BCL2L10蛋白对人胃癌细胞凋亡和增殖的影响及其机制的研究
摘要
前言
胃癌是全球最常见的恶性肿瘤之一,更是引起恶性肿瘤患者死亡的第二大原因。胃癌在全球地理上的分布有广泛的国家间差异。高危险地区(男性年龄标准化发生率>20每100000人)包括东亚地区(中国,日本)、东欧和中南美洲的部分地区。在北美洲,胃癌相对少见,但其在恶性肿瘤死亡率中也占有相当大的比例。
人类BCL2L10 (Bcl-B、Diva、Boo)基因位于人染色体15q12.2, mRNA全长887个核苷酸,cDNA全长615个核苷酸,表达含有204个氨基酸残基的蛋白,其分子量约为23kDa。BCL2L10表达有组织差异性,成人大脑、心脏、肾脏、脾脏、肝脏、结肠、肺脏、小肠、肌肉、胃、睾丸和胎盘中有表达,骨髓和所有的腺体有非常高的表达,然而,卵巢、子宫和前列腺组织中几乎没有BCL2L10的表达。同样,在不同癌组织中,其表达也存在着差异。滤泡性淋巴瘤不表达BCL2L10蛋白,18%的多发性骨髓瘤中表达BCL2L10,弥漫性大B细胞淋巴瘤则有近半数表达BCL2L10。而乳腺癌、前列腺癌、结直肠癌和小细胞肺癌中BCL2L10高表达。研究表明,BCL2L10表达与一些肿瘤不良预后的指标有相关性,如与乳腺癌的肿瘤高级别,与结直肠癌的微卫星稳定性和结直肠癌的解剖位置,与前列腺癌患者更高的死亡率,与小细胞肺癌更短的生存率之间均存在相关性。
成人正常胃组织中,BCL2L10 mRNA表达水平非常高。也有研究报道胃癌组织中BCL2L10蛋白高表达,而其高表达与癌组织高分化有关,这样的结论显然是相互矛盾的。我们没有检索到BCL2L10与胃癌患者预后有意义联系的报道。
BCL2L10是Bcl-2家族最近被发现的蛋白成员。Bcl-2家族至少有20种可以在哺乳动物细胞发挥促凋亡或者抗凋亡作用的蛋白。有趣的是,除了调节凋亡的中心作用,Bcl-2家族的一些蛋白也影响细胞周期,与凋亡调节功能一起,构成了它们在肿瘤发生中的重要作用。关于BCL2L10调节胃癌细胞生物学行为,国内外也未见相关报道。
本课题试图从人胃癌组织、人胃癌细胞株和裸鼠移植瘤模型三方面对BCL2L10与胃癌患者预后、与胃癌细胞生物学行为的相关关系及其分子机制进行研究。本课题的研究不仅对了解肿瘤的生物学特性具有明显的理论意义,而且也具有显著的临床价值和社会效益。
第一部分BCL2L10蛋白的低表达提示胃癌患者的预后不良
目的：探究BCL2L10在胃癌细胞中的表达水平,以及它对胃癌患者临床和预后的意义。
方法和结果：我们应用免疫组织化学方法检测了213例胃癌组织BCL2L10的蛋白表达。免疫组织化学结果显示了胃癌细胞中BCL2L10普遍低表达。BCL2L10表达等级数据分成3组(组0到组2),以利于统计分析。完成数据统计分析后发现,BCL2L10低表达与较短的肿瘤相关生存率有显著的相关性(x2=81.55,P=1.956×10-18)。多因素回归分析指出BCL2L10低表达是胃癌的独立预后指标(P=4.883x10-8,HR=0.252)。受试者工作特征曲线(ROC curve)显示BCL2L10的面积为0.817(P=8.331×10-14),这说明BCL2L10低表达是胃癌的预后指标。为了加强和证实免疫组织化学结果的可靠性,我们通过实时定量PCR和免疫印迹检测10例新鲜胃正常组织、30例胃癌组织和6种胃癌细胞株中BCL2L10的表达水平,并且通过亚硫酸氢钠甲基化测序方法检测了胃正常组织和癌组织中BCL2L10基因启动子甲基化状态。实时定量PCR和免疫印迹的结果与免疫组织化学的结果一致,并经数据统计分析发现,基因启动子CpG岛高甲基化是胃癌组织中BCL2L10低表达的重要原因。
小结：人胃癌组织中BCL2L10的表达广泛低于正常人胃粘膜上皮；人胃癌细胞中BCL2L10基因启动子的高甲基化是其低表达的重要原因；BCL2L10的低表达提示胃癌患者的预后不良。
第二部分BCL2L10蛋白通过不同的通路调节胃癌细胞的凋亡和增殖
目的：探究BCL2L10蛋白调节癌细胞凋亡和增殖的作用及其相关机制。
方法和结果：我们通过流式细胞计数、荧光染色、裸鼠移植瘤模型和免疫印迹的方法研究了BCL2L10对胃癌细胞凋亡和增殖的调节作用。我们也应用相应的通路抑制剂来证实涉及凋亡或者增殖的主要通路。我们观察到胃癌细胞中上调的BCL2L10通过线粒体途径诱导凋亡,下调的BCL2L10通过PI3K/Akt信号通路促进增殖。
小结：上调的BCL2L10蛋白通过线粒体途径诱导胃癌细胞凋亡；下调的BCL2L10激活PI3K/Akt信号通路,并通过后者促进胃癌细胞快速通过细胞周期G1/S期完成促增殖作用。上调BCL2L10后的促凋亡作用和下调BCL2L10后的促增殖作用很大程度上提示了BCL2L10是一种抑癌蛋白。
Introduction
Though it is no longer the second most common cancer worldwide, gastric cancer is still the second most common cause of death from cancer. The geographical distribution of gastric cancer is characterized by wide international variations. High-risk areas (age-standardized rate in men> 20 per 100,000) include East Asia (China, Japan), Eastern Europe, and parts of Central and South America. It is a relatively uncommon neoplasm in North America, but gastric cancer is the third most lethal neoplasm overall in North America, contributing substantially to the burden of cancer deaths.
BCL2L10 gene is located on human chromesome 15q12.2 and expresses 204 amino acids protein, about 23kDa. BDL2L10 protein is strongly expressed in all normal plasma cells but found in only 18% of multiple myelomas. BCL2L10 immunostaining is also present in approximately half of diffuse large B-cell lymphoma specimens, whereas follicular lymphomas do not contain BCL2L10. In normal adult human stomach tissues, BCL2L10 mRNA is expressed at high levels (three-plus). However, no significant association with survival was observed in gastric cancer patients.
BCL2L10 is the last protein member found in Bcl-2 family. There are at least 20 Bcl-2-related proteins in the life or death decision of mammalian cells. Intriguingly, in addition to its central role in regulating apoptosis, the Bcl-2 family influences the cell cycle or more specifically, the transit between quiescence and proliferation, which, together with apoptosis regulation, makes its important role in oncogenesis. However, no such research on BCL2L10 regulation on gastric cancer cells.
Using three experimental models - retrospective clinical specimens of human gastric carcinoma, gastric cancer cell lines, and mouse xenograft model - our study investigated impact of BCL2L10 on gastric cancer cells.
PartⅠLoss of BCL2L10 Protein Expression as Prognostic Predictor for Poor Clinical Outcome in Gastric Carcinoma
Aims: BCL2L10 protein is an apoptosis-related member of the Bcl-2 protein family. The clinical significance of its expression in gastric carcinoma is poorly understood. Our aim was to investigate BCL2L10 expression and its clinical and prognostic significance in gastric carcinoma patients.
Methods and results: Immunohistochemistry revealed extensive loss of BCL2L10 expression in gastric cancer cells. The scaled BCL2L10 expression data was categorized into 3 groups (groups 0-2) to facilitate statistical analysis. We observed a significant correlation between the lower BCL2L10 expression group and shorter disease-free survival (P= 1.956×10-18). Multivariate regression analysis showed that loss of BCL2L10 protein expression (P= 4.883×10-8, HR= 0.252) is an independent prognostic predictor of gastric carcinoma. The receiver operator characteristic (ROC) curve showed that the area for BCL2L10 protein was 0.817 (P= 8.331×10-14), indicating that loss of BCL2L10 protein expression is an excellent prognostic predictor of gastric carcinoma. We re-investigated BCL2L10 expression by quantitative real time PCR, immunoblotting and examined methylation status of BCL2L10 gene promoter by bisulfite sequencing in fresh gastric normal and carcinoma tissues. We observed a significant correlation of lower BCL2L10 expression with hypermethylated CpG island of gene promoter in gastric carcinoma.
Conclusions: To our knowledge, it is the first report that loss of BCL2L10 protein expression predicts poor clinical outcome in gastric carcinoma. Hypermethylated gene promoter is responsible for loss of BCL2L10 in gastric carcinoma.
Part II BCL2L10 Protein Regulates Apoptosis/Proliferation through Differential Pathways in Gastric Cancer Cells
Aims: The reason and consequence of BCL2L10 downregulation in gastric carcinoma is poorly understood. Our aim was to investigate the function of BCL2L10 protein in gastric carcinoma.
Methods and results: We studied its apoptosis and proliferation regulation in gastric cancer cell lines by flow cytometry, fluorescence staining, murine xenograft model and immunoblotting. Pathway inhibitors were also applied to confirm the major pathway involved in apoptosis or proliferation regulation. We observed apoptosis induced by upregualted BCL2L10 through the mitochondrial pathway and proliferation accelerated by BCL2L10 siRNA via PI3K/Akt signaling pathway in gastric cancer cell lines.
Conclusions: The pro-apoptotic effect of BCL2L10 and growth promotion by BCL2L10 siRNA in gastric cancer cells might suggest a tumor suppressor of BCL2L10.
