18;307(5712):1101-4.
55.Edwards SW,Derouet M,Howse M,Moots RJ.Regulation of neutrophil apoptosis by Mcl-1. Biochem Soc Trans.2004 Jun;32(Pt3):489-92.
56.Fujise K,Zhang D,Liu J,Yeh ET.Regulation of apoptosis and cell cycle progression by MCLl.Differential role of proliferating cell nuclear antigen.J Biol Chem.2000 Dec 15;275(50):39458-65.
57.Croxton R,Ma Y,Song L,Haura EB,Cress WD.Direct repression of the Mcl-1 promoter by E2F1.Oncogene.2002 Feb 21;21(9):1359-69.
2.Bouchard MJ,Schneider RJ.The enigmatic X gene of hepatitis B virus.J Virol.2004 Dec;78(23):12725-34.
3.Kim CM,Koike K,Saito I,Miyamura T,Jay G.HBx gene of hepatitis B virus induces liver cancer in transgenic mice.Nature 1991 May 23;351(6324):317-20.
4.Kanzler S,Galle PR.Apoptosis and the liver.Semin Cancer Biol.2000 Jun;10(3):173-84.
5.Zhang X,Zhang H,Ye L.Effects of hepatitis B virus X protein on the development of liver cancer.J Lab Clin Med.2006 Feb;147(2):58-66.
6.Grasl-Kraupp B,Ruttkay-Nedecky B,M(?)llauer L,et al.Inherent increase of apoptosis in liver tumors:implications for carcinogenesis and tumor regression.Hepatology 1997 Apr;25(4):906-12.
7.Michels J,Johnson PW,Packham G Mcl-1.Int J Biochem Cell Biol.2005 Feb;37(2):267-71.
8.Sieghart W,Losert D,Strommer S,et al.Mcl-1 overexpression in hepatocellular carcinoma:a potential target for antisense therapy.J Hepatol 2006 Jan;44(1):151-7.
9.Vick B,Weber A,Urbanik T,et al.Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes.Hepatology.2009 Feb;49(2):627-36.
10.Su F,Schneider RJ.Hepatitis B virus HBx protein sensitizes cells to apoptotic killing by tumor necrosis factor alpha.Proc Natl Acad Sci USA.1997 Aug 5;94(16):8744-9.
11.Lee AT,Ren J,Wong ET,et al.The Hepatitis B Virus X Protein Sensitizes HepG2 Cells to UV Light-induced DNA Damage.J Biol Chem 2005 Sep 30;280(39):33525-35.
12.Liang X,Liu Y,Zhang Q,et al.Hepatitis B virus sensitizes hepatocytes to TRAIL-induced apoptosis through Bax.2007 Jan 1;178(1):503-10.
13.Youle RJ,Strasser A.The BCL-2 protein family:opposing activities that mediate cell death.Nat Rev Mol Cell Biol.2008 Jan;9(1):47-59.
14.Elmore LW,Hancock AR,Chang SF,Wang XW,Chang S,Callahan CP,Geller DA,Will H, Harris CC.Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis.Proc Natl Acad Sci U S A.1997 Dec 23;94(26):14707-12.
15.Takehara T,Liu X,Fujimoto J,Friedman SL,Takahashi H.Expression and role of Bcl-xL in human hepatocellular carcinomas.Hepatology.2001 Jul;34(1):55-61.
16.Kobayashi S,Werneburg NW,Bronk SF,Kaufmann SH,Gores GJ.InterIeukin-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells.Gastroenterology.2005 Jun;128(7):2054-65.
17.Isomoto H,Kobayashi S,Werneburg NW,Bronk SF,Guicciardi ME,Frank DA,Gores GJ.Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells.Hepatology.2005 Dec;42(6):1329-38.
18.Opferman JT.Unraveling MCL-1 degradation.Cell Death Differ.2006 Aug;13(8):1260-2.
19.Domina AM,Vrana JA,Gregory MA,Hann SR,Craig RW.MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells,and at additional sites with cytotoxic okadaic acid or taxol.Oncogene.2004 Jul 8;23(31):5301-15.
20.Derouet M,Thomas L,Cross A,Moots RJ,Edwards SW.Granulocyte macrophage colony-stimulating factor signaling and proteasome inhibition delay neutrophil apoptosis by increasing the stability of Mcl-1.J Biol Chem.2004 Jun 25;279(26):26915-21.
21.Han Y,Amin HM,Franko B,Frantz C,Shi X,Lai R.Loss of SHPl enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM-ALK in ALK+ anaplastic large-cell lymphoma.Blood.2006 Oct 15;108(8):2796-803.
22.Inoshita S,Takeda K,Hatai T,Terada Y,Sano M,Hata J,Umezawa A,Ichijo H.Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress.J Biol Chem.2002 Nov 15;277(46):43730-4.
23.Derouet M,Thomas L,Moulding DA,Akgul C,Cross A,Moots RJ,Edwards SW.Sodium salicylate promotes neutrophil apoptosis by stimulating caspase-dependent turnover of Mcl-1.J Immunol.2006 Jan 15;176(2):957-65.
24.Ding Q,He X,Xia W,Hsu JM,Chen CT,Li LY,Lee DF,Yang JY,Xie X,Liu JC,Hung MC.Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer.Cancer Res.2007 May 15;67(10):4564-71.
25.Michels J,O'Neill JW,Dallman CL,Mouzakiti A,Habens F,Brimmell M,Zhang KY,Craig RW,Marcusson EG,Johnson PW,Packham G Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage.Oncogene.2004 Jun 17;23(28):4818-27.
26.Herrant M,Jacquel A,Marchetti S,et al.Cleavage of Mcl-1 by caspases impaired its ability to counteract Bim-induced apoptosis.Oncogene.2004 Oct 14;23(47):7863-73.
27.Pan J,Quintas-Cardama A,Manshouri T,Giles FJ,Lamb P,Tefferi A,Cortes J,Kantarjian H,Verstovsek S.The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-alpha-expressing cells through caspase-3-mediated cleavage of Mcl-1.Leukemia.2007 Jul;21(7):1395-404.
28.Jiang M,Wei Q,Pabla N,Dong G,Wang CY,Yang T,Smith SB,Dong Z.Effects of hydroxyl radical scavenging on cisplatin-induced p53 activation,tubular cell apoptosis and nephrotoxicity.Biochem Pharmacol.2007 May 1;73(9):1499-510.
29.Ding WX,Shen HM,Ong CN.Critical role of reactive oxygen species and mitochondrial permeability transition in microcystin-induced rapid apoptosis in rat hepatocytes.Hepatology.2000 Sep;32(3):547-55.
