Grim-19 mRNA在肺癌组织中的表达及其与临床病理特征之间的关系
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摘要
研究背景
干扰素/维甲酸诱导凋亡相关基因-19(gene associated with retinoid-IFN-induced mortality-19,Grim-19),是2000年由Angell等应用反义基因敲除的方法分离发现的一种细胞凋亡调节因子。在一些原发性肾细胞肿瘤和泌尿生殖系肿瘤中Grim-19表达缺失或被严重抑制,用肾细胞肿瘤细胞系的研究证实Grim-19的下调通过增强依赖Stat3(signal transducers and activators of transcription 3)基因的表达而促进肿瘤生长,并且首次表明Grim-19具有肿瘤抑制因子作用。Maximo等证实甲状腺Hurthle细胞肿瘤病例携带有Grim-19基因的突变。而对肺癌组织中Grim-19基因及蛋白表达水平的研究,国内外尚未有报道。本研究采用RT-PCR(Reverse transcript–polymerase chain reaction)及real time RT-PCR检测40例肺癌组织中Grim-19基因水平的表达,RT- PCR检测Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc基因水平的表达,Western blot验证20例肺癌组织中Grim-19蛋白表达水平,分析Grim-19基因水平的表达与临床病理特征之间的关系,并进一步探讨Grim-19在肺癌发生发展中的意义。
目的
本研究以人肺癌组织及癌旁组织为材料,检测Grim-19、Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc在肺癌及癌旁组织中的基因与蛋白水平表达情况,并分析Grim-19基因水平表达与临床病理特征之间的关系,以期探讨Grim-19在肺癌发生发展中的意义。
方法
1. RT-PCR检测40例肺癌患者的癌组织和癌旁组织中Grim-19、Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc基因水平的表达
分别抽取40例患者肺癌组织及癌旁组织中的总RNA,然后采用RT-PCR法分别检测Grim-19 mRNA、Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc表达的变化
2. real time RT-PCR检测40例肺癌患者的癌组织和癌旁组织中Grim-19基因水平的表达
分别抽取40例患者肺癌组织及癌旁组织中的总RNA,然后采用real time RT-PCR法分别检测Grim-19基因水平表达的变化
3.用Western blot法验证20例肺癌组织中Grim-19蛋白表达情况
分别抽取20例患者肺癌组织及癌旁组织中的总蛋白,然后采用Western Blot法分别检测Grim-19蛋白表达的变化。
4.分析肺癌组织中Grim-19基因水平的表达与临床病理参数之间的关系
将肺癌组40例临床标本Grim-19基因水平的表达量按组织学类型、临床病理分期、性别、年龄、吸烟指数等参数进行分组,然后分析Grim-19基因水平的表达与临床病理参数之间的关系。
5.统计方法
所有试验至少分3次独立完成,数据用均数±标准差表示。多组间的差异用one-way ANOVA分析,两组之间的差异用t检验,统计在SPSS 15.0软件统计包中进行,P<0.05表示差异有显著性。
结果
1.肺癌及癌旁组织Grim-19、Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc基因水平的表达水平检测
RT-PCR、real time RT-PCR结果均表明:肺癌组与癌旁组相比,Grim-19基因表达水平有明显改变;肺癌组Grim-19基因表达水平均低于其在相对应的癌旁组的表达,RT-PCR结果发现Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc基因表达水平在肺癌组织中均高于其在癌旁组织中的表达。
2.肺癌及癌旁组织Grim-19蛋白水平检测
Western Blot结果表明:肺癌组与癌旁组相比,Grim-19蛋白表达水平有明显差异;肺癌组Grim-19蛋白水平低于其在相对应的癌旁组的表达,并且蛋白表达的相应下降与基因表达水平的降低相一致。
3.肺癌组织中Grim-19基因水平的表达与临床病理参数之间的关系
将肺癌组40例临床标本Grim-19基因水平的表达量按组织学类型、临床病理分期、性别、年龄、吸烟指数等参数进行分组,在不同的临床病理分期中,I–II期Grim-19基因水平的相对表达量显著高于III-IV期的表达,差异有统计学意义;而肺癌组织中Grim-19基因水平表达量与其性别、年龄、吸烟指数、组织学分型等参数无统计学差异。
结论
1.肺癌组Grim-19基因水平及蛋白水平均低于其在相对应的癌旁组的表达,并且基因表达水平的降低伴随有蛋白表达的相应下降;
2.在肺癌组不同的临床病理分期中,I–II期Grim-19基因水平相对表达量显著高于III-IV期的表达;而与性别、年龄、吸烟指数及组织学分型等无明显相关性。
3.肺癌组织中Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc基因表达水平均高于其在癌旁组织中的表达。并且在肺癌组织中存在Stat3高表达与Grim-19低表达的共存。
4. Grim-19基因水平的表达下降是肺癌发生过程中的重要事件,可能与肺癌的发生及进展有关。
Background
Gene associated with retinoid interferon-induced mortality(GRIM)-19, was originally identified as a cell death regulatory gene using the antisense technical knockout approach by Angell et al. In a number of primary RCC and in some urinogenital tumors.the expression of Grim-19 is lost or severely depressed .By using an RCC cell line, researchers show that down regulation of Grim-19 promotes tumor growth via an augmentation of Stat3-dependent gene expression. These studies for the first time show a tumor suppressor like activity of Grim-19. Maximo et al confirmed that Hurthle cell tumors exist mutation of Grim-19. As researches on Grim-19 expression in lung cancer tissues have not yet been reported both at home and abroad, In this study, We detected mRNA expression of Grim-19 ,Stat3 and it’s downstream target gene Bcl2, CyclinB1,CyclinD1,c-Myc in 40 cases lung cancer tissues using RT-PCR, For further quantitative Grim-19 mRNA expression, we used the methods real time quantitive RT-PCR. verify Grim-19 protein expression levels using western blot, Analyzing the relationship between Grim-19 mRNA and clinicopathological features, and to further explore the role of Grim-19 in lung cancer carcinogenesis and the association with the development of lung cancer.