胃癌是全球最常见的恶性肿瘤之一,更是引起恶性肿瘤患者死亡的第二大原因。胃癌在全球地理上的分布有广泛的国家间差异。高危险地区(男性年龄标准化发生率>20每100000人)包括东亚地区(中国,日本)、东欧和中南美洲的部分地区。在北美洲,胃癌相对少见,但其在恶性肿瘤死亡率中也占有相当大的比例。
人类BCL2L10 (Bcl-B、Diva、Boo)基因位于人染色体15q12.2, mRNA全长887个核苷酸,cDNA全长615个核苷酸,表达含有204个氨基酸残基的蛋白,其分子量约为23kDa。BCL2L10表达有组织差异性,成人大脑、心脏、肾脏、脾脏、肝脏、结肠、肺脏、小肠、肌肉、胃、睾丸和胎盘中有表达,骨髓和所有的腺体有非常高的表达,然而,卵巢、子宫和前列腺组织中几乎没有BCL2L10的表达。同样,在不同癌组织中,其表达也存在着差异。滤泡性淋巴瘤不表达BCL2L10蛋白,18%的多发性骨髓瘤中表达BCL2L10,弥漫性大B细胞淋巴瘤则有近半数表达BCL2L10。而乳腺癌、前列腺癌、结直肠癌和小细胞肺癌中BCL2L10高表达。研究表明,BCL2L10表达与一些肿瘤不良预后的指标有相关性,如与乳腺癌的肿瘤高级别,与结直肠癌的微卫星稳定性和结直肠癌的解剖位置,与前列腺癌患者更高的死亡率,与小细胞肺癌更短的生存率之间均存在相关性。
成人正常胃组织中,BCL2L10 mRNA表达水平非常高。也有研究报道胃癌组织中BCL2L10蛋白高表达,而其高表达与癌组织高分化有关,这样的结论显然是相互矛盾的。我们没有检索到BCL2L10与胃癌患者预后有意义联系的报道。
BCL2L10是Bcl-2家族最近被发现的蛋白成员。Bcl-2家族至少有20种可以在哺乳动物细胞发挥促凋亡或者抗凋亡作用的蛋白。有趣的是,除了调节凋亡的中心作用,Bcl-2家族的一些蛋白也影响细胞周期,与凋亡调节功能一起,构成了它们在肿瘤发生中的重要作用。关于BCL2L10调节胃癌细胞生物学行为,国内外也未见相关报道。
本课题试图从人胃癌组织、人胃癌细胞株和裸鼠移植瘤模型三方面对BCL2L10与胃癌患者预后、与胃癌细胞生物学行为的相关关系及其分子机制进行研究。本课题的研究不仅对了解肿瘤的生物学特性具有明显的理论意义,而且也具有显著的临床价值和社会效益。
第一部分BCL2L10蛋白的低表达提示胃癌患者的预后不良
目的：探究BCL2L10在胃癌细胞中的表达水平,以及它对胃癌患者临床和预后的意义。
方法和结果：我们应用免疫组织化学方法检测了213例胃癌组织BCL2L10的蛋白表达。免疫组织化学结果显示了胃癌细胞中BCL2L10普遍低表达。BCL2L10表达等级数据分成3组(组0到组2),以利于统计分析。完成数据统计分析后发现,BCL2L10低表达与较短的肿瘤相关生存率有显著的相关性(x2=81.55,P=1.956×10-18)。多因素回归分析指出BCL2L10低表达是胃癌的独立预后指标(P=4.883x10-8,HR=0.252)。受试者工作特征曲线(ROC curve)显示BCL2L10的面积为0.817(P=8.331×10-14),这说明BCL2L10低表达是胃癌的预后指标。为了加强和证实免疫组织化学结果的可靠性,我们通过实时定量PCR和免疫印迹检测10例新鲜胃正常组织、30例胃癌组织和6种胃癌细胞株中BCL2L10的表达水平,并且通过亚硫酸氢钠甲基化测序方法检测了胃正常组织和癌组织中BCL2L10基因启动子甲基化状态。实时定量PCR和免疫印迹的结果与免疫组织化学的结果一致,并经数据统计分析发现,基因启动子CpG岛高甲基化是胃癌组织中BCL2L10低表达的重要原因。
小结：人胃癌组织中BCL2L10的表达广泛低于正常人胃粘膜上皮；人胃癌细胞中BCL2L10基因启动子的高甲基化是其低表达的重要原因；BCL2L10的低表达提示胃癌患者的预后不良。
第二部分BCL2L10蛋白通过不同的通路调节胃癌细胞的凋亡和增殖
目的：探究BCL2L10蛋白调节癌细胞凋亡和增殖的作用及其相关机制。
方法和结果：我们通过流式细胞计数、荧光染色、裸鼠移植瘤模型和免疫印迹的方法研究了BCL2L10对胃癌细胞凋亡和增殖的调节作用。我们也应用相应的通路抑制剂来证实涉及凋亡或者增殖的主要通路。我们观察到胃癌细胞中上调的BCL2L10通过线粒体途径诱导凋亡,下调的BCL2L10通过PI3K/Akt信号通路促进增殖。
小结：上调的BCL2L10蛋白通过线粒体途径诱导胃癌细胞凋亡；下调的BCL2L10激活PI3K/Akt信号通路,并通过后者促进胃癌细胞快速通过细胞周期G1/S期完成促增殖作用。上调BCL2L10后的促凋亡作用和下调BCL2L10后的促增殖作用很大程度上提示了BCL2L10是一种抑癌蛋白。
Introduction
Though it is no longer the second most common cancer worldwide, gastric cancer is still the second most common cause of death from cancer. The geographical distribution of gastric cancer is characterized by wide international variations. High-risk areas (age-standardized rate in men> 20 per 100,000) include East Asia (China, Japan), Eastern Europe, and parts of Central and South America. It is a relatively uncommon neoplasm in North America, but gastric cancer is the third most lethal neoplasm overall in North America, contributing substantially to the burden of cancer deaths.
BCL2L10 gene is located on human chromesome 15q12.2 and expresses 204 amino acids protein, about 23kDa. BDL2L10 protein is strongly expressed in all normal plasma cells but found in only 18% of multiple myelomas. BCL2L10 immunostaining is also present in approximately half of diffuse large B-cell lymphoma specimens, whereas follicular lymphomas do not contain BCL2L10. In normal adult human stomach tissues, BCL2L10 mRNA is expressed at high levels (three-plus). However, no significant association with survival was observed in gastric cancer patients.
BCL2L10 is the last protein member found in Bcl-2 family. There are at least 20 Bcl-2-related proteins in the life or death decision of mammalian cells. Intriguingly, in addition to its central role in regulating apoptosis, the Bcl-2 family influences the cell cycle or more specifically, the transit between quiescence and proliferation, which, together with apoptosis regulation, makes its important role in oncogenesis. However, no such research on BCL2L10 regulation on gastric cancer cells.
Using three experimental models - retrospective clinical specimens of human gastric carcinoma, gastric cancer cell lines, and mouse xenograft model - our study investigated impact of BCL2L10 on gastric cancer cells.
PartⅠLoss of BCL2L10 Protein Expression as Prognostic Predictor for Poor Clinical Outcome in Gastric Carcinoma
Aims: BCL2L10 protein is an apoptosis-related member of the Bcl-2 protein family. The clinical significance of its expression in gastric carcinoma is poorly understood. Our aim was to investigate BCL2L10 expression and its clinical and prognostic significance in gastric carcinoma patients.
Methods and results: Immunohistochemistry revealed extensive loss of BCL2L10 expression in gastric cancer cells. The scaled BCL2L10 expression data was categorized into 3 groups (groups 0-2) to facilitate statistical analysis. We observed a significant correlation between the lower BCL2L10 expression group and shorter disease-free survival (P= 1.956×10-18). Multivariate regression analysis showed that loss of BCL2L10 protein expression (P= 4.883×10-8, HR= 0.252) is an independent prognostic predictor of gastric carcinoma. The receiver operator characteristic (ROC) curve showed that the area for BCL2L10 protein was 0.817 (P= 8.331×10-14), indicating that loss of BCL2L10 protein expression is an excellent prognostic predictor of gastric carcinoma. We re-investigated BCL2L10 expression by quantitative real time PCR, immunoblotting and examined methylation status of BCL2L10 gene promoter by bisulfite sequencing in fresh gastric normal and carcinoma tissues. We observed a significant correlation of lower BCL2L10 expression with hypermethylated CpG island of gene promoter in gastric carcinoma.
Conclusions: To our knowledge, it is the first report that loss of BCL2L10 protein expression predicts poor clinical outcome in gastric carcinoma. Hypermethylated gene promoter is responsible for loss of BCL2L10 in gastric carcinoma.
Part II BCL2L10 Protein Regulates Apoptosis/Proliferation through Differential Pathways in Gastric Cancer Cells
Aims: The reason and consequence of BCL2L10 downregulation in gastric carcinoma is poorly understood. Our aim was to investigate the function of BCL2L10 protein in gastric carcinoma.
Methods and results: We studied its apoptosis and proliferation regulation in gastric cancer cell lines by flow cytometry, fluorescence staining, murine xenograft model and immunoblotting. Pathway inhibitors were also applied to confirm the major pathway involved in apoptosis or proliferation regulation. We observed apoptosis induced by upregualted BCL2L10 through the mitochondrial pathway and proliferation accelerated by BCL2L10 siRNA via PI3K/Akt signaling pathway in gastric cancer cell lines.
Conclusions: The pro-apoptotic effect of BCL2L10 and growth promotion by BCL2L10 siRNA in gastric cancer cells might suggest a tumor suppressor of BCL2L10.
引文
[1]Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics,2002. CA Cancer J. Clin.2005; 55(2):74-108.
[2]Dicken BJ, Bigam DL, Cass C, et al. Gastric adenocarcinoma:review and considerations for future directions. Ann. Surg.2005; 241(1):27-39.
[3]Luciano F, Krajewska M, Ortiz-Rubio P, et al. Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma. Blood 2007; 109(9):3849-55.
[4]Kim JH, Yoon S, Won M, et al. HIP1R interacts with a member of Bcl-2 family, BCL2L10, and induces BAK-dependent cell death. Cell. Physiol. Biochem.2009; 23(1-3):43-52.
[5]Ke N, Godzik A, Reed JC. Bcl-B, a novel Bcl-2 family member that differentially binds and regulates Bax and Bak. J. Biol. Chem.2001; 276(16):12481-4.
[6]Zhang H, Holzgreve W, De Geyter C. Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway. Hum. Mol. Genet.2001; 10(21):2329-39.
[7]Krajewska M, Kitada S, Winter JN, et al. Bcl-B expression in human epithelial and nonepithelial malignancies. Clin. Cancer Res.2008; 14(10): 3011-21.
[8]Watanabe H, Jass JR, Sobin LH (1990). WHO:Histological Typing of Oesophageal and Gastric Tumours. Springer-Verlag:Berlin.
[9]Hamilton S.R., Aaltonen L.A. (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. IARC Press:Lyon 2000.
[10]AJCC Cancer Staging Manual (1997). Fifth edition. Lippincott: Philadelphia.
[11]Anon. (1997). UICC:TNM classification of malignant tumors. Wiley Press: New York.
[12]Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma - 2nd English Edition -. Gastric Cancer 1998; 1(1):10-24.
[13]Ikeguchi M, Saito H, Katano K, et al. Expression of p53 and p21 are independent prognostic factors in patients with serosal invasion by gastric carcinoma. Dig. Dis. Sci.1998; 43(5):964-70.
[14]Ogawa M, Maeda K, Onoda N, et al. Loss of p21WAF1/CIP1 expression correlates with disease progression in gastric carcinoma. Br. J. Cancer 1997; 75(11):1617-20.