30.Wang Y,Cui F,Lv Y,Li C,Xu X,Deng C,Wang D,Sun Y,Hu G,Lang Z,Huang C,Yang X.HBsAg and HBx knocked into the p21 locus causes hepatocellular carcinoma in mice.Hepatology.2004 Feb;39(2):318-24.
31.Tsung A,Sahai R,Tanaka H,Nakao A,Fink MP,Lotze MT,Yang H,Li J,Tracey KJ,Geller DA,Billiar TR.The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion.J Exp Med.2005 Apr 4;201(7):1135-43.
32.Jiingst C,Cheng B,Gehrke R,et al.Oxidative Damage Is Increased in Human Liver Tissue Adjacent to Hepatocellular Carcinoma.Hepatology 2004 Jun;39(6):1663-72.
33.Arbuthnot P,Kew M.Hepatitis B virus and hepatocellular carcinoma.Int J Exp Pathol.2001 Apr;82(2):77-100.
34.Mevorach D,Zhou JL,Song X,Elkon KB.Systemic exposure to irradiated apoptotic cells induces autoantibody production.J Exp Med.1998 Jul 20;188(2):387-92.
35.Kim HS,Han MS,Chung KW,Kim S,Kim E,Kim MJ,Jang E,Lee HA,Youn J,Akira S,Lee MS.Toll-like receptor 2 senses beta-cell death and contributes to the initiation of autoimmune diabetes.Immunity.2007 Aug;27(2):321-33.
36.Coussens LM,Werb Z.Inflammation and cancer.Nature.2002 Dec 19-26;420(6917):860-7.
37.Murakami S.Hepatitis B virus X protein:a multifunctional viral regulator.J Gastroenterol.2001 Oct;36(10):651-60.
38.Kim WH,Hong F,Jaruga B,Zhang ZS,Fan SJ,Liang TJ,Gao B.Hepatitis B virus X protein sensitizes primary mouse hepatocytes to ethanol-and TNF-alpha-induced apoptosis by a caspase-3-dependent mechanism.Cell Mol Immunol.2005 Feb;2(l):40-8.
39.Terradillos O,de La Coste A,Pollicino T,Neuveut C,Sitterlin D,Lecoeur H,Gougeon ML,Kahn A,Buendia MA.The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver.Oncogene.2002 Jan 17;21(3):377-86.
40.Shirakata Y,Koike K.Hepatitis B Virus X Protein Induces Cell Death by Causing Loss of Mitochondrial Membrane Potential.2003 Jun 13;278(24):22071-8.
41.Chirillo P,Pagano S,Natoli G,Puri PL,Burgio VL,Balsano C,Levrero M.The hepatitis B virus X gene induces p53-mediated programmed cell death.Proc Natl Acad Sci U S A.1997 Jul 22;94(15):8162-7.
42.Yoo YG,Lee MO.Hepatitis B virus X protein induces expression of Fas ligand gene through enhancing transcriptional activity of early growth response factor.J Biol Chem.2004 Aug 27;279(35):36242-9.
43.Chami M,Ferrari D,Nicotera P,Paterlini-Brechot P,Rizzuto R.Caspase-dependent alterations of Ca2+ signaling in the induction of apoptosis by hepatitis B virus X protein.J Biol Chem.2003 Aug 22;278(34):31745-55.
44.Miao J,Chen GG,Chun SY,Lai PP.Hepatitis B virus X protein induces apoptosis in hepatoma cells through inhibiting Bcl-xL expression.Cancer Lett.2006 May 8;236(1):115-24.
45.Waris G,Huh KW,Siddiqui A.Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-kappa B via oxidative stress.Mol Cell Biol.2001 Nov;21(22):7721-30.
46.Allen RG,and Tresini M.Oxidative stress and gene regulation.Free Radic.Biol.Med 2000 Feb 1;28(3):463-99.
47.Lim SO,Gu JM,Kim MS,et al.Epigenetic changes induced by reactive oxygen species in
hepatocellular carcinoma:methylation of the E-cadherin promoter.Gastroenterology 2008 Dec;135(6):2128-40,2140.e1-8.
48.Sakurai T,He G,Matsuzawa A,et al.Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis.Cancer Cell 2008 Aug 12;14(2):156-65.
49.Toyokuni S.Novel aspects of oxidative stress-associated carcinogenesis.Antioxid Redox Signal.2006 Jul-Aug;8(7-8):1373-7.
50.Tien Kuo M,Savaraj N.Roles of reactive oxygen species in hepatocarcinogenesis and drug resistance gene expression in liver cancers.Mol Carcinog.2006 Sep;45(9):701-9.
1.Adams LA,Lindor KD.Nonalcoholic fatty liver disease.Ann Epidemiol.2007 Nov;17(11):863-9.
2.Malhi H,Bronk SF,Werneburg NW,Gores GJ.Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis.J Biol Chem.2006 Apr 28;281(17):12093-101.
3.Utzschneider KM,Kahn SE.Review:The role of insulin resistance in nonalcoholic fatty liver disease.J Clin Endocrinol Metab.2006 Dec;91(12):4753-61.
4.Malhi H,Gores GJ.Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease.Semin Liver Dis.2008 Nov;28(4):360-9.
5.Nehra V,Angulo P,Buchman AL,Lindor KD.Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis.Dig Dis Sci.2001 Nov;46(11):2347-52.
6.Vick B,Weber A,Urbanik T,et al.Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes.Hepatology.2009 Feb;49(2):627-36.
7.Barreyro FJ,Kobayashi S,Bronk SF,Werneburg NW,Malhi H,Gores GJ.Transcriptional regulation of Bim by FoxO3A mediates hepatocyte lipoapoptosis.J Biol Chem.2007 Sep 14;282(37):27141-54.
8.Malhi H,Barreyro FJ,Isomoto H,Bronk SF,Gores GJ.Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity.Gut.2007 Aug;56(8):1124-31.
9.Youle RJ,Strasser A.The BCL-2 protein family:opposing activities that mediate cell death.Nat Rev Mol Cell Biol.2008 Jan;9(1):47-59.
10.Takehara T,Liu X,Fujimoto J,Friedman SL,Takahashi H.Expression and role of Bcl-xL in human hepatocellular carcinomas.Hepatology.2001 Jul;34(1):55-61.
11.Opferman JT.Unraveling MCL-1 degradation.Cell Death Differ.2006 Aug;13(8):1260-2.
12.Browning JD,Horton JD.Molecular mediators of hepatic steatosis and liver injury.J Clin Invest.2004 Jul;114(2):147-52.
13.Michels J,O'Neill JW,Dallman CL,Mouzakiti A,Habens F,Brimmell M,Zhang KY,Craig RW,Marcusson EG,Johnson PW,Packham G Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage. Oncogene.2004 Jun 17;23(28):4818-27.