Objective
In the present study, we used lung cancer and adjacent tissues to investigate the expression of Grim-19, Stat3 and it’s downstream target gene Bcl2, CyclinB1,CyclinD1,c-Myc, Analyzing the relationship between Grim-19 mRNA and clinicopathological features, and to further explore the role of Grim-19 in lung cancer carcinogenesis and the association with the development of lung cancer.
Method
1. Detect Grim-19, Stat3 and its downstream target genes Bcl2, CyclinB1, CyclinD1, c-Myc mRNA expression in 40 cases lung cancer and adjacent tissues using RT-PCR analysis
Total RNA were extracted from 40 cases lung cancer and adjacent tissues, respectively, and the expression of Grim-19, Stat3 and its downstream target genes Bcl2, CyclinB1, CyclinD1, c-Myc was measured by RT-PCR.
2. Quantitative Grim-19 mRNA expression in 40 cases lung cancer and adjacent tissues using real time RT-PCR analysis
Total RNA were extracted from 40 cases lung cancer and adjacent tissues, respectively, and the expression of Grim-19 was measured by real time RT-PCR.
3. Protein extraction and Western blot analysis
Total protein were extracted from 40 cases lung cancer and adjacent tissues, respectively, and the expression of Grim-19 was measured by Western Blot.
4. Analyze the relationship between Grim-19 mRNA in lung cancer tissues and clinicopathological features of patients
Set 40 cases Grim-19 mRNA expression in lung cancer tissues according to sex, histological type, clinical staging, age and smoking index , then Analyze the relationship between Grim-19 mRNA in lung cancer tissues and clinicopathological features of patients.
5. Statistical method
All experiments were performed at least three independent times. Data were expressed as the means±standard and were analyzed for significant differences by independent Student’s t test and one-way ANOVA with SPSS 15.0. Differences were considered statistically significant if P value <0.05.
Result
1. Grim-19, Stat3 and it’s downstream target gene Bcl2、CyclinB1、CyclinD1、c-Myc mRNA analysis in lung cancer and adjacent tissues RT-PCR, real time RT-PCR results all indicated that: the mRNA expression of Grim-19 in lung cancer group decreased significantly compared to the corresponding adjacent group, respectively. RT-PCR results showed the mRNA expression of Stat3 and it’s downstream target gene Bcl2、CyclinB1、CyclinD1、c-Myc in lung cancer tissues were significantly higher than in its’adjacent tissues.
2. Grim-19 protein expression analysis in lung cancer and adjacent tissues
Western Blot results indicated that: the protein expression of Grim-19 in lung cancer group decreased significantly compared to the corresponding adjacent group, respectively. a decrease Grim-19 mRNA expression corresponded to a similar effect on Grim-19 protein expression.