[15]Cordon-Cardo C, Koff A, Drobnjak M, et al. Distinct altered patterns of p27KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. J. Natl. Cancer Inst.1998; 90(17):1284-91.
[16]Liu XP, Oga A, Suehiro Y, et al. Inverse relationship between matrilysin expression and proliferative activity of cells in advanced gastric carcinoma. Hum. Pathol.2002; 33(7):741-7.
[17]Hosmer DW, Lemeshow S:Applied Logistic Regression,2nd edition. New York:Wiley; 2000.
[18]Tamura G. Promoter methylation status of tumor suppressor and tumor-related genes in neoplastic and non-neoplastic gastric epithelia. Histol. Histopathol.2004; 19(1):221-8.
[19]Sato F, Meltzer SJ. CpG island hypermethylation in progression of esophageal and gastric cancer. Cancer 2006; 106(3):483-93.
[20]Hamilton JP, Meltzer SJ. A review of the genomics of gastric cancer. Clin. Gastroenterol. Hepatol.2006; 4(4):416-25.
[21]Johnson SM, Evers BM. Translational research in gastric malignancy. Surg. Oncol. Clin. N. Am.2008; 17(2):323-40, viii.
[22]Song Q, Kuang Y, Dixit VM, et al. Boo, a novel negative regulator of cell death, interacts with Apaf-1. EMBO J.1999; 18(1):167-78.
[23]Kang Y, Lee DC, Han J, et al. NM23-H2 involves in negative regulation of Diva and Bcl2L10 in apoptosis signaling. Biochem. Biophys. Res. Commun.2007; 359(1):76-82.
[24]Zhu W, Cowie A, Wasfy GW, et al. Bcl-2 mutants with restricted subcellular location reveal spatially distinct pathways for apoptosis in different cell types. EMBO J.1996; 15(16):4130-41.
[25]Nechushtan A, Smith CL, Hsu YT, et al. Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J.1999; 18(9):2330-41.
[26]Suzuki M, Youle RJ, Tjandra N. Structure of Bax: coregulation of dimer formation and intracellular localization. Cell 2000; 103(4):645-54.
[27]Upreti M, Lyle CS, Skaug B, et al. Vinblastine-induced apoptosis is mediated by discrete alterations in subcellular location, oligomeric structure, and activation status of specific Bcl-2 family members. J. Biol. Chem.2006; 281(23):15941-50.
[28]Zhang L, Xing D, Chen M. Bim(L) displacing Bcl-x(L) promotes Bax translocation during TNFalpha-induced apoptosis. Apoptosis 2008; 13(7): 950-8.
[29]Aslan JE, Thomas G. Death by Committee:Organellar Trafficking and Communication in Apoptosis. Traffic 2009; 10(10):1390-404.
[30]Zhai D, Ke N, Zhang H, et al. Characterization of the anti-apoptotic mechanism of Bcl-B. Biochem. J.2003; 376(Pt 1):229-36.
[31]Hsu YT, Youle RJ. Nonionic detergents induce dimerization among members of the Bcl-2 family. J Biol Chem.1997; 272(21):13829-34.
[32]Wolter KG, Hsu YT, Smith CL, et al. Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol.1997; 139(5):1281-92.
[33]Green DR, Reed JC. Mitochondria and apoptosis. Science.1998; 281(5381):1309-12.
[34]Mikata R, Yokosuka O, Fukai K, et al. Analysis of genes upregulated by the demethylating agent 5-aza-2'-deoxycytidine in gastric cancer cell lines. Int. J. Cancer 2006; 119(7):1616-22.
[35]Tanaka S, Louie DC, Kant JA, et al. Frequent incidence of somatic mutations in translocated BCL2 oncogenes of non-Hodgkin's lymphomas. Blood 1992; 79(1):229-37.
[36]Reed JC. Bcl-2-family proteins and hematologic malignancies:history and future prospects. Blood 2008; 111(7):3322-30.
[37]Kutuk O, Letai A. Regulation of Bcl-2 family proteins by posttranslational modifications. Curr Mol. Med.2008; 8(2); 102-18.
[38]Lauren T. The two histologic main types of gastric carcinoma. Acta. Pathol. Microbiol. Scand.1965; 64:34.
[39]Soetikno R, Kaltenbach T, Yeh R, et al. Endoscopic mucosal resection for early cancers of the upper gastrointestinal tract. J. Clin. Oncol.2005; 23(20):4490-8.
[40]Kreisberg JI, Malik SN, Prihoda TJ, et al. Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res.2004; 64(15):5232-6.
[41]Wang Z, Zhang B, Jiang L, et al. RACK1, an excellent predictor for poor clinical outcome in oral squamous carcinoma, similar to Ki67. Eur. J. Cancer2009; 45(3):490-6.
[1]Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics,2002. CA Cancer J. Clin.2005; 55(2); 74-108.
[2]JingDa Xu, Tomoko Furuya, XiXi Cao et al. Loss of BCL2L10 protein expression as prognostic predictor for poor clinical outcome in gastric carcinoma. Histopathology (accepted).
[3]Mikata R, Yokosuka O, Fukai K, et al. Analysis of genes upregulated by the demethylating agent 5-aza-2'-deoxycytidine in gastric cancer cell lines. Int J Cancer 2006; 119(7):1616-22.
[4]Inohara N, Gourley TS, Carrio R, et al. Diva, a Bcl-2 homologue that binds directly to Apaf-1 and induces BH3-independent cell.death. J Biol Chem.1998; 273(49):32479-86.
[5]Luciano F, Krajewska M, Ortiz-Rubio P, et al. Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma. Blood 2007; 109(9):3849-55.
[6]Kang Y, Lee DC, Han J, et al. NM23-H2 involves in negative regulation of Diva and Bcl2L10 in apoptosis signaling. Biochem Biophys Res Commun. 2007; 359(1):76-82.
[7]Kim JH, Yoon S, Won M, et al. HIP1R interacts with a member of Bcl-2 family, BCL2L10, and induces BAK-dependent cell death. Cell Physiol Biochem.2009; 23(1-3):43-52.
[8]Song Q, Kuang Y, Dixit VM, et al. Boo, a novel negative regulator of cell death, interacts with Apaf-1. EMBO J.1999; 18(1):167-78.
[9]Ke N, Godzik A, Reed JC. Bcl-B, a novel Bcl-2 family member that differentially binds and regulates Bax and Bak. J. Biol. Chem.2001; 276(16):12481-4.
[10]Naumann U, Weit S, Wischhusen J, et al. Diva/Boo is a negative regulator of cell death in human glioma cells. FEBS Lett.2001; 505(1): 23-6.
[11]Zhang H, Holzgreve W, De Geyter C. Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway. Hum. Mol. Genet.2001; 10(21):2329-39.
[12]Zhai D, Ke N, Zhang H, et al. Characterization of the anti-apoptotic mechanism of Bcl-B. Biochem. J.2003; 376(Pt 1):229-36.
[13]Beverly LJ, Varmus HE. MYC-induced myeloid leukemogenesis is accelerated by all six members of the antiapoptotic BCL family. Oncogene.2009; 28(9):1274-9.
[14]Guillemin Y, Lalle P, Gillet G, et al. Oocytes and early embryos selectively express the survival factor BCL2L10. J Mol Med.2009; 87(9):923-40.
[15]Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science.1998; 281(5381):1322-6.
[16]Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev.1999; 13(15):1899-911.
[17]Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer.2002; 2(9):647-56.
[18]Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene.2003; 22(53):8590-607.
[19]Leung WK, Yu J, To KF, et al. Apoptosis and proliferation in Helicobacter pylori-associated gastric intestinal metaplasia. Aliment Pharmacol Ther. 2001; 15(9):1467-72.
[20]Wambura C, Aoyama N, Shirasaka D, et al. Effect of Helicobacter pylori-induced cyclooxygenase-2 on gastric epithelial cell kinetics: implication for gastric carcinogenesis. Helicobacter.2002; 7(2):129-38.
[21]Wambura C, Aoyama N, Shirasaka D, et al. Cell kinetic balance in gastric mucosa with intestinal metaplasia after Helicobacter pylori eradication: 2-year follow-up study. Dig Liver Dis.2004; 36(3):178-86.
[22]Tang C, Liu C, Zhou X, et al. Enhanced inhibitive effects of combination of rofecoxib and octreotide on the growth of human gastric cancer. Int J Cancer.2004; 112(3):470-4.
[23]Liu X, Kim CN, Yang J, et al. Induction of apoptotic program in cell-free extracts:requirement for dATP and cytochrome c. Cell 1996; 86(1): 147-57.
[24]Tournier C, Hess P, Yang DD, et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science.2000; 288(5467):870-4.
[25]Luo JL, Kamata H, Karin M. IKK/NF-kappaB signaling:balancing life and death-a new approach to cancer therapy. J Clin Invest.2005; 115(10): 2625-32.
[26]Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell2003; 114(2):181-90.
[27]Luo JL, Maeda S, Hsu LC, et al. Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell.2004; 6(3):297-305.
[28]O'Reilly LA, Huang DC, Strasser A. The cell death inhibitor Bcl-2 and its homologues influence control of cell cycle entry. EMBO J.1996 Dec 16; 15(24):6979-90.
[29]Crescenzi E, Palumbo G, Brady HJ. Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem J.2003 Oct 15;375(Pt 2):263-74.
[30]Linette GP, Li Y, Roth K, Korsmeyer SJ. Cross talk between cell death and cell cycle progression:BCL-2 regulates NFAT-mediated activation. Proc Natl Acad Sci U S A.1996 Sep 3;93(18):9545-52.
[31]Chattopadhyay A, Chiang CW, Yang E. BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest. Oncogene.2001 Jul 27;20(33):4507-18.
[32]Brady HJ, Gil-Gomez G, Kirberg J, et al. Bax alpha perturbs T cell development and affects cell cycle entry of T cells. EMBO J.1996 Dec 16; 15(24):6991-7001.
[33]Han Z, Wu K, Shen H, et al. Akt1/protein kinase B alpha is involved in gastric cancer progression and cell proliferation. Dig Dis Sci.2008; 53(7): 1801-10.
[34]Datta SR, Brunet A, Greenberg ME. Cellular survival:a play in three Akts. Genes Dev.1999; 13(22):2905-27.
[35]Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol. 2004; 15(2):177-82.
[36]Chang F, Lee JT, Navolanic PM, et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation:a target for cancer chemotherapy. Leukemia.2003; 17(3):590-603.
[37]Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle.2003; 2(4):339-45.
[38]Manning BD, Cantley LC. Rheb fills a GAP between TSC and TOR. Trends Biochem Sci.2003; 28(11):573-6.
[39]Martin P, Pognonec P. ERK and cell death:cadmium toxicity, sustained ERK activation and cell death. FEBS J.2010; 277(1):39-46.