14.Herrant M,Jacquel A,Marchetti S,et al.Cleavage of Mcl-1 by caspases impaired its ability to counteract Bim-induced apoptosis.Oncogene.2004 Oct 14;23(47):7863-73.
15.Pan J,Quintas-Cardama A,Manshouri T,Giles FJ,Lamb P,Tefferi A,Cortes J,Kantarjian H,Verstovsek S.The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human IP1L1-PDGFR-alpha-expressing cells through caspase-3-mediated cleavage of Mcl-1.Leukemia.2007 Jul;21(7):1395-404.
16.Inoshita S,Takeda K,Hatai T,Terada Y,Sano M,Hata J,Umezawa A,Ichijo H.Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress.J Biol Chem.2002 Nov 15;277(46):43730-4.
17.Mehta K,Van Thiel DH,Shah N,Mobarhan S.Nonalcoholic fatty liver disease:pathogenesis and the role of antioxidants.Nutr Rev.2002 Sep;60(9):289-93.
18.Li Z,Berk M,Mclntyre TM,Gores GJ,Feldstein AE.The lysosomal-mitochondrial axis in free fatty acid-induced hepatic lipotoxicity.Hepatology.2008 May;47(5):1495-503.
19.Yang SQ,Lin HZ,Mandal AK,Huang J,Diehl AM.Disrupted signaling and inhibited regeneration in obese mice with fatty livers:implications for nonalcoholic fatty liver disease pathophysiology.Hepatology.2001 Oct;34(4 Pt 1):694-706.
20.Li Z,Yang S,Lin H,Huang J,Watkins PA,Moser AB,Desimone C,Song XY,Diehl AM.Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease.Hepatology.2003 Feb;37(2):343-50.
21.Dhanasekaran DN,Reddy EP.JNK signaling in apoptosis.Oncogene.2008 Oct 20;27(48):6245-51.
22.Wang Y,Ausman LM,Russell RM,Greenberg AS,Wang XD.Increased apoptosis in high-fat diet-induced nonalcoholic steatohepatitis in rats is associated with c-Jun NH2-terminal kinase activation and elevated proapoptotic Bax.J Nutr.2008 Oct;138(10):1866-71.
23.Kane to H,Matsuoka TA,Katakami N,Kawamori D,Miyatsuka T,Yoshiuchi K,Yasuda T,Sakamoto K,Yamasaki Y,Matsuhisa M.Oxidative stress and the JNK pathway are involved in the development of type 1 and type 2 diabetes.Curr Mol Med.2007 Nov;7(7):674-86.
24.Boden G,Duan X,Homko C,Molina EJ,Song W,Perez O,Cheung P,Merali S.Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals.Diabetes.2008 Sep;57(9):2438-44.
25.Schattenberg JM,Singh R,Wang Y,Lefkowitch JH,Rigoli RM,Scherer PE,Czaja MJ.JNKl but not JNK2 promotes the development of steatohepatitis in mice.Hepatology.2006 Jan;43(1):163-72.
26.Singh R,Wang Y,Xiang Y,Tanaka KE,Gaarde WA,Czaja MJ.Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance.Hepatology.2009 Jan;49(1):87-96.
27.Nanji AA.Role of different dietary fatty acids in the pathogenesis of experimental alcoholic liver disease.Alcohol.2004 Aug;34(1):21-5.
1.Feitelson MA,Clayton MM,Reis HM,Wu G,Lu EP.Pharmacotherapy of chronic viral hepatitis and hepatocellular carcinoma.Expert Opin Pharmacother.2008 Sep;9(13):2233-45.
2.Bouchard MJ,Schneider RJ.The enigmatic X gene of hepatitis B virus.J Virol.2004 Dec;78(23):12725-34.
3.Guo WT,Wang J,Tarn G,Yen TS,Ou JS.Leaky transcription termination produces larger and smaller than genome size hepatitis B virus X gene transcripts.Virology.1991 Apr;181(2):630-6.
4.Colgrove R,Simon G,Ganem D.Transcriptional activation of homologous and heterologous genes by the hepatitis B virus X gene product in cells permissive for viral replication.J Virol.1989 Sep;63(9):4019-26.
5.Kodama K,Ogasawara N,Yoshikawa H and Murakami S.Nucleotide sequence of a cloned woodchuck hepatitis virus genome:evolutional relationship between hepadnaviruses.J Virol.1985 Dec;56(3):978-86.
6.Urban S,Hildt E,Eckerskorn C,Sirma H,Kekule A,Hofschneider PH.Isolation and molecular characterization of hepatitis B virus X-protein from a baculovirus expression system.Hepatology.1997 Oct;26(4):1045-53.
7.Lin MH,Lo SC.Dimerization of hepatitis B viral X protein synthesized in a cell-free system.Biochem Biophys Res Commun.1989 Oct 16;164(1):14-21.
8.Schek N,Bartenschlager R,Kuhn C,Schaller H.Phosphorylation and rapid turnover of hepatitis B virus X-protein expressed in HepG2 cells from a recombinant vaccinia virus.Oncogene.1991 Oct;6(10):1735-44.
9.Summers J,O'Connell A,Millman I.Genome of hepatitis B virus:restriction enzyme cleavage and structure of DNA extracted from Dane particles.Proc Natl Acad Sci U S A.1975 Nov;72(11):4597-601.
10.Murakami S,Cheong JH,Kaneko S.Human hepatitis virus X gene encodes a regulatory domain that represses transactivation of X protein.J Biol Chem.1994 May 27;269(21):15118-23.
11.Dandri M,Petersen J,Stockert RJ,Harris TM,Rogler CE.Metabolic labeling of woodchuck hepatitis B virus X protein in naturally infected hepatocytes reveals a bimodal half-life and association with the nuclear framework.J Virol.1998 Nov;72(11):9359-64.
12.Doria M,Klein N,Lucito R,Schneider RJ.The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors.EMBO J.1995 Oct 2;14(19):4747-57.
13.Henkler F,Hoare J,Waseem N,Goldin RD,McGarvey MJ,Koshy R,King JA.Intracellular localization of the hepatitis B virus HBx protein.J Gen Virol.2001 Apr;82(Pt 4):871-82.
14.Forgues M,Marrogi AJ,SpiUare EA,Wu CG,Yang Q,Yoshida M,Wang XW.Interaction of the hepatitis B virus X protein with the Crml-dependent nuclear export pathway.J Biol Chem.2001 Jun 22;276(25):22797-803.
15.Kumar V,Jayasuryan N,Kumar R.A truncated mutant(residues 58-140)of the hepatitis B virus X protein retains transactivation function.Proc Natl Acad Sci U S A.1996 May 28;93(11):5647-52.
16.Nijhara R,Jana SS,Goswami SK,Rana A,Majumdar SS,Kumar V,Sarkar DP.Sustained activation of mitogen-activated protein kinases and activator protein 1 by the hepatitis B virus X protein in mouse hepatocytes in vivo.J Virol.2001 Nov;75(21):10348-58.