3. The relationship between Grim-19 mRNA expression and clinical and pathological parameters of lung cancer patients
Set 40 cases Grim-19 mRNA expression in lung cancer tissues as five groups according to histology, TNM stage, sex, age, smoking condition .the relative amount of Grim-19 mRNA expression of stage I–II were significantly higher than those of stage III-IV. However, the expression of Grim-19 was determined not to be associated with the patients’sex, age, smoking condition, histology.
Conclusion
1. The expression of Grim-19 mRNA and protein in lung cancer group decreased significantly compared to the corresponding adjacent group, respectively. a decrease Grim-19 mRNA expression corresponded to a similar effect on Grim-19 protein expression.;
2. The relative amount of Grim-19 mRNA expression of stage I–II were significantly higher than those of stage III-IV;However, the expression of Grim-19 was determined not to be associated with the patients’sex, age, smoking condition, histology.
3. The mRNA expression of Stat3 and its downstream target genes Bcl2, CyclinB1, CyclinD1, c-Myc were higher in lung cancer tissues compared to the corresponding adjacent group, respectively. a decreased Grim-19 mRNA expression co-existence high expression of Stat3 in lung cancer tissues.
4. Grim-19 mRNA was down-regulated in tumor tissue and the lower expression of Grim-19 mRNA may play a major role in lung cancer carcinogenesis, suggesting that it may have very intimate association with the development of lung cancer.
干扰素/维甲酸诱导凋亡相关基因-19(gene associated with retinoid-IFN-induced mortality-19,Grim-19),是2000年由Angell等应用反义基因敲除的方法分离发现的一种细胞凋亡调节因子。在一些原发性肾细胞肿瘤和泌尿生殖系肿瘤中Grim-19表达缺失或被严重抑制,用肾细胞肿瘤细胞系的研究证实Grim-19的下调通过增强依赖Stat3(signal transducers and activators of transcription 3)基因的表达而促进肿瘤生长,并且首次表明Grim-19具有肿瘤抑制因子作用。Maximo等证实甲状腺Hurthle细胞肿瘤病例携带有Grim-19基因的突变。而对肺癌组织中Grim-19基因及蛋白表达水平的研究,国内外尚未有报道。本研究采用RT-PCR(Reverse transcript–polymerase chain reaction)及real time RT-PCR检测40例肺癌组织中Grim-19基因水平的表达,RT- PCR检测Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc基因水平的表达,Western blot验证20例肺癌组织中Grim-19蛋白表达水平,分析Grim-19基因水平的表达与临床病理特征之间的关系,并进一步探讨Grim-19在肺癌发生发展中的意义。
目的
本研究以人肺癌组织及癌旁组织为材料,检测Grim-19、Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc在肺癌及癌旁组织中的基因与蛋白水平表达情况,并分析Grim-19基因水平表达与临床病理特征之间的关系,以期探讨Grim-19在肺癌发生发展中的意义。
方法
1. RT-PCR检测40例肺癌患者的癌组织和癌旁组织中Grim-19、Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc基因水平的表达
分别抽取40例患者肺癌组织及癌旁组织中的总RNA,然后采用RT-PCR法分别检测Grim-19 mRNA、Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc表达的变化
2. real time RT-PCR检测40例肺癌患者的癌组织和癌旁组织中Grim-19基因水平的表达
分别抽取40例患者肺癌组织及癌旁组织中的总RNA,然后采用real time RT-PCR法分别检测Grim-19基因水平表达的变化
3.用Western blot法验证20例肺癌组织中Grim-19蛋白表达情况
分别抽取20例患者肺癌组织及癌旁组织中的总蛋白,然后采用Western Blot法分别检测Grim-19蛋白表达的变化。
4.分析肺癌组织中Grim-19基因水平的表达与临床病理参数之间的关系
将肺癌组40例临床标本Grim-19基因水平的表达量按组织学类型、临床病理分期、性别、年龄、吸烟指数等参数进行分组,然后分析Grim-19基因水平的表达与临床病理参数之间的关系。
5.统计方法
所有试验至少分3次独立完成,数据用均数±标准差表示。多组间的差异用one-way ANOVA分析,两组之间的差异用t检验,统计在SPSS 15.0软件统计包中进行,P<0.05表示差异有显著性。
结果
1.肺癌及癌旁组织Grim-19、Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc基因水平的表达水平检测
RT-PCR、real time RT-PCR结果均表明:肺癌组与癌旁组相比,Grim-19基因表达水平有明显改变;肺癌组Grim-19基因表达水平均低于其在相对应的癌旁组的表达,RT-PCR结果发现Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc基因表达水平在肺癌组织中均高于其在癌旁组织中的表达。
2.肺癌及癌旁组织Grim-19蛋白水平检测
Western Blot结果表明:肺癌组与癌旁组相比,Grim-19蛋白表达水平有明显差异;肺癌组Grim-19蛋白水平低于其在相对应的癌旁组的表达,并且蛋白表达的相应下降与基因表达水平的降低相一致。
3.肺癌组织中Grim-19基因水平的表达与临床病理参数之间的关系
将肺癌组40例临床标本Grim-19基因水平的表达量按组织学类型、临床病理分期、性别、年龄、吸烟指数等参数进行分组,在不同的临床病理分期中,I–II期Grim-19基因水平的相对表达量显著高于III-IV期的表达,差异有统计学意义;而肺癌组织中Grim-19基因水平表达量与其性别、年龄、吸烟指数、组织学分型等参数无统计学差异。