[40]Chen CY, Gherzi R, Andersen JS, et al. Nucleolin and YB-1 are required for JNK-mediated interleukin-2 mRNA stabilization during T-cell activation. Genes Dev.2000; 14(10):1236-48.
[41]Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell. 2000; 103(2):239-52.
[42]Ono K, Han J. The p38 signal transduction pathway: activation and function. Cell Signal.2000; 12(1):1-13.
[43]Drudi Metalli V, Mancino MG, Mancino A, et al. Bile salts regulate proliferation and apoptosis of liver cells by modulating the IGF1 system. Dig Liver Dis.2007; 39(7):654-62.
[44]Coen L, Le Blay K, Rowe I, et al. Caspase-9 regulates apoptosis/proliferation balance during metamorphic brain remodeling in Xenopus. Proc Natl Acad Sci U S A.2007; 104(20):8502-7.
[45]Li RJ, Qiu SD, Wang HX, et al. Androgen receptor: a new player associated with apoptosis and proliferation of pancreatic beta-cell in type 1 diabetes mellitus. Apoptosis.2008; 13(8):959-71.
[46]McMurtry MS, Bonnet S, Wu X, et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res.2004; 95(8):830-40.
[47]Efrati S, Berman S, Goldfinger N, et al. Enhanced angiotensin II production by renal mesangium is responsible for apoptosis/proliferation of endothelial and epithelial cells in a model of malignant hypertension. J Hypertens.2007; 25(5):1041-52.
[48]Arici M, Chana R, Lewington A, et al. Stimulation of proximal tubular cell apoptosis by albumin-bound fatty acids mediated by peroxisome proliferator activated receptor-gamma. J Am Soc Nephrol.2003; 14(1): 17-27.
[49]Parker JE, Mufti GJ, Rasool F, et al. The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Slood. 2000; 96(12):3932-8.
[50]Schmitz KJ, Lang H, Wohlschlaeger J, et al. Elevated expression of cyclooxygenase-2 is a negative prognostic factor for overall survival in intrahepatic cholangiocarcinoma. Virchows Arch.2007; 450(2):135-41.
[51]Sinicrope FA, Rego RL, Garrity-Park MM, et al. Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability. Int J Cancer.2007; 120(6):1232-8.
[1]Ellis SM, Nabeshima K, Biswas C. Monoclonal antibody preparation and purification of a tumor cell collagenase-stimulatory factor. Cancer Res. 1989 Jun 15;49(12):3385-91.
[2]Kataoka H, DeCastro R, Zucker S, et al. Tumor cell-derived collagenase-stimulatory factor increases expression of interstitial collagenase, stromelysin, and 72-kDa gelatinase. Cancer Res.1993 Jul 1;53(13):3154-8.
[3]Sameshima T, Nabeshima K, Toole BP, et al. Glioma cell extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147) stimulates production of membrane-type matrix metalloproteinases and activated gelatinase A in co-cultures with brain-derived fibroblasts. Cancer Lett. 2000 Sep 1;157(2):177-84.
[4]Li R, Huang L, Guo H, et al. Basigin (murine EMMPRIN) stimulates matrix metalloproteinase production by fibroblasts. J Cell Physiol.2001 Mar; 186(3):371-9.
[5]Suzuki S, Sato M, Senoo H, et al. Direct cell-cell interaction enhances pro-MMP-2 production and activation in co-culture of laryngeal cancer cells and fibroblasts:involvement of EMMPRIN and MT1-MMP. Exp Cell Res.2004 Feb 15;293(2):259-66.
[6]Guo H, Zucker S, Gordon MK, et al. Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cells. J Biol Chem.1997 Jan 3;272(1):24-7.
[7]Sun J, Hemler ME. Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions. Cancer Res.2001 Mar 1;61(5):2276-81.
[8]Cao XX, Xu JD, Xu JW, et al. RACK1 promotes breast carcinoma proliferation and invasion/metastasis in vitro and in vivo. Breast Cancer Res Treat.2009 Nov 28. [Epub ahead of print]
[9]Li QQ, Wang WJ, Xu JD, et al. Up-regulation of CD147 and matrix metalloproteinase-2,-9 induced by P-glycoprotein substrates in multidrug resistant breast cancer cells. Cancer Sci.2007 Nov;98(11):1767-74.
[10]Li QQ, Wang WJ, Xu JD, et al. Involvement of CD147 in regulation of multidrug resistance to P-gp substrate drugs and in vitro invasion in breast cancer cells. Cancer Sci.2007 Jul;98(7):1064-9.
[1]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.
[2]Danial NN, Korsmeyer SJ. Cell death:critical control points. Cell.2004 Jan 23;116(2):205-19.
[3]Strasser A. The role of BH3-only proteins in the immune system. Nat Rev Immunol.2005 Mar;5(3):189-200.
[4]Veis DJ, Sorenson CM, Shutter JR, et al. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell.1993 Oct 22;75(2):229-40.
[5]Knudson CM, Tung KS, Tourtellotte WG, et al. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science.1995 Oct 6;270(5233):96-9.
[6]Lindsten T, Ross AJ, King A, et al. The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell.2000 Dec;6(6):1389-99.
[7]Zong WX, Lindsten T, Ross AJ, et al. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev.2001 Jun 15;15(12):1481-6.
[8]Cheng EH, Wei MC, Weiler S, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell.2001 Sep;8(3):705-11.
[9]Yin XM, Wang K, Gross A, et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature.1999 Aug 26,400(6747): 886-91.
[10]Gross A, Yin XM, Wang K, et al. Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem.1999 Jan 8;274(2):1156-63.
[11]Puthalakath H, O'Reilly LA, Gunn P, et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell.2007 Jun 29; 129(7):1337-49.
[12]Tsujimoto Y, Finger LR, Yunis J, et al. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science.1984 Nov 30;226(4678):1097-9.
[13]Bakhshi A, Jensen JP, Goldman P, et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell.1985 Jul;41 (3):899-906.
[14]Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell.1986 Oct 10;47(1):19-28.
[15]Yunis JJ, Frizzera G, Oken MM, et al. Multiple recurrent genomic defects in follicular lymphoma. A possible model for cancer. N Engl J Med.1987 Jan 8;316(2):79-84.
[16]Adachi M, Tefferi A, Greipp PR, et al. Preferential linkage of bcl-2 to immunoglobulin light chain gene in chronic lymphocytic leukemia. J Exp Med.1990 Feb 1;171(2):559-64.
[17]Tashiro S, Takechi M, Asou H, et al. Cytogenetic 2; 18 and 18; 22 translocation in chronic lymphocytic leukemia with juxtaposition of bcl-2 and immunoglobulin light chain genes. Oncogene.1992 Mar;7(3):573-7.
[18]Grumont RJ, Rourke IJ, Gerondakis S. Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev.1999 Feb 15;13(4):400-11.
[19]Cory S. Regulation of lymphocyte survival by the bcl-2 gene family. Annu Rev Immunol.1995;13:513-43.
[20]McDonnell TJ, Korsmeyer SJ. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature.1991 Jan 17;349(6306):254-6.
[21]Strasser A, Harris AW, Cory S. E mu-bcl-2 transgene facilitates spontaneous transformation of early pre-B and immunoglobulin-secreting cells but not T cells. Oncogene.1993 Jan;8(1):1-9.
[22]Linette GP, Hess JL, Sentman CL, et al. Peripheral T-cell lymphoma in lckpr-bcl-2 transgenic mice. Blood.1995 Aug 15;86(4):1255-60.
[23]Liu Y, Hernandez AM, Shibata D, BCL2 translocation frequency rises with age in humans. Proc Natl Acad Sci U SA.1994 Sep 13;91(19):8910-4.
[24]Ji W, Qu GZ, Ye P, et al. Frequent detection of bcl-2/JH translocations in human blood and organ samples by a quantitative polymerase chain reaction assay. Cancer Res.1995 Jul 1;55(13):2876-82.
[25]Limpens J, Stad R, Vos C, et al. Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood.1995 May 1;85(9): 2528-36.
[26]Zelenetz AD, Chen TT, Levy R. Clonal expansion in follicular lymphoma occurs subsequent to antigenic selection. J Exp Med.1992 Oct 1;176(4): 1137-48.
[27]Egle A, Harris AW, Bath ML, et al. VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood. 2004 Mar 15; 103(6):2276-83.
[28]Yano T, Jaffe ES, Longo DL, et al. MYC rearrangements in histologically progressed follicular lymphomas. Blood.1992 Aug 1;80(3):758-67.
[29]Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988 Sep 29;335(6189):440-2.
[30]Strasser A, Harris AW, Bath ML, et al. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature.1990 Nov 22;348(6299):331-3.
[31]Strasser A, Elefanty AG, Harris AW, et al. Progenitor tumours from Emu-bcl-2-myc transgenic mice have lymphomyeloid differentiation potential and reveal developmental differences in cell survival. EMBO J. 1996 Aug 1;15(15):3823-34.
[32]Jager R, Herzer U, Schenkel J, et al. Overexpression of Bcl-2 inhibits alveolar cell apoptosis during involution and accelerates c-myc-induced tumorigenesis of the mammary gland in transgenic mice. Oncogene. 1997 Oct 9; 15(15):1787-95.
[33]Naik P, Karrim J, Hanahan D. The rise and fall of apoptosis during multistage tumorigenesis:down-modulation contributes to tumor progression from angiogenic progenitors. Genes Dev.1996 Sep 1;10(17): 2105-16.
[34]Pelengaris S, Khan M, Evan GI. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell.2002 May 3;109(3):321-34.
[35]Askew DS, Ashmun RA, Simmons BC, et al. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene.1991 Oct;6(10):1915-22.
[36]Bissonnette RP, Echeverri F, Mahboubi A, et al. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature.1992 Oct 8;359(6395): 552-4.
[37]Evan GI, Wyllie AH, Gilbert CS, et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell.1992 Apr 3;69(1):119-28.
[38]Evan G, Littlewood T. A matter of life and cell death. Science.1998 Aug 28;281(5381):1317-22.
[39]Cory S, Vaux DL, Strasser A, et al. Insights from Bcl-2 and Myc: malignancy involves abrogation of apoptosis as well as sustained proliferation. Cancer Res.1999 Apr 1;59(7 Suppl):1685s-1692s.
[40]Kanazawa S, Soucek L, Evan G, et al. c-Myc recruits P-TEFb for transcription, cellular proliferation and apoptosis. Oncogene.2003 Aug 28;22(36):5707-11.
[41]Green DR, Evan GI. A matter of life and death. Cancer Cell.2002 Feb;1(1):19-30.
[42]Hanahan D, Weinberg RA. The hallmarks of cancer. Cell.2000 Jan 7;100(1):57-70.