17.Lucito R,Schneider RJ.Hepatitis B virus X protein activates transcription factor NF-kappa B without a requirement for protein kinase C.J Virol.1992 Feb;66(2):983-91.
18.Maguire HF,Hoeffler JP,Siddiqui A.HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions.Science.1991 May 10;252(5007):842-4.
19.Aufiero B,Schneider RJ.The hepatitis B virus X-gene product trans-activates both RNA polymerase Ⅱ and Ⅲ promoters.EMBO J.1990 Feb;9(2):497-504.
20.Wang HD,Trivedi A,Johnson DL.Regulation of RNA polymerase I-dependent promoters by the hepatitis B virus X protein via activated Ras and TATA-binding protein.Mol Cell Biol.1998 Dec;18(12):7086-94.
21.Murakami S.Hepatitis B virus X protein:a multifunctional viral regulator.J Gastroenterol.2001 Oct;36(10):651-60.
22.Tarn C,Lee S,Hu Y,Ashendel C,Andrisani OM.Hepatitis B virus X protein differentially activates RAS-RAF-MAPK and JNK pathways in X-transforming versus non-transforming AML12 hepatocytes.J Biol Chem.2001 Sep 14;276(37):34671-80.
23.Shih WL,Kuo ML,Chuang SE,Cheng AL,Doong SL.Hepatitis B virus X protein inhibits transforming growth factor-beta-induced apoptosis through the activation of phosphatidylinositol 3-kinase pathway.J Biol Chem.2000 Aug 18;275(33):25858-64.
24.Lee YI,Kang-Park S,Do SI,Lee YI.The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade.J Biol Chem.2001 May 18;276(20):16969-77.
25.Mansour SJ,Matten WT,Hermann AS,Candia JM,Rong S,Fukasawa K,Vande Woude GF,Ahri NG Transformation of mammalian cells by constitutively active MAP kinase kinase.Science.1994 Aug 12;265(5174):966-70.
26.Cougot D,Wu Y,Cairo S,Caramel J,Renard CA,Levy L,Buendia MA,Neuveut C.The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription.J Biol Chem.2007 Feb 16;282(7):4277-87.
27.Wang WH,Gregori G,Hullinger RL,Andrisani OM.Sustained activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase pathways by hepatitis B virus X protein mediates apoptosis via induction of Fas/FasL and tumor necrosis factor(TNF)receptor 1/TNF-alpha expression.Mol Cell Biol.2004 Dec;24(23):10352-65.
28.Tarn C,Zou L,Hullinger RL,Andrisani OM.Hepatitis B virus X protein activates the p38 mitogen-activated protein kinase pathway in dedifferentiated hepatocytes.J Virol.2002 Oct;76(19):9763-72.
29.Klein NP,Schneider RJ.Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras.Mol Cell Biol.1997 Nov;17(11):6427-36
30.Lee YH,Yun Y.HBx protein of hepatitis B virus activates Jakl-STAT signaling.J Biol Chem.1998 Sep 25;273(39):25510-5.
31.Waris G,Huh KW,Siddiqui A.Mitochondrially associated hepatitis B virus X protein constitutively activates transcription factors STAT-3 and NF-kappa B via oxidative stress.Mol Cell Biol.2001 Nov;21(22):7721-30.
32.Ruff-Jamison S,Chen K,Cohen S.Epidermal growth factor induces the tyrosine phosphorylation and nuclear translocation of Stat 5 in mouse liver.Proc Natl Acad Sci.1995 May 9;92(10):4215-8.
33.Seto E,Mitchell PJ,Yen TS.Transactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors.Nature.1990 Mar 1;344(6261):72-4.
34.Siddiqui A,Gaynor R,Srinivasan A,Mapoles J,Farr RW.Trans-activation of viral enhancers including long terminal repeat of the human immunodeficiency virus by the hepatitis B virus X protein.Virology.1989 Apr;169(2):479-84.
35.Yun C,Um HR,Jin YH,Wang JH,Lee MO,Park S,Lee JH,Cho H.NF-kappaB activation by hepatitis B virus X(HBx)protein shifts the cellular fate toward survival.Cancer Lett.2002 Oct 8;184(1):97-104.
36.Pan J,Duan LX,Sun BS,Feitelson MA.Hepatitis B virus X protein protects against anti-Fas-mediated apoptosis in human liver cells by inducing NF-kappa B.J Gen Virol.2001 Jan;82(Pt 1):171-82.
37.Yun C,Um HR,Jin YH,Wang JH,Lee MO,Park S,Lee JH,Cho H.NF-kappaB activation by hepatitis B virus X(HBx)protein shifts the cellular fate toward survival.Cancer Lett.2002 Oct 8;184(1):97-104.
38.Diao J,Khine AA,Sarangi F,Hsu E,Iorio C,Tibbies LA,Woodgett JR,Penninger J,Richardson CD.X protein of hepatitis B virus inhibits Fas-mediated apoptosis and is associated with up-regulation of the SAPK/JNK pathway.J Biol Chem.2001 Mar 16;276(11):8328-40.
39.Cha MY,Kim CM,Park YM,Ryu WS.Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells.Hepatology.2004 Jun;39(6):1683-93.
40.Ding Q,Xia W,Liu JC,Yang JY,Lee DF,Xia J,Bartholomeusz G,Li Y,Pan Y,Li Z,Bargou RC,Qin J,Lai CC,Tsai FJ,Tsai CH,Hung MC.Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin.Mol Cell.2005 Jul 22;19(2):159-70.
41.Jung JK,Kwun HJ,Lee JO,Arora P,Jang KL.Hepatitis B virus X protein differentially affects the ubiquitin-mediated proteasomal degradation of beta-catenin depending on the status of cellular p53.J Gen Virol.2007 Aug;88(Pt 8):2144-54.
42.Murata M,Matsuzaki K,Yoshida K,Sekimoto G,Tahashi Y,Mori S,Uemura Y,Sakaida N,Fujisawa J,Seki T,Kobayashi K,Yokote K,Koike K,Okazaki K Hepatitis B virus X protein shifts human hepatic transforming growth factor(TGF)-beta signaling from tumor suppression to oncogenesis in early chronic hepatitis B.Hepatology.2008 Dec 30.[Epub ahead of print]
43.Kanzler S,Galle PR.Apoptosis and the liver.Semin Cancer Biol.2000 Jun;10(3):173-84.
44.Wang XW,Gibson MK,Vermeulen W,Yeh H,Forrester K,Sturzbecher HW,Hoeijmakers JH,Harris CC.Abrogation of p53-induced apoptosis by the hepatitis B virus X gene.Cancer Res.1995 Dec 15;55(24):6012-6.