结论
1.肺癌组Grim-19基因水平及蛋白水平均低于其在相对应的癌旁组的表达,并且基因表达水平的降低伴随有蛋白表达的相应下降;
2.在肺癌组不同的临床病理分期中,I–II期Grim-19基因水平相对表达量显著高于III-IV期的表达;而与性别、年龄、吸烟指数及组织学分型等无明显相关性。
3.肺癌组织中Stat3及其下游靶基因Bcl2、CyclinB1、CyclinD1、c-Myc基因表达水平均高于其在癌旁组织中的表达。并且在肺癌组织中存在Stat3高表达与Grim-19低表达的共存。
4. Grim-19基因水平的表达下降是肺癌发生过程中的重要事件,可能与肺癌的发生及进展有关。
Background
Gene associated with retinoid interferon-induced mortality(GRIM)-19, was originally identified as a cell death regulatory gene using the antisense technical knockout approach by Angell et al. In a number of primary RCC and in some urinogenital tumors.the expression of Grim-19 is lost or severely depressed .By using an RCC cell line, researchers show that down regulation of Grim-19 promotes tumor growth via an augmentation of Stat3-dependent gene expression. These studies for the first time show a tumor suppressor like activity of Grim-19. Maximo et al confirmed that Hurthle cell tumors exist mutation of Grim-19. As researches on Grim-19 expression in lung cancer tissues have not yet been reported both at home and abroad, In this study, We detected mRNA expression of Grim-19 ,Stat3 and it’s downstream target gene Bcl2, CyclinB1,CyclinD1,c-Myc in 40 cases lung cancer tissues using RT-PCR, For further quantitative Grim-19 mRNA expression, we used the methods real time quantitive RT-PCR. verify Grim-19 protein expression levels using western blot, Analyzing the relationship between Grim-19 mRNA and clinicopathological features, and to further explore the role of Grim-19 in lung cancer carcinogenesis and the association with the development of lung cancer.
Objective
In the present study, we used lung cancer and adjacent tissues to investigate the expression of Grim-19, Stat3 and it’s downstream target gene Bcl2, CyclinB1,CyclinD1,c-Myc, Analyzing the relationship between Grim-19 mRNA and clinicopathological features, and to further explore the role of Grim-19 in lung cancer carcinogenesis and the association with the development of lung cancer.
Method
1. Detect Grim-19, Stat3 and its downstream target genes Bcl2, CyclinB1, CyclinD1, c-Myc mRNA expression in 40 cases lung cancer and adjacent tissues using RT-PCR analysis
Total RNA were extracted from 40 cases lung cancer and adjacent tissues, respectively, and the expression of Grim-19, Stat3 and its downstream target genes Bcl2, CyclinB1, CyclinD1, c-Myc was measured by RT-PCR.
2. Quantitative Grim-19 mRNA expression in 40 cases lung cancer and adjacent tissues using real time RT-PCR analysis
Total RNA were extracted from 40 cases lung cancer and adjacent tissues, respectively, and the expression of Grim-19 was measured by real time RT-PCR.
3. Protein extraction and Western blot analysis
Total protein were extracted from 40 cases lung cancer and adjacent tissues, respectively, and the expression of Grim-19 was measured by Western Blot.
4. Analyze the relationship between Grim-19 mRNA in lung cancer tissues and clinicopathological features of patients
Set 40 cases Grim-19 mRNA expression in lung cancer tissues according to sex, histological type, clinical staging, age and smoking index , then Analyze the relationship between Grim-19 mRNA in lung cancer tissues and clinicopathological features of patients.
5. Statistical method
All experiments were performed at least three independent times. Data were expressed as the means±standard and were analyzed for significant differences by independent Student’s t test and one-way ANOVA with SPSS 15.0. Differences were considered statistically significant if P value <0.05.