[43]Eischen CM, Weber JD, Roussel MF, et al. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev.1999 Oct 15; 13(20):2658-69.
[44]Eischen CM, Roussel MF, Korsmeyer SJ, et al. Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. Mol Cell Biol.2001 Nov;21(22): 7653-62.
[45]Lee JT, Innes DJ Jr, Williams ME. Sequential bcl-2 and c-myc oncogene rearrangements associated with the clinical transformation of non-Hodgkin's lymphoma. J Clin Invest.1989 Nov;84(5):1454-9.
[46]Sander CA, Yano T, Clark HM, et al. p53 mutation is associated with progression in follicular lymphomas. Blood.1993 Oct 1;82(7):1994-2004.
[47]Lossos IS, Levy R. Higher-grade transformation of follicle center lymphoma is associated with somatic mutation of the 5' noncoding regulatory region of the BCL-6 gene. Blood.2000 Jul 15;96(2):635-9.
[48]Kogan SC, Brown DE, Shultz DB, et al. BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor alpha chimeric protein (PMLRARalpha) to block neutrophil differentiation and initiate acute leukemia. J Exp Med.2001 Feb 19;193(4):531-43.
[49]Traver D, Akashi K, Weissman IL, et al. Mice defective in two apoptosis pathways in the myeloid lineage develop acute myeloblastic leukemia. Immunity.1998 Jul;9(1):47-57.
[50]Gibbons DL, MacDonald D, McCarthy KP, et al. An E mu-BCL-2 transgene facilitates leukaemogenesis by ionizing radiation. Oncogene. 1999 Jul 1;18(26):3870-7.
[51]Bouillet P, Metcalf D, Huang DC, et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science.1999 Nov 26;286(5445):1735-8.
[52]Bouillet P, Purton JF, Godfrey DI, et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature.2002 Feb 21;415(6874):922-6.
[53]Bouillet P, Zhang LC, Huang DC, et al. Gene structure alternative splicing, and chromosomal localization of pro-apoptotic Bcl-2 relative Bim. Mamm Genome.2001 Feb; 12(2):163-8.
[54]Zinkel SS, Ong CC, Ferguson DO, et al. Proapoptotic BID is required for myeloid homeostasis and tumor suppression. Genes Dev.2003 Jan 15; 17(2):229-39.
[55]Puthalakath H, Villunger A, O'Reilly LA, et al. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin Ⅴ actin motor complex, activated by anoikis. Science.2001 Sep 7;293(5536):1829-32.
[56]Oda E, Ohki R, Murasawa H, et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 2000 May 12,288(5468):1053-8.
[57]Han J, Flemington C, Houghton AB, et al. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc Natl Acad Sci U S A.2001 Sep 25;98(20): 11318-23.
[58]Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell.2001 Mar;7(3):683-94.
[59]Yu J, Zhang L, Hwang PM, et al. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell.2001 Mar;7(3):673-82.
[60]Yu J, Wang Z, Kinzler KW, et al. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci U S A.2003 Feb 18; 100(4):1931-6.
[61]Shibue T, Takeda K, Oda E, et al. Integral role of Noxa in p53-mediated apoptotic response. Genes Dev.2003 Sep 15;17(18):2233-8.
[62]Villunger A, Michalak EM, Coultas L, et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science.2003 Nov 7;302(5647):1036-8.
[63]Knudson CM, Johnson GM, Lin Y, et al. Bax accelerates tumorigenesis in p53-deficient mice. Cancer Res.2001 Jan 15;61(2):659-65.
[64]McCurrach ME, Connor TM, Knudson CM, et al. bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. Proc Natl Acad Sci U S A.1997 Mar 18;94(6): 2345-9.
[65]Villunger A, Michalak EM, Coultas L, et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science.2003 Nov 7;302(5647):1036-8.
[66]Shibata MA, Liu ML, Knudson MC, et al. Haploid loss of bax leads to accelerated mammary tumor development in C3(1)/SV40-TAg transgenic mice:reduction in protective apoptotic response at the preneoplastic stage. EMBO J.1999 May 17;18(10):2692-701.
[67]Eischen CM, Roussel MF, Korsmeyer SJ, et al. Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. Mol Cell Biol.2001 Nov;21(22): 7653-62.
[68]Rampino N, Yamamoto H, lonov Y, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science.1997 Feb 14;275(5302):967-9.
[69]Meijerink JP, Mensink EJ, Wang K, et al. Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood.1998 Apr 15;91(8): 2991-7.
[70]Kondo S, Shinomura Y, Miyazaki Y, et al. Mutations of the bak gene in human gastric and colorectal cancers. Cancer Res.2000 Aug 15;60(16): 4328-30.
[71]Zhang L, Yu J, Park BH, et al. Role of BAX in the apoptotic response to anticancer agents. Science.2000 Nov 3;290(5493):989-92.
[72]O'Reilly LA, Huang DC, Strasser A. The cell death inhibitor Bcl-2 and its homologues influence control of cell cycle entry. EMBO J.1996 Dec 16; 15(24):6979-90.
[73]Borner C. Diminished cell proliferation associated with the death-protective activity of Bcl-2. J Biol Chem.1996 May 31;271(22): 12695-8.
[74]Linette GP, Li Y, Roth K, Korsmeyer SJ. Cross talk between cell death and cell cycle progression:BCL-2 regulates NFAT-mediated activation. Proc Natl Acad Sci U S A.1996 Sep 3;93(18):9545-52.
[75]Simpson NH, Singh RP, Emery AN, et al. Bcl-2 over-expression reduces growth rate and prolongs G1 phase in continuous chemostat cultures of hybridoma cells. Biotechnol Bioeng.1999 Jul 20;64(2):174-86.
[76]Marvel J, Perkins GR, Lopez Rivas A, et al. Growth factor starvation of bcl-2 overexpressing murine bone marrow cells induced refractoriness to IL-3 stimulation of proliferation. Oncogene.1994 Apr;9(4):1117-22.
[77]Mazel S, Burtrum D, Petrie HT. Regulation of cell division cycle progression by bcl-2 expression:a potential mechanism for inhibition of programmed cell death. J Exp Med.1996 May 1;183(5):2219-26.
[78]Crescenzi E, Palumbo G, Brady HJ. Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem J.2003 Oct 15;375(Pt 2):263-74.
[79]O'Reilly LA, Harris AW, Strasser A. bcl-2 transgene expression promotes survival and reduces proliferation of CD3-CD4-CD8- T cell progenitors. Int Immunol.1997 Sep;9(9):1291-301.
[80]O'Reilly LA, Harris AW, Tarlinton DM, et al. Expression of a bcl-2 transgene reduces proliferation and slows turnover of developing B lymphocytes in vivo. J Immunol.1997 Sep 1;159(5):2301-11.
[81]Chattopadhyay A, Chiang CW, Yang E. BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest. Oncogene.2001 Jul 27;20(33):4507-18.
[82]Brady HJ, Gil-Gomez G, Kirberg J, et al. Bax alpha perturbs T cell development and affects cell cycle entry of T cells. EMBO J.1996 Dec 16; 15(24):6991-7001.
[83]Huang DC, O'Reilly LA, Strasser A, et al. The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry. EMBO J.1997 Aug 1;16(15):4628-38.
[84]Quinn L, Coombe M, Mills K, et al. Buffy, a Drosophila Bcl-2 protein, has anti-apoptotic and cell cycle inhibitory functions. EMBO J.2003 Jul 15;22(14):3568-79.
[85]Greider C, Chattopadhyay A, Parkhurst C, et al. BCL-x(L) and BCL2 delay Myc-induced cell cycle entry through elevation of p27 and inhibition of G1 cyclin-dependent kinases. Oncogene.2002 Nov 7;21(51):7765-75.
[86]Gil-Gomez G, Berns A, Brady HJ. Bcl-2 retards cell cycle entry through p27(Kip1), pRB relative p130, and altered E2F regulation. Mol Cell Biol. 2000 Jul;20(13):4745-53.
[87]Lind EF, Wayne J, Wang QZ, et al. Bcl-2-induced changes in E2F regulatory complexes reveal the potential for integrated cell cycle and cell death functions. J Immunol.1999 May 1;162(9):5374-9.
[88]Vairo G, Soos TJ, Upton TM, et al. Bcl-2 retards cell cycle entry through p27(Kip1), pRB relative p130, and altered E2F regulation. Mol Cell Biol. 2000 Jul;20(13):4745-53.
[89]Wang HG, Rapp UR, Reed JC. Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell.1996 Nov 15;87(4):629-38.
[90]Shibasaki F, Kondo E, Akagi T, et al. Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2. Nature.1997 Apr 17;386(6626):728-31.
[91]Tanaka S, Louie DC, Kant JA, et al. Frequent incidence of somatic mutations in translocated BCL2 oncogenes of non-Hodgkin's lymphomas. Blood.1992 Jan 1;79(1):229-37.
[92]Matolcsy A, Casali P, Warnke RA, et al. Morphologic transformation of follicular lymphoma is associated with somatic mutation of the translocated Bcl-2 gene. Blood.1996 Nov 15;88(10):3937-44.
[93]Fero ML, Randel E, Gurley KE, et al. The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature.1998 Nov 12;396(6707):177-80.
[94]Knudson CM, Johnson GM, Lin Y, et al. Bax accelerates tumorigenesis in p53-deficient mice. Cancer Res.2001 Jan 15;61(2):659-65.
[95]Vairo G, Innes KM, Adams JM. Bcl-2 has a cell cycle inhibitory function separable from its enhancement of cell survival. Oncogene.1996 Oct 3;13(7):1511-9.
[2]Dicken BJ, Bigam DL, Cass C, et al. Gastric adenocarcinoma:review and considerations for future directions. Ann. Surg.2005; 241(1):27-39.
[3]Luciano F, Krajewska M, Ortiz-Rubio P, et al. Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma. Blood 2007; 109(9):3849-55.
[4]Kim JH, Yoon S, Won M, et al. HIP1R interacts with a member of Bcl-2 family, BCL2L10, and induces BAK-dependent cell death. Cell. Physiol. Biochem.2009; 23(1-3):43-52.
[5]Ke N, Godzik A, Reed JC. Bcl-B, a novel Bcl-2 family member that differentially binds and regulates Bax and Bak. J. Biol. Chem.2001; 276(16):12481-4.
[6]Zhang H, Holzgreve W, De Geyter C. Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway. Hum. Mol. Genet.2001; 10(21):2329-39.
[7]Krajewska M, Kitada S, Winter JN, et al. Bcl-B expression in human epithelial and nonepithelial malignancies. Clin. Cancer Res.2008; 14(10): 3011-21.
[8]Watanabe H, Jass JR, Sobin LH (1990). WHO:Histological Typing of Oesophageal and Gastric Tumours. Springer-Verlag:Berlin.