45.Elmore LW,Hancock AR,Chang SF,Wang XW,Chang S,Callahan CP,Geller DA,Will H,Harris CC.Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis.Proc Natl Acad Sci U S A.1997 Dec 23;94(26):14707-12.
46.Marusawa H,Matsuzawa S,Welsh K,Zou H,Armstrong R,Tamm I,Reed JC.HBXIP functions as a cofactor of survivin in apoptosis suppression.EMBO J.2003 Jun 2;22(11):2729-40.
47.Zhang X,Dong N,Yin L,Cai N,Ma H,You J,Zhang H,Wang H,He R,Ye L.Hepatitis B virus X protein upregulates survivin expression in hepatoma tissues.J Med Virol.2005 Nov;77(3):374-81.
48.Kojima H,Kaita KD,Xu Z,Ou JH,Gong Y,Zhang M,Minuk GY.The absence of up-regulation of telomerase activity during regeneration after partial hepatectomy in hepatitis B virus X gene transgenic mice.J Hepatol.2003 Aug;9(2):262-8.
49.Gottlob K,Fulco M,Levrero M,Graessmann A.The hepatitis B virus HBx protein inhibits caspase 3 activity.J Biol Chem.1998 Dec 11;273(50):33347-53.
50.Chirillo P,Pagano S,Natoli G,Puri PL,Burgio VL,Balsano C,Levrero M.The hepatitis B virus X gene induces p53-mediated programmed cell death.Proc Natl Acad Sci U S A.1997 Jul 22;94(15):8162-7.
51.Shintani Y,Yotsuyanagi H,Moriya K,Fujie H,Tsutsumi T,Kanegae Y,Kimura S,Saito I,Koike K.Induction of apoptosis after switch-on of the hepatitis B virus X gene mediated by the Cre/loxP recombination system.J Gen Virol.1999 Dec;80(Pt 12):3257-65.
52.Terradillos O,Pollicino T,Lecoeur H,Tripodi M,Gougeon ML,Tiollais P,Buendia MA.p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro.Oncogene.1998 Oct 22;17(16):2115-23.
53.Kim H,Lee H,Yun Y X-gene product of hepatitis B virus induces apoptosis in liver cells.J Biol Chem.1998 Jan 2;273(1):381-5.
54.Kim KH,Seong BL.Pro-apoptotic function of HBV X protein is mediated by interaction with c-FLIP and enhancement of death-inducing signal.EMBO J.2003 Mayl;22(9):2104-16.
55.Shirakata Y,Koike K.Hepatitis B Virus X Protein Induces Cell Death by Causing Loss of Mitochondrial Membrane Potential.2003 Jun 13;278(24):22071-8.
56.Yoo YG,Lee MO.Hepatitis B virus X protein induces expression of Fas ligand gene through enhancing transcriptional activity of early growth response factor.J Biol Chem.2004 Aug 27;279(35):36242-9.
57.Chami M,Ferrari D,Nicotera P,Paterlini-Brechot P,Rizzuto R.Caspase-dependent alterations of Ca2+ signaling in the induction of apoptosis by hepatitis B virus X protein.J Biol Chem.2003 Aug 22;278(34):31745-55.
58.Bouchard MJ,Wang LH,Schneider RJ.Calcium signaling by HBx protein in hepatitis B virus DNA replication.Science.2001 Dec 14;294(5550):2376-8.
59.Miao J,Chen GG,Chun SY,Lai PP.Hepatitis B virus X protein induces apoptosis in hepatoma cells through inhibiting Bcl-xL expression.Cancer Lett.2006 May 8;236(1):115-24.
60.Su F,Schneider RJ.Hepatitis B virus HBx protein sensitizes cells to apoptotic killing by tumor necrosis factor alpha.Proc Natl Acad Sci U S A.1997 Aug 5;94(16):8744-9.
61.Terradillos O,de La Coste A,Pollicino T,Neuveut C,Sitterlin D,Lecoeur H,Gougeon ML,Kahn A,Buendia MA.The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver.Oncogene.2002 Jan 17;21(3):377-86.
62.Kim WH,Hong F,Jaruga B,Zhang ZS,Fan SJ,Liang TJ,Gao B.Hepatitis B virus X protein sensitizes primary mouse hepatocytes to ethanol-and TNF-alpha-induced apoptosis by a caspase-3-dependent mechanism.Cell Mol Immunol.2005 Feb;2(1):40-8.
63.Liang X,Liu Y,Zhang Q,et al.Hepatitis B virus sensitizes hepatocytes to TRAIL-induced apoptosis through Bax.2007 Jan 1;178(1):503-10.
64.Lee AT,Ren J,Wong ET,et al.The Hepatitis B Virus X Protein Sensitizes HepG2 Cells to UV Light-induced DNA Damage.J Biol Chem 2005 Sep 30;280(39):33525-35.
65.Kim SY,Kim JK,Kim HJ,Ahn JK Hepatitis B virus X protein sensitizes UV-induced apoptosis by transcriptional transactivation of Fas ligand gene expression.IUBMB Life.2005 Sep;57(9):651-8.
66.Pollicino T,Terradillos 0,Lecoeur H,Gougeon ML,Buendia MA.Pro-apoptotic effect of the hepatitis B virus X gene.Biomed Pharmacother.1998;52(9):363-8.
67.Liu X,Wang L,Zhang S,Lin J,Zhang S,Feitelson MA,Gao H,Zhu M.Mutations in the C-terminus of the X protein of hepatitis B virus regulate Wnt-5a expression in hepatoma Huh7 cells:cDNA microarray and proteomic analyses.Carcinogenesis.2008 Jun;29(6):1207-14.
68.Zhang H,Shan CL,Li N,Zhang X,Zhang XZ,Xu FQ,Zhang S,Qiu LY,Ye LH,Zhang XD.Identification of a natural mutant of HBV X protein truncated 27 amino acids at the COOH terminal and its effect on liver cell proliferation.Acta Pharmacol Sin.2008 Apr;29(4):473-80.
69.Benn J,Schneider RJ.Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls.Proc Natl Acad Sci U S A.1995 Nov 21;92(24):11215-9.
70.Bouchard M,Giannakopoulos S,Wang EH,Tanese N,Schneider RJ.Hepatitis B virus HBx protein activation of cyclin A-cyclin-dependent kinase 2 complexes and Gl transit via a Src kinase pathway.J Virol.2001 May;75(9):4247-57.
71.Park US,Park SK,Lee YI,Park JG,Lee YI.Hepatitis B virus-X protein upregulates the expression of p21wafl/cipl and prolongs G1-->S transition via a p53-independent pathway in human hepatoma cells.Oncogene.2000 Jul 13;19(30):3384-94.