[9]Hamilton S.R., Aaltonen L.A. (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. IARC Press:Lyon 2000.
[10]AJCC Cancer Staging Manual (1997). Fifth edition. Lippincott: Philadelphia.
[11]Anon. (1997). UICC:TNM classification of malignant tumors. Wiley Press: New York.
[12]Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma - 2nd English Edition -. Gastric Cancer 1998; 1(1):10-24.
[13]Ikeguchi M, Saito H, Katano K, et al. Expression of p53 and p21 are independent prognostic factors in patients with serosal invasion by gastric carcinoma. Dig. Dis. Sci.1998; 43(5):964-70.
[14]Ogawa M, Maeda K, Onoda N, et al. Loss of p21WAF1/CIP1 expression correlates with disease progression in gastric carcinoma. Br. J. Cancer 1997; 75(11):1617-20.
[15]Cordon-Cardo C, Koff A, Drobnjak M, et al. Distinct altered patterns of p27KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. J. Natl. Cancer Inst.1998; 90(17):1284-91.
[16]Liu XP, Oga A, Suehiro Y, et al. Inverse relationship between matrilysin expression and proliferative activity of cells in advanced gastric carcinoma. Hum. Pathol.2002; 33(7):741-7.
[17]Hosmer DW, Lemeshow S:Applied Logistic Regression,2nd edition. New York:Wiley; 2000.
[18]Tamura G. Promoter methylation status of tumor suppressor and tumor-related genes in neoplastic and non-neoplastic gastric epithelia. Histol. Histopathol.2004; 19(1):221-8.
[19]Sato F, Meltzer SJ. CpG island hypermethylation in progression of esophageal and gastric cancer. Cancer 2006; 106(3):483-93.
[20]Hamilton JP, Meltzer SJ. A review of the genomics of gastric cancer. Clin. Gastroenterol. Hepatol.2006; 4(4):416-25.
[21]Johnson SM, Evers BM. Translational research in gastric malignancy. Surg. Oncol. Clin. N. Am.2008; 17(2):323-40, viii.
[22]Song Q, Kuang Y, Dixit VM, et al. Boo, a novel negative regulator of cell death, interacts with Apaf-1. EMBO J.1999; 18(1):167-78.
[23]Kang Y, Lee DC, Han J, et al. NM23-H2 involves in negative regulation of Diva and Bcl2L10 in apoptosis signaling. Biochem. Biophys. Res. Commun.2007; 359(1):76-82.
[24]Zhu W, Cowie A, Wasfy GW, et al. Bcl-2 mutants with restricted subcellular location reveal spatially distinct pathways for apoptosis in different cell types. EMBO J.1996; 15(16):4130-41.
[25]Nechushtan A, Smith CL, Hsu YT, et al. Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J.1999; 18(9):2330-41.
[26]Suzuki M, Youle RJ, Tjandra N. Structure of Bax: coregulation of dimer formation and intracellular localization. Cell 2000; 103(4):645-54.
[27]Upreti M, Lyle CS, Skaug B, et al. Vinblastine-induced apoptosis is mediated by discrete alterations in subcellular location, oligomeric structure, and activation status of specific Bcl-2 family members. J. Biol. Chem.2006; 281(23):15941-50.
[28]Zhang L, Xing D, Chen M. Bim(L) displacing Bcl-x(L) promotes Bax translocation during TNFalpha-induced apoptosis. Apoptosis 2008; 13(7): 950-8.
[29]Aslan JE, Thomas G. Death by Committee:Organellar Trafficking and Communication in Apoptosis. Traffic 2009; 10(10):1390-404.
[30]Zhai D, Ke N, Zhang H, et al. Characterization of the anti-apoptotic mechanism of Bcl-B. Biochem. J.2003; 376(Pt 1):229-36.
[31]Hsu YT, Youle RJ. Nonionic detergents induce dimerization among members of the Bcl-2 family. J Biol Chem.1997; 272(21):13829-34.
[32]Wolter KG, Hsu YT, Smith CL, et al. Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol.1997; 139(5):1281-92.
[33]Green DR, Reed JC. Mitochondria and apoptosis. Science.1998; 281(5381):1309-12.
[34]Mikata R, Yokosuka O, Fukai K, et al. Analysis of genes upregulated by the demethylating agent 5-aza-2'-deoxycytidine in gastric cancer cell lines. Int. J. Cancer 2006; 119(7):1616-22.
[35]Tanaka S, Louie DC, Kant JA, et al. Frequent incidence of somatic mutations in translocated BCL2 oncogenes of non-Hodgkin's lymphomas. Blood 1992; 79(1):229-37.
[36]Reed JC. Bcl-2-family proteins and hematologic malignancies:history and future prospects. Blood 2008; 111(7):3322-30.
[37]Kutuk O, Letai A. Regulation of Bcl-2 family proteins by posttranslational modifications. Curr Mol. Med.2008; 8(2); 102-18.
[38]Lauren T. The two histologic main types of gastric carcinoma. Acta. Pathol. Microbiol. Scand.1965; 64:34.
[39]Soetikno R, Kaltenbach T, Yeh R, et al. Endoscopic mucosal resection for early cancers of the upper gastrointestinal tract. J. Clin. Oncol.2005; 23(20):4490-8.
[40]Kreisberg JI, Malik SN, Prihoda TJ, et al. Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res.2004; 64(15):5232-6.
[41]Wang Z, Zhang B, Jiang L, et al. RACK1, an excellent predictor for poor clinical outcome in oral squamous carcinoma, similar to Ki67. Eur. J. Cancer2009; 45(3):490-6.
[1]Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics,2002. CA Cancer J. Clin.2005; 55(2); 74-108.
[2]JingDa Xu, Tomoko Furuya, XiXi Cao et al. Loss of BCL2L10 protein expression as prognostic predictor for poor clinical outcome in gastric carcinoma. Histopathology (accepted).
[3]Mikata R, Yokosuka O, Fukai K, et al. Analysis of genes upregulated by the demethylating agent 5-aza-2'-deoxycytidine in gastric cancer cell lines. Int J Cancer 2006; 119(7):1616-22.
[4]Inohara N, Gourley TS, Carrio R, et al. Diva, a Bcl-2 homologue that binds directly to Apaf-1 and induces BH3-independent cell.death. J Biol Chem.1998; 273(49):32479-86.
[5]Luciano F, Krajewska M, Ortiz-Rubio P, et al. Nur77 converts phenotype of Bcl-B, an antiapoptotic protein expressed in plasma cells and myeloma. Blood 2007; 109(9):3849-55.
[6]Kang Y, Lee DC, Han J, et al. NM23-H2 involves in negative regulation of Diva and Bcl2L10 in apoptosis signaling. Biochem Biophys Res Commun. 2007; 359(1):76-82.
[7]Kim JH, Yoon S, Won M, et al. HIP1R interacts with a member of Bcl-2 family, BCL2L10, and induces BAK-dependent cell death. Cell Physiol Biochem.2009; 23(1-3):43-52.
[8]Song Q, Kuang Y, Dixit VM, et al. Boo, a novel negative regulator of cell death, interacts with Apaf-1. EMBO J.1999; 18(1):167-78.
[9]Ke N, Godzik A, Reed JC. Bcl-B, a novel Bcl-2 family member that differentially binds and regulates Bax and Bak. J. Biol. Chem.2001; 276(16):12481-4.
[10]Naumann U, Weit S, Wischhusen J, et al. Diva/Boo is a negative regulator of cell death in human glioma cells. FEBS Lett.2001; 505(1): 23-6.
[11]Zhang H, Holzgreve W, De Geyter C. Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway. Hum. Mol. Genet.2001; 10(21):2329-39.
[12]Zhai D, Ke N, Zhang H, et al. Characterization of the anti-apoptotic mechanism of Bcl-B. Biochem. J.2003; 376(Pt 1):229-36.
[13]Beverly LJ, Varmus HE. MYC-induced myeloid leukemogenesis is accelerated by all six members of the antiapoptotic BCL family. Oncogene.2009; 28(9):1274-9.
[14]Guillemin Y, Lalle P, Gillet G, et al. Oocytes and early embryos selectively express the survival factor BCL2L10. J Mol Med.2009; 87(9):923-40.
[15]Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science.1998; 281(5381):1322-6.
[16]Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes Dev.1999; 13(15):1899-911.
[17]Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer.2002; 2(9):647-56.
[18]Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene.2003; 22(53):8590-607.
[19]Leung WK, Yu J, To KF, et al. Apoptosis and proliferation in Helicobacter pylori-associated gastric intestinal metaplasia. Aliment Pharmacol Ther. 2001; 15(9):1467-72.
[20]Wambura C, Aoyama N, Shirasaka D, et al. Effect of Helicobacter pylori-induced cyclooxygenase-2 on gastric epithelial cell kinetics: implication for gastric carcinogenesis. Helicobacter.2002; 7(2):129-38.
[21]Wambura C, Aoyama N, Shirasaka D, et al. Cell kinetic balance in gastric mucosa with intestinal metaplasia after Helicobacter pylori eradication: 2-year follow-up study. Dig Liver Dis.2004; 36(3):178-86.
[22]Tang C, Liu C, Zhou X, et al. Enhanced inhibitive effects of combination of rofecoxib and octreotide on the growth of human gastric cancer. Int J Cancer.2004; 112(3):470-4.
[23]Liu X, Kim CN, Yang J, et al. Induction of apoptotic program in cell-free extracts:requirement for dATP and cytochrome c. Cell 1996; 86(1): 147-57.
[24]Tournier C, Hess P, Yang DD, et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science.2000; 288(5467):870-4.
[25]Luo JL, Kamata H, Karin M. IKK/NF-kappaB signaling:balancing life and death-a new approach to cancer therapy. J Clin Invest.2005; 115(10): 2625-32.
[26]Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell2003; 114(2):181-90.
[27]Luo JL, Maeda S, Hsu LC, et al. Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell.2004; 6(3):297-305.
[28]O'Reilly LA, Huang DC, Strasser A. The cell death inhibitor Bcl-2 and its homologues influence control of cell cycle entry. EMBO J.1996 Dec 16; 15(24):6979-90.
[29]Crescenzi E, Palumbo G, Brady HJ. Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem J.2003 Oct 15;375(Pt 2):263-74.
[30]Linette GP, Li Y, Roth K, Korsmeyer SJ. Cross talk between cell death and cell cycle progression:BCL-2 regulates NFAT-mediated activation. Proc Natl Acad Sci U S A.1996 Sep 3;93(18):9545-52.
[31]Chattopadhyay A, Chiang CW, Yang E. BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest. Oncogene.2001 Jul 27;20(33):4507-18.
[32]Brady HJ, Gil-Gomez G, Kirberg J, et al. Bax alpha perturbs T cell development and affects cell cycle entry of T cells. EMBO J.1996 Dec 16; 15(24):6991-7001.
[33]Han Z, Wu K, Shen H, et al. Akt1/protein kinase B alpha is involved in gastric cancer progression and cell proliferation. Dig Dis Sci.2008; 53(7): 1801-10.
[34]Datta SR, Brunet A, Greenberg ME. Cellular survival:a play in three Akts. Genes Dev.1999; 13(22):2905-27.
[35]Downward J. PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol. 2004; 15(2):177-82.
[36]Chang F, Lee JT, Navolanic PM, et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation:a target for cancer chemotherapy. Leukemia.2003; 17(3):590-603.
[37]Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle.2003; 2(4):339-45.
[38]Manning BD, Cantley LC. Rheb fills a GAP between TSC and TOR. Trends Biochem Sci.2003; 28(11):573-6.
[39]Martin P, Pognonec P. ERK and cell death:cadmium toxicity, sustained ERK activation and cell death. FEBS J.2010; 277(1):39-46.
[40]Chen CY, Gherzi R, Andersen JS, et al. Nucleolin and YB-1 are required for JNK-mediated interleukin-2 mRNA stabilization during T-cell activation. Genes Dev.2000; 14(10):1236-48.
[41]Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell. 2000; 103(2):239-52.
[42]Ono K, Han J. The p38 signal transduction pathway: activation and function. Cell Signal.2000; 12(1):1-13.
[43]Drudi Metalli V, Mancino MG, Mancino A, et al. Bile salts regulate proliferation and apoptosis of liver cells by modulating the IGF1 system. Dig Liver Dis.2007; 39(7):654-62.
[44]Coen L, Le Blay K, Rowe I, et al. Caspase-9 regulates apoptosis/proliferation balance during metamorphic brain remodeling in Xenopus. Proc Natl Acad Sci U S A.2007; 104(20):8502-7.
[45]Li RJ, Qiu SD, Wang HX, et al. Androgen receptor: a new player associated with apoptosis and proliferation of pancreatic beta-cell in type 1 diabetes mellitus. Apoptosis.2008; 13(8):959-71.
[46]McMurtry MS, Bonnet S, Wu X, et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res.2004; 95(8):830-40.
[47]Efrati S, Berman S, Goldfinger N, et al. Enhanced angiotensin II production by renal mesangium is responsible for apoptosis/proliferation of endothelial and epithelial cells in a model of malignant hypertension. J Hypertens.2007; 25(5):1041-52.
[48]Arici M, Chana R, Lewington A, et al. Stimulation of proximal tubular cell apoptosis by albumin-bound fatty acids mediated by peroxisome proliferator activated receptor-gamma. J Am Soc Nephrol.2003; 14(1): 17-27.
[49]Parker JE, Mufti GJ, Rasool F, et al. The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Slood. 2000; 96(12):3932-8.
[50]Schmitz KJ, Lang H, Wohlschlaeger J, et al. Elevated expression of cyclooxygenase-2 is a negative prognostic factor for overall survival in intrahepatic cholangiocarcinoma. Virchows Arch.2007; 450(2):135-41.
[51]Sinicrope FA, Rego RL, Garrity-Park MM, et al. Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability. Int J Cancer.2007; 120(6):1232-8.
[1]Ellis SM, Nabeshima K, Biswas C. Monoclonal antibody preparation and purification of a tumor cell collagenase-stimulatory factor. Cancer Res. 1989 Jun 15;49(12):3385-91.
[2]Kataoka H, DeCastro R, Zucker S, et al. Tumor cell-derived collagenase-stimulatory factor increases expression of interstitial collagenase, stromelysin, and 72-kDa gelatinase. Cancer Res.1993 Jul 1;53(13):3154-8.
[3]Sameshima T, Nabeshima K, Toole BP, et al. Glioma cell extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147) stimulates production of membrane-type matrix metalloproteinases and activated gelatinase A in co-cultures with brain-derived fibroblasts. Cancer Lett. 2000 Sep 1;157(2):177-84.
[4]Li R, Huang L, Guo H, et al. Basigin (murine EMMPRIN) stimulates matrix metalloproteinase production by fibroblasts. J Cell Physiol.2001 Mar; 186(3):371-9.
[5]Suzuki S, Sato M, Senoo H, et al. Direct cell-cell interaction enhances pro-MMP-2 production and activation in co-culture of laryngeal cancer cells and fibroblasts:involvement of EMMPRIN and MT1-MMP. Exp Cell Res.2004 Feb 15;293(2):259-66.
[6]Guo H, Zucker S, Gordon MK, et al. Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cells. J Biol Chem.1997 Jan 3;272(1):24-7.
[7]Sun J, Hemler ME. Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions. Cancer Res.2001 Mar 1;61(5):2276-81.
[8]Cao XX, Xu JD, Xu JW, et al. RACK1 promotes breast carcinoma proliferation and invasion/metastasis in vitro and in vivo. Breast Cancer Res Treat.2009 Nov 28. [Epub ahead of print]
[9]Li QQ, Wang WJ, Xu JD, et al. Up-regulation of CD147 and matrix metalloproteinase-2,-9 induced by P-glycoprotein substrates in multidrug resistant breast cancer cells. Cancer Sci.2007 Nov;98(11):1767-74.
[10]Li QQ, Wang WJ, Xu JD, et al. Involvement of CD147 in regulation of multidrug resistance to P-gp substrate drugs and in vitro invasion in breast cancer cells. Cancer Sci.2007 Jul;98(7):1064-9.
[1]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.
[2]Danial NN, Korsmeyer SJ. Cell death:critical control points. Cell.2004 Jan 23;116(2):205-19.
[3]Strasser A. The role of BH3-only proteins in the immune system. Nat Rev Immunol.2005 Mar;5(3):189-200.
[4]Veis DJ, Sorenson CM, Shutter JR, et al. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell.1993 Oct 22;75(2):229-40.
[5]Knudson CM, Tung KS, Tourtellotte WG, et al. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science.1995 Oct 6;270(5233):96-9.
[6]Lindsten T, Ross AJ, King A, et al. The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell.2000 Dec;6(6):1389-99.
[7]Zong WX, Lindsten T, Ross AJ, et al. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev.2001 Jun 15;15(12):1481-6.
[8]Cheng EH, Wei MC, Weiler S, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell.2001 Sep;8(3):705-11.
[9]Yin XM, Wang K, Gross A, et al. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature.1999 Aug 26,400(6747): 886-91.
[10]Gross A, Yin XM, Wang K, et al. Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem.1999 Jan 8;274(2):1156-63.
[11]Puthalakath H, O'Reilly LA, Gunn P, et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell.2007 Jun 29; 129(7):1337-49.
[12]Tsujimoto Y, Finger LR, Yunis J, et al. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science.1984 Nov 30;226(4678):1097-9.
[13]Bakhshi A, Jensen JP, Goldman P, et al. Cloning the chromosomal breakpoint of t(14;18) human lymphomas: clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell.1985 Jul;41 (3):899-906.
[14]Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell.1986 Oct 10;47(1):19-28.
[15]Yunis JJ, Frizzera G, Oken MM, et al. Multiple recurrent genomic defects in follicular lymphoma. A possible model for cancer. N Engl J Med.1987 Jan 8;316(2):79-84.
[16]Adachi M, Tefferi A, Greipp PR, et al. Preferential linkage of bcl-2 to immunoglobulin light chain gene in chronic lymphocytic leukemia. J Exp Med.1990 Feb 1;171(2):559-64.
[17]Tashiro S, Takechi M, Asou H, et al. Cytogenetic 2; 18 and 18; 22 translocation in chronic lymphocytic leukemia with juxtaposition of bcl-2 and immunoglobulin light chain genes. Oncogene.1992 Mar;7(3):573-7.
[18]Grumont RJ, Rourke IJ, Gerondakis S. Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev.1999 Feb 15;13(4):400-11.
[19]Cory S. Regulation of lymphocyte survival by the bcl-2 gene family. Annu Rev Immunol.1995;13:513-43.
[20]McDonnell TJ, Korsmeyer SJ. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature.1991 Jan 17;349(6306):254-6.
[21]Strasser A, Harris AW, Cory S. E mu-bcl-2 transgene facilitates spontaneous transformation of early pre-B and immunoglobulin-secreting cells but not T cells. Oncogene.1993 Jan;8(1):1-9.
[22]Linette GP, Hess JL, Sentman CL, et al. Peripheral T-cell lymphoma in lckpr-bcl-2 transgenic mice. Blood.1995 Aug 15;86(4):1255-60.
[23]Liu Y, Hernandez AM, Shibata D, BCL2 translocation frequency rises with age in humans. Proc Natl Acad Sci U SA.1994 Sep 13;91(19):8910-4.
[24]Ji W, Qu GZ, Ye P, et al. Frequent detection of bcl-2/JH translocations in human blood and organ samples by a quantitative polymerase chain reaction assay. Cancer Res.1995 Jul 1;55(13):2876-82.
[25]Limpens J, Stad R, Vos C, et al. Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. Blood.1995 May 1;85(9): 2528-36.
[26]Zelenetz AD, Chen TT, Levy R. Clonal expansion in follicular lymphoma occurs subsequent to antigenic selection. J Exp Med.1992 Oct 1;176(4): 1137-48.
[27]Egle A, Harris AW, Bath ML, et al. VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood. 2004 Mar 15; 103(6):2276-83.
[28]Yano T, Jaffe ES, Longo DL, et al. MYC rearrangements in histologically progressed follicular lymphomas. Blood.1992 Aug 1;80(3):758-67.
[29]Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988 Sep 29;335(6189):440-2.
[30]Strasser A, Harris AW, Bath ML, et al. Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature.1990 Nov 22;348(6299):331-3.
[31]Strasser A, Elefanty AG, Harris AW, et al. Progenitor tumours from Emu-bcl-2-myc transgenic mice have lymphomyeloid differentiation potential and reveal developmental differences in cell survival. EMBO J. 1996 Aug 1;15(15):3823-34.
[32]Jager R, Herzer U, Schenkel J, et al. Overexpression of Bcl-2 inhibits alveolar cell apoptosis during involution and accelerates c-myc-induced tumorigenesis of the mammary gland in transgenic mice. Oncogene. 1997 Oct 9; 15(15):1787-95.
[33]Naik P, Karrim J, Hanahan D. The rise and fall of apoptosis during multistage tumorigenesis:down-modulation contributes to tumor progression from angiogenic progenitors. Genes Dev.1996 Sep 1;10(17): 2105-16.
[34]Pelengaris S, Khan M, Evan GI. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell.2002 May 3;109(3):321-34.
[35]Askew DS, Ashmun RA, Simmons BC, et al. Constitutive c-myc expression in an IL-3-dependent myeloid cell line suppresses cell cycle arrest and accelerates apoptosis. Oncogene.1991 Oct;6(10):1915-22.