72.Qiao L,Leach K,McKinstry R,Gilfor D,Yacoub A,Park JS,Grant S,Hylemon PB,Fisher PB,Dent P.Hepatitis B virus X protein increases expression of p21(Cip-1/WAF1/MDA6)and p27(Kip-1)in primary mouse hepatocytes,leading to reduced cell cycle progression.Hepatology.2001 Nov;34(5):906-17.
73.Mukherji A,Janbandhu VC,Kumar V.HBx-dependent cell cycle deregulation involves interaction with cyclin E/A-cdk2 complex and destabilization of p27Kipl.Biochem J.2007 Jan l;401(1):247-56.
74.Ahn JY,Chung EY,Kwun HJ,Jang KL.Transcriptional repression of p21(wafl)promoter by hepatitis B virus X protein via a p53-independent pathway.Gene.2001 Sep 5;275(1):163-8.
75.Lee S,Tarn C,Wang WH,Chen S,Hullinger RL,Andrisani OM.Hepatitis B virus X protein differentially regulates cell cycle progression in X-transforming versus nontransforming hepatocyte(AML12)cell lines.J Biol Chem.2002 Mar 8;277(10):8730-40.
76.Madden CR,Finegold MJ,Slagle BL.Hepatitis B virus X protein acts as a tumor promoter in development of diethylnitrosamine-induced preneoplastic lesions.J Virol.2001 Apr;75(8):3851-8.
77.Madden CR,Slagle BL.Stimulation of cellular proliferation by hepatitis B virus X protein.Dis Markers.2001;17(3):153-7.
78.Lara-Pezzi E,Majano PL,Yanez-M6 M,Gomez-Gonzalo M,Carretero M,Moreno-Otero R,Sanchez-Madrid F,Lopez-Cabrera M.Effect of the hepatitis B virus HBx protein on integrin-mediated adhesion to and migration on extracellular matrix.J Hepatol.2001 Mar;34(3):409-15.
79.Lee JO,Kwun HJ,Jung JK,Choi KH,Min DS,Jang KL.Hepatitis B virus X protein represses E-cadherin expression via activation of DNA methyl transferase 1.Oncogene.2005 Oct 6;24(44):6617-25.
80.Lara-Pezzi E,Roche S,Andrisani OM,Sanchez-Madrid F,Lopez-Cabrera M.The hepatitis B virus HBx protein induces adherens junction disruption in a src-dependent manner.Oncogene.2001 Jun 7;20(26):3323-31.
81.Lara-Pezzi E,Gomez-Gaviro MV,Galvez BQ Mira E,Iniguez MA,Fresno M,Martinez-A C,Arroyo AG Lopez-Cabrera M.The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression.J Clin Invest.2002 Dec;110(12):1831-8.
82.Chung TW,Lee YC,Kim CH.Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways:involvement of invasive potential.FASEB J.2004 Jul;18(10):1123-5.
83.Yu FL,Liu HJ,Lee JW,Liao MH,Shih WL.Hepatitis B virus X protein promotes cell migration by inducing matrix metalloproteinase-3.J Hepatol.2005 Apr;42(4):520-7.
84.Ou DP,Tao YM,Tang FQ,Yang LY.The hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by upregulation of matrix metalloproteinases.Int J Cancer.2007 Mar 15;120(6):1208-14.
85.Yoo YG Oh SH,Park ES,Cho H,Lee N,Park H,Kim DK,Yu DY,Seong JK,Lee MO.Hepatitis B virus X protein enhances transcriptional activity of hypoxia-inducible factor-1 alpha through activation of mitogen-activated protein kinase pathway.J Biol Chem. 2003 Oct 3;278(40):39076-84.
86.Moon EJ,Jeong CH,Jeong JW,Kim KR,Yu DY,Murakami S,Kim CW,Kim KW.Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor-lalpha.FASEB J.2004 Feb;18(2):382-4.
87.Yoo YG,Na TY,Seo HW,Seong JK,Park CK,Shin YK,Lee MO.Hepatitis B virus X protein induces the expression of MTA1 and HDAC1,which enhances hypoxia signaling in hepatocellular carcinoma cells.Oncogene.2008 May 29;27(24):3405-13.
88.Benn J,Schneider RJ.Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras,Raf,MAP kinase signaling cascade.Proc Natl Acad Sci U S A.1994 Oct 25;91(22):10350-4.
89.Lee TK,Man K,Poon RT,Lo CM,Yuen AP,Ng IO,Ng KT,Leonard W,Fan ST.Signal transducers and activators of transcription 5b activation enhances hepatocellular carcinoma aggressiveness through induction of epithelial-mesenchymal transition.Cancer Res.2006 Oct 15;66(20):9948-56.
90.Jaitovich-Groisman I,Benlimame N,Slagle BL,Perez MH,Alpert L,Song DJ,Fotouhi-Ardakani N,Galipeau J,Alaoui-Jamali MA.Transcriptional regulation of the TFIIH transcription repair components XPB and XPD by the hepatitis B virus x protein in liver cells and transgenic liver tissue.J Biol Chem.2001 Apr 27;276(17):14124-32.
91.Jia L,Wang XW,Harris CC.Hepatitis B virus X protein inhibits nucleotide excision repair.Int J Cancer.1999 Mar 15;80(6):875-9.
92.Nag A,Datta A,Yoo K,Bhattacharyya D,Chakrabortty A,Wang X,Slagle BL,Costa RH,Raychaudhuri P.DDB2 induces nuclear accumulation of the hepatitis B virus X protein independently of binding to DDB1.J Virol.2001 Nov;75(21):10383-92.
93.Forgues M,Difilippantonio MJ,Linke SP,Ried T,Nagashima K,Feden J,Valerie K,Fukasawa K,Wang XW.Involvement of Crml in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles.Mol Cell Biol.2003 Aug;23(15):5282-92.
94.Yun C,Cho H,Kim SJ,Lee JH,Park SY,Chan GK,Cho H.Mitotic aberration coupled with centrosome amplification is induced by hepatitis B virus X oncoprotein via the Ras-mitogen-activated protein/extracellular signal-regulated kinase-mitogen-activated protein pathway.Mol Cancer Res.2004 Mar;2(3):159-69.
95.Kim KH,Shin HJ,Kim K,Choi HM,Rhee SH,Moon HB,Kim HH,Yang US,Yu DY,Cheong J.Hepatitis B virus X protein induces hepatic steatosis via transcriptional activation of SREBP1 and PPARgamma.Gastroenterology.2007 May;132(5):1955-67.