[36]Bissonnette RP, Echeverri F, Mahboubi A, et al. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature.1992 Oct 8;359(6395): 552-4.
[37]Evan GI, Wyllie AH, Gilbert CS, et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell.1992 Apr 3;69(1):119-28.
[38]Evan G, Littlewood T. A matter of life and cell death. Science.1998 Aug 28;281(5381):1317-22.
[39]Cory S, Vaux DL, Strasser A, et al. Insights from Bcl-2 and Myc: malignancy involves abrogation of apoptosis as well as sustained proliferation. Cancer Res.1999 Apr 1;59(7 Suppl):1685s-1692s.
[40]Kanazawa S, Soucek L, Evan G, et al. c-Myc recruits P-TEFb for transcription, cellular proliferation and apoptosis. Oncogene.2003 Aug 28;22(36):5707-11.
[41]Green DR, Evan GI. A matter of life and death. Cancer Cell.2002 Feb;1(1):19-30.
[42]Hanahan D, Weinberg RA. The hallmarks of cancer. Cell.2000 Jan 7;100(1):57-70.
[43]Eischen CM, Weber JD, Roussel MF, et al. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev.1999 Oct 15; 13(20):2658-69.
[44]Eischen CM, Roussel MF, Korsmeyer SJ, et al. Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. Mol Cell Biol.2001 Nov;21(22): 7653-62.
[45]Lee JT, Innes DJ Jr, Williams ME. Sequential bcl-2 and c-myc oncogene rearrangements associated with the clinical transformation of non-Hodgkin's lymphoma. J Clin Invest.1989 Nov;84(5):1454-9.
[46]Sander CA, Yano T, Clark HM, et al. p53 mutation is associated with progression in follicular lymphomas. Blood.1993 Oct 1;82(7):1994-2004.
[47]Lossos IS, Levy R. Higher-grade transformation of follicle center lymphoma is associated with somatic mutation of the 5' noncoding regulatory region of the BCL-6 gene. Blood.2000 Jul 15;96(2):635-9.
[48]Kogan SC, Brown DE, Shultz DB, et al. BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor alpha chimeric protein (PMLRARalpha) to block neutrophil differentiation and initiate acute leukemia. J Exp Med.2001 Feb 19;193(4):531-43.
[49]Traver D, Akashi K, Weissman IL, et al. Mice defective in two apoptosis pathways in the myeloid lineage develop acute myeloblastic leukemia. Immunity.1998 Jul;9(1):47-57.
[50]Gibbons DL, MacDonald D, McCarthy KP, et al. An E mu-BCL-2 transgene facilitates leukaemogenesis by ionizing radiation. Oncogene. 1999 Jul 1;18(26):3870-7.
[51]Bouillet P, Metcalf D, Huang DC, et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science.1999 Nov 26;286(5445):1735-8.
[52]Bouillet P, Purton JF, Godfrey DI, et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature.2002 Feb 21;415(6874):922-6.
[53]Bouillet P, Zhang LC, Huang DC, et al. Gene structure alternative splicing, and chromosomal localization of pro-apoptotic Bcl-2 relative Bim. Mamm Genome.2001 Feb; 12(2):163-8.
[54]Zinkel SS, Ong CC, Ferguson DO, et al. Proapoptotic BID is required for myeloid homeostasis and tumor suppression. Genes Dev.2003 Jan 15; 17(2):229-39.
[55]Puthalakath H, Villunger A, O'Reilly LA, et al. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin Ⅴ actin motor complex, activated by anoikis. Science.2001 Sep 7;293(5536):1829-32.
[56]Oda E, Ohki R, Murasawa H, et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science. 2000 May 12,288(5468):1053-8.
[57]Han J, Flemington C, Houghton AB, et al. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc Natl Acad Sci U S A.2001 Sep 25;98(20): 11318-23.
[58]Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell.2001 Mar;7(3):683-94.
[59]Yu J, Zhang L, Hwang PM, et al. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol Cell.2001 Mar;7(3):673-82.
[60]Yu J, Wang Z, Kinzler KW, et al. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc Natl Acad Sci U S A.2003 Feb 18; 100(4):1931-6.
[61]Shibue T, Takeda K, Oda E, et al. Integral role of Noxa in p53-mediated apoptotic response. Genes Dev.2003 Sep 15;17(18):2233-8.
[62]Villunger A, Michalak EM, Coultas L, et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science.2003 Nov 7;302(5647):1036-8.
[63]Knudson CM, Johnson GM, Lin Y, et al. Bax accelerates tumorigenesis in p53-deficient mice. Cancer Res.2001 Jan 15;61(2):659-65.
[64]McCurrach ME, Connor TM, Knudson CM, et al. bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. Proc Natl Acad Sci U S A.1997 Mar 18;94(6): 2345-9.
[65]Villunger A, Michalak EM, Coultas L, et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science.2003 Nov 7;302(5647):1036-8.
[66]Shibata MA, Liu ML, Knudson MC, et al. Haploid loss of bax leads to accelerated mammary tumor development in C3(1)/SV40-TAg transgenic mice:reduction in protective apoptotic response at the preneoplastic stage. EMBO J.1999 May 17;18(10):2692-701.
[67]Eischen CM, Roussel MF, Korsmeyer SJ, et al. Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. Mol Cell Biol.2001 Nov;21(22): 7653-62.
[68]Rampino N, Yamamoto H, lonov Y, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science.1997 Feb 14;275(5302):967-9.
[69]Meijerink JP, Mensink EJ, Wang K, et al. Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. Blood.1998 Apr 15;91(8): 2991-7.
[70]Kondo S, Shinomura Y, Miyazaki Y, et al. Mutations of the bak gene in human gastric and colorectal cancers. Cancer Res.2000 Aug 15;60(16): 4328-30.
[71]Zhang L, Yu J, Park BH, et al. Role of BAX in the apoptotic response to anticancer agents. Science.2000 Nov 3;290(5493):989-92.
[72]O'Reilly LA, Huang DC, Strasser A. The cell death inhibitor Bcl-2 and its homologues influence control of cell cycle entry. EMBO J.1996 Dec 16; 15(24):6979-90.
[73]Borner C. Diminished cell proliferation associated with the death-protective activity of Bcl-2. J Biol Chem.1996 May 31;271(22): 12695-8.
[74]Linette GP, Li Y, Roth K, Korsmeyer SJ. Cross talk between cell death and cell cycle progression:BCL-2 regulates NFAT-mediated activation. Proc Natl Acad Sci U S A.1996 Sep 3;93(18):9545-52.
[75]Simpson NH, Singh RP, Emery AN, et al. Bcl-2 over-expression reduces growth rate and prolongs G1 phase in continuous chemostat cultures of hybridoma cells. Biotechnol Bioeng.1999 Jul 20;64(2):174-86.
[76]Marvel J, Perkins GR, Lopez Rivas A, et al. Growth factor starvation of bcl-2 overexpressing murine bone marrow cells induced refractoriness to IL-3 stimulation of proliferation. Oncogene.1994 Apr;9(4):1117-22.
[77]Mazel S, Burtrum D, Petrie HT. Regulation of cell division cycle progression by bcl-2 expression:a potential mechanism for inhibition of programmed cell death. J Exp Med.1996 May 1;183(5):2219-26.
[78]Crescenzi E, Palumbo G, Brady HJ. Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem J.2003 Oct 15;375(Pt 2):263-74.
[79]O'Reilly LA, Harris AW, Strasser A. bcl-2 transgene expression promotes survival and reduces proliferation of CD3-CD4-CD8- T cell progenitors. Int Immunol.1997 Sep;9(9):1291-301.
[80]O'Reilly LA, Harris AW, Tarlinton DM, et al. Expression of a bcl-2 transgene reduces proliferation and slows turnover of developing B lymphocytes in vivo. J Immunol.1997 Sep 1;159(5):2301-11.
[81]Chattopadhyay A, Chiang CW, Yang E. BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest. Oncogene.2001 Jul 27;20(33):4507-18.
[82]Brady HJ, Gil-Gomez G, Kirberg J, et al. Bax alpha perturbs T cell development and affects cell cycle entry of T cells. EMBO J.1996 Dec 16; 15(24):6991-7001.
[83]Huang DC, O'Reilly LA, Strasser A, et al. The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry. EMBO J.1997 Aug 1;16(15):4628-38.
[84]Quinn L, Coombe M, Mills K, et al. Buffy, a Drosophila Bcl-2 protein, has anti-apoptotic and cell cycle inhibitory functions. EMBO J.2003 Jul 15;22(14):3568-79.
[85]Greider C, Chattopadhyay A, Parkhurst C, et al. BCL-x(L) and BCL2 delay Myc-induced cell cycle entry through elevation of p27 and inhibition of G1 cyclin-dependent kinases. Oncogene.2002 Nov 7;21(51):7765-75.
[86]Gil-Gomez G, Berns A, Brady HJ. Bcl-2 retards cell cycle entry through p27(Kip1), pRB relative p130, and altered E2F regulation. Mol Cell Biol. 2000 Jul;20(13):4745-53.
[87]Lind EF, Wayne J, Wang QZ, et al. Bcl-2-induced changes in E2F regulatory complexes reveal the potential for integrated cell cycle and cell death functions. J Immunol.1999 May 1;162(9):5374-9.
[88]Vairo G, Soos TJ, Upton TM, et al. Bcl-2 retards cell cycle entry through p27(Kip1), pRB relative p130, and altered E2F regulation. Mol Cell Biol. 2000 Jul;20(13):4745-53.
[89]Wang HG, Rapp UR, Reed JC. Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell.1996 Nov 15;87(4):629-38.
[90]Shibasaki F, Kondo E, Akagi T, et al. Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2. Nature.1997 Apr 17;386(6626):728-31.
[91]Tanaka S, Louie DC, Kant JA, et al. Frequent incidence of somatic mutations in translocated BCL2 oncogenes of non-Hodgkin's lymphomas. Blood.1992 Jan 1;79(1):229-37.
[92]Matolcsy A, Casali P, Warnke RA, et al. Morphologic transformation of follicular lymphoma is associated with somatic mutation of the translocated Bcl-2 gene. Blood.1996 Nov 15;88(10):3937-44.
[93]Fero ML, Randel E, Gurley KE, et al. The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature.1998 Nov 12;396(6707):177-80.
[94]Knudson CM, Johnson GM, Lin Y, et al. Bax accelerates tumorigenesis in p53-deficient mice. Cancer Res.2001 Jan 15;61(2):659-65.
[95]Vairo G, Innes KM, Adams JM. Bcl-2 has a cell cycle inhibitory function separable from its enhancement of cell survival. Oncogene.1996 Oct 3;13(7):1511-9.