96.Na TY,Shin YK,Roh KJ,Kang SA,Hong 1,Oh SJ,Seong JK,Park CK,Choi YL,Lee MO.Liver X receptor mediates hepatitis B virus X protein-induced lipogenesis in hepatitis B virus-associated hepatocellular carcinoma.Hepatology.2008 Nov 13.[Epub ahead of print]
97.Martin-Vilchez S,Sanz-Cameno P,Rodriguez-Munoz Y,Majano PL,Molina-Jimenez F,Lopez-Cabrera M,Moreno-Otero R,Lara-Pezzi E.The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells.Hepatology.2008 Jun;47(6):1872-83.
98.Tang H,Da L,Mao Y,Li Y,Li D,Xu Z,Li F,Wang Y,Tiollais P,Li T,Zhao M.Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression.Hepatology.2009 Jan;49(1):60-71.
1.Kozopas KM,Yang T,Buchan HL,Zhou P,Craig RW.MCL1,a gene expressed in programmed myeloid cell differentiation,has sequence similarity to BCL2.Proc Natl Acad Sci U S A.1993 Apr 15;90(8):3516-20.
2.Michels J,Johnson PW,Packham G Mcl-l.Int J Biochem Cell Biol.2005 Feb;37(2):267-71.
3.Youle RJ,Strasser A.The BCL-2 protein family:opposing activities that mediate cell death.Nat Rev Mol Cell Biol.2008 Jan;9(1):47-59.
4.Yang T,Kozopas KM,Craig RW.The intracellular distribution and pattern of expression of Mcl-1 overlap with,but are not identical to,those of Bcl-2.J Cell Biol.1995 Mar;128(6):1173-84.
5.Craig RW.MCL1 provides a window on the role of the BCL2 family in cell proliferation,differentiation and tumorigenesis.Leukemia.2002 Apr;16(4):444-54.
6.Nijhawan D,Fang M,Traer E,Zhong Q,Gao W,Du F,Wang X.Elimination of Mcl-l is required for the initiation of apoptosis following ultraviolet irradiation.Genes Dev.2003 Jun 15;17(12):1475-86.
7.Bae J,Leo CP,Hsu SY,Hsueh AJ.MCL-IS,a splicing variant of the antiapoptotic BCL-2 family member MCL-1,encodes a proapoptotic protein possessing only the BH3 domain.J Biol Chem.2000 Aug 18;275(33):25255-61.
8.Gross A,McDonnell JM,Korsmeyer SJ.BCL-2 family members and the mitochondria in apoptosis.Genes Dev.1999 Aug 1;13(15):1899-911.
9.Krajewski S,Bodrug S,Krajewska M,Shabaik A,Gascoyne R,Berean K and Reed JC.Immunohistochemical analysis of Mcl-l protein in human tissues.Differential regulation of Mcl-1 and Bcl-2 protein production suggests a unique role for Mcl-1 in control of programmed cell death in vivo.Am J Pathol.1995 Jun;146(6):1309-19.
10.Zhuang J,Brady HJ.Emerging role of Mcl-l in actively counteracting BH3-only proteins in apoptosis.Cell Death Differ.2006 Aug;13(8):1263-7.
11.Cuconati A,Mukherjee C,Perez D,White E.DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells.Genes Dev.2003 Dec 1;17(23):2922-32.
12.Gojo I,Zhang B,Fenton RG The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1.Clin Cancer Res.2002 Nov;8(11):3527-38.
13.Zhong Q,Gao W,Du F,Wang X.Mule/ARF-BPl,a BH3-only E3 ubiquitin ligase,catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis.Cell.2005 Jul l;121(7):1085-95.
14.Kim H,Rafiuddin-Shah M,Tu HC,Jeffers JR,Zambetti GP,Hsieh JJ,Cheng EH.Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies.Nat Cell Biol.2006 Dec;8(12):1348-58.
15.Adhikary S,Marinoni F,Hock A,Hulleman E,Popov N,Beier R,Bernard S,Quarto M,Capra M,Goettig S,Kogel U,Scheffner M,Helin K,Eilers M.The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation.Cell.2005 Nov 4;123(3):409-21.
16.Chen D,Kon N,Li M,Zhang W,Qin J,Gu W.ARF-BPl/Mule is a critical mediator of the ARF tumor suppressor.Cell.2005 Jul 1;121(7):1071-83.
17.Liu Z,Oughtred R,Wing SS.Characterization of E3Histone,a novel testis ubiquitin protein ligase which ubiquitinates histones.Mol Cell Biol.2005 Apr;25(7):2819-31.
18.Domina AM,Vrana JA,Gregory MA,Hann SR,Craig RW.MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells,and at additional sites with cytotoxic okadaic acid or taxol.Oncogene.2004 Jul 8;23(31):5301-15.
19.Longo PG,Laurenti L,Gobessi S,Sica S,Leone G,Efremov DG The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells.Blood.2008 Jan 15;111(2):846-55.
20.Kodama Y,Taura K,Miura K,Schnabl B,Osawa Y,Brenner DA.Antiapoptotic Effect of c-Jun N-terminal Kinase-1 through Mcl-1 Stabilization in TNF-induced Hepatocyte Apoptosis.Gastroenterology.2009 Jan 6.[Epub ahead of print]
21.Inoshita S,Takeda K,Hatai T,Terada Y,Sano M,Hata J,Umezawa A,Ichijo H.Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress.J Biol Chem.2002 Nov 15;277(46):43730-4.
22.Maurer U,Charvet C,Wagman AS,Dejardin E,Green DR..Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1.Mol Cell.2006 Mar 17;21(6):749-60.
23.Sitailo LA,Tibudan SS,Denning MR The protein kinase C delta catalytic fragment targets Mcl-l for degradation to trigger apoptosis.J Biol Chem.2006 Oct 6;281(40):29703-10.
24.Michels J,O'Neill JW,Dallman CL,Mouzakiti A,Habens F,Brimmell M,Zhang KY,Craig RW,Marcusson EG,Johnson PW,Packham G Mcl-l is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage.Oncogene.2004 Jun 17;23(28):4818-27.
25.Herrant M,Luciano F,Loubat A,Auberger P.The protective effect of phorbol esters on Fas-mediated apoptosis in T cells.Transcriptional and postranscriptional regulation.Oncogene.2002 Jul 25;21(32):4957-68.
26.Clohessy JG,Zhuang J,Brady HJ.Characterisation of Mcl-l cleavage during apoptosis of haematopoietic cells.Br J Haematol.2004 Jun;125(5):655-65.
27.Herrant M,Jacquel A,Marchetti S,et al.Cleavage of Mcl-l by caspases impaired its ability to counteract Bim-induced apoptosis.Oncogene.2004 Oct 14;23(47):7863-73.
28.Snowden RT,Sun XM,Dyer MJ,Cohen GM.Bisindolylmaleimide IX is a potent inducer of apoptosis in chronic lymphocytic leukaemic cells and activates cleavage of Mcl-l.Leukemia.2003 Oct;17(10):1981-9.
29.Weng C,Li Y,Xu D,Shi Y,Tang H.Specific cleavage of Mcl-l by caspase-3 in tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-induced apoptosis in Jurkat leukemia T cells.J Biol Chem.2005 Mar 18;280(11):10491-500.
30.Opferman JT.Life and death during hematopoietic differentiation.Curr Opin Immunol.2007 Oct;19(5):497-502.
31.Zhou P,Levy NB,Xie H,Qian L,Lee CY,Gascoyne RD,Craig RW.MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes.Blood.2001 Jun 15;97(12):3902-9.
32.Kitada S,Andersen J,Akar S,Zapata JM,Takayama S,Krajewski S,Wang HG,Zhang X,Bullrich F,Croce CM,Rai K,Hines J,Reed JC.Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia:correlations with In vitro and In vivo chemoresponses.Blood.1998 May l;91(9):3379-89.
33.Kaufmann SH,Karp JE,Svingen PA,Krajewski S,Burke PJ,Gore SD,Reed JC.Elevated expression of the apoptotic regulator Mcl-l at the time of leukemic relapse.Blood.1998 Feb 1;91(3):991-1000.
34.Podar K,Gouill SL,Zhang J,Opferman JT,Zorn E,Tai YT,Hideshima T,Amiot M,Chauhan D,Harousseau JL,Anderson KC.A pivotal role for Mcl-l in Bortezomib-induced apoptosis.Oncogene.2008 Jan 31;27(6):721-31.
35.Gomez-Bougie P,Wuilleme-Toumi S,Menoret E,Trichet V,Robillard N,Philippe M,Bataille R,Amiot M.Noxa up-regulation and Mcl-l cleavage are associated to apoptosis induction by bortezomib in multiple myeloma.Cancer Res.2007 Jun l;67(11):5418-24.
36.Zhang B,Gojo I,Fenton RG.Myeloid cell factor-1 is a critical survival factor for multiple myeloma.Blood.2002 Mar 15;99(6):1885-93.
37.Fleischer B,Schulze-Bergkamen H,Schuchmann M,Weber A,Biesterfeld S,Müller M,Krammer PH,Galle PR.Mcl-l is an anti-apoptotic factor for human hepatocellular carcinoma.Int J Oncol.2006 Jan;28(1):25-32.
38.Sieghart W,Losert D,Strommer S,et al.Mcl-l overexpression in hepatocellular carcinoma:a potential target for antisense therapy.J Hepatol.2006 Jan;44(1):151-7.
39.Vick B,Weber A,Urbanik T,et al.Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes.Hepatology.2009 Feb;49(2):627-36.
40.Zhuang J,Brady HJ.Emerging role of Mcl-l in actively counteracting BH3-only proteins in apoptosis.Cell Death Differ.2006 Aug;13(8):1263-7.
41.Opferman JT,Letai A,Beard C,Sorcinelli MD,Ong CC,Korsmeyer SJ.Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1.Nature.2003 Dec 11;426(6967):671-6.
42.Han J,Goldstein LA,Gastman BR,Froelich CJ,Yin XM,Rabinowich H.Degradation of Mcl-l by granzyme B:implications for Bim-mediated mitochondrial apoptotic events.J Biol Chem.2004 May 21;279(21):22020-9.
43.Clohessy JG Zhuang J,de Boer J,Gil-Gomez G,Brady HJ.Mcl-l interacts with truncated Bid and inhibits its induction of cytochrome c release and its role in receptor-mediated apoptosis.J Biol Chem.2006 Mar 3;281(9):5750-9.
44.Villunger A,Michalak EM,Coultas L,Mullauer F,Bock G,Ausserlechner MJ,Adams JM,Strasser A.p53-and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa.Science.2003 Nov 7;302(5647):1036-8.
45.Jeffers JR,Parganas E,Lee Y,Yang C,Wang J,Brennan J,MacLean KH,Han J,Chittenden T,Ihle JN,McKinnon PJ,Cleveland JL,Zambetti GP.Puma is an essential mediator of p53-dependent and-independent apoptotic pathways.Cancer Cell.2003 Oct;4(4):321-8.
46.Shibue T,Takeda K,Oda E,Tanaka H,Murasawa H,Takaoka A,Morishita Y,Akira S,Taniguchi T,Tanaka N.Integral role of Noxa in p53-mediated apoptotic response.Genes Dev.2003 Sep 15;17(18):2233-8.
47.Chen L,Willis SN,Wei A,Smith BJ,Fletcher JI,Hinds MG,Colman PM,Day CL,Adams JM,Huang DC.Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.Mol Cell.2005 Feb 4;17(3):393-403.
48.Kuwana T,Bouchier-Hayes L,Chipuk JE,Bonzon C,Sullivan BA,Green DR,Newmeyer DD.BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly.Mol Cell.2005 Feb18;17(4):525-35.
49.Leu JI,Dumont P,Hafey M,Murphy ME,George DL.Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcll complex.Nat Cell Biol.2004 May;6(5):443-50.
50.Willis SN,Chen L,Dewson G,Wei A,Naik E,Fletcher JI,Adams JM,Huang DC.Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL,but not Bcl-2,until displaced by BH3-only proteins.Genes Dev.2005 Jun l;19(11):1294-305.
51.Rinkenberger JL,Horning S,Klocke B,Roth K,Korsmeyer SJ.Mcl-1 deficiency results in peri-implantation embryonic lethality.Genes Dev.2000 Janl;14(1):23-7.
52.Veis DJ,Sorenson CM,Shutter JR,Korsmeyer SJ.Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis,polycystic kidneys,and hypopigmented hair.Cell.1993 Oct 22;75(2):229-40.
53.Nakayama K,Nakayama K,Negishi I,Kuida K,Shinkai Y,Louie MC,Fields LE,Lucas PJ,Stewart V,Alt FW,et al.Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice.Science.1993 Sep 17;261(5128):1584-8.
54.Opferman JT,Iwasaki H,Ong CC,Suh H,Mizuno S,Akashi K,Korsmeyer SJ.Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells.Science.2005 Feb 18;307(5712):1101-4.
55.Edwards SW,Derouet M,Howse M,Moots RJ.Regulation of neutrophil apoptosis by Mcl-1. Biochem Soc Trans.2004 Jun;32(Pt3):489-92.
56.Fujise K,Zhang D,Liu J,Yeh ET.Regulation of apoptosis and cell cycle progression by MCLl.Differential role of proliferating cell nuclear antigen.J Biol Chem.2000 Dec 15;275(50):39458-65.
57.Croxton R,Ma Y,Song L,Haura EB,Cress WD.Direct repression of the Mcl-1 promoter by E2F1.Oncogene.2002 Feb 21;21(9):1359-69.