Result
1. Grim-19, Stat3 and it’s downstream target gene Bcl2、CyclinB1、CyclinD1、c-Myc mRNA analysis in lung cancer and adjacent tissues RT-PCR, real time RT-PCR results all indicated that: the mRNA expression of Grim-19 in lung cancer group decreased significantly compared to the corresponding adjacent group, respectively. RT-PCR results showed the mRNA expression of Stat3 and it’s downstream target gene Bcl2、CyclinB1、CyclinD1、c-Myc in lung cancer tissues were significantly higher than in its’adjacent tissues.
2. Grim-19 protein expression analysis in lung cancer and adjacent tissues
Western Blot results indicated that: the protein expression of Grim-19 in lung cancer group decreased significantly compared to the corresponding adjacent group, respectively. a decrease Grim-19 mRNA expression corresponded to a similar effect on Grim-19 protein expression.
3. The relationship between Grim-19 mRNA expression and clinical and pathological parameters of lung cancer patients
Set 40 cases Grim-19 mRNA expression in lung cancer tissues as five groups according to histology, TNM stage, sex, age, smoking condition .the relative amount of Grim-19 mRNA expression of stage I–II were significantly higher than those of stage III-IV. However, the expression of Grim-19 was determined not to be associated with the patients’sex, age, smoking condition, histology.
Conclusion
1. The expression of Grim-19 mRNA and protein in lung cancer group decreased significantly compared to the corresponding adjacent group, respectively. a decrease Grim-19 mRNA expression corresponded to a similar effect on Grim-19 protein expression.;
2. The relative amount of Grim-19 mRNA expression of stage I–II were significantly higher than those of stage III-IV;However, the expression of Grim-19 was determined not to be associated with the patients’sex, age, smoking condition, histology.
3. The mRNA expression of Stat3 and its downstream target genes Bcl2, CyclinB1, CyclinD1, c-Myc were higher in lung cancer tissues compared to the corresponding adjacent group, respectively. a decreased Grim-19 mRNA expression co-existence high expression of Stat3 in lung cancer tissues.
4. Grim-19 mRNA was down-regulated in tumor tissue and the lower expression of Grim-19 mRNA may play a major role in lung cancer carcinogenesis, suggesting that it may have very intimate association with the development of lung cancer.
引文
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17. Lovegrove FE,Gharib SA, Patel SN, et al. Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria. Am J Pathol, 2007,171(6):1894-1903.
18. Murray J, Zhang B, Taylor SW, et al. The subunit composition of the human NADH dehydrogenase obtained by rapid one-step immunopurification [J]. J Biol Chem, 2003, 278(16): 13619-22.
19. Fearnley IM, Carroll J, Shannon RJ,et al. Grim-19, a cell death regulatory gene product, is a subunit of bovine mitochondrial NADH:ubiquinone oxidoreductase (complex I) [J]. J Biol Chem, 2001, 276(42): 38345-8.
20. Alchanati I, Nallar SC, Sun P, et al. A proteomic analysis reveals the loss of expression of the cell death regulatory gene Grim-19 in human renal cell carcinomas [J]. Oncogene, 2006, 25(54): 7138-47.
21. Máximo V, Botelho T, Capela J,et al. Somatic and germline mutation in Grim-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hurthle cell) tumours of the thyroid [J]. Br J Cancer, 2005, 92(10): 1892-8.
22. GONG Long -Bo, LUO Xue -Lai, LIU Shuang -You, et al. Correlations of Grim-19 and Its Target Gene Product Stat3 to Malignancy of Human Colorectal Carcinoma [J]. Ai Zheng, 2007,26(7): 683-687
23. Mora LB, Buettner R, Seigne J, et al. Constitutive activation of Stat3 inhuman prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Research, 2002, 62(22):6659-6666.
24. Ni Z, Lou W, Leman ES, et al. Inhibition of constitutively activated Stat3 signaling pathway suppresses growth of prostate cancer cells. Cancer Res, 2000, 60(5):1225-1228.
25. Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res,2002,8(4):945-954.
26. Barton BE, Karras JG, Murphy TF, et al. Signal transducer and activator of transcription 3(Stat3) activation in prostate cancer: Direct Stat3 inhibition induces apoptosis in prostate cancer lines. Mol Cancer Ther 2004, 3(1):11-20.
27. Barton BE, Murphy TF, Adem P, et al. IL-6 signaling by Stat3 participates in the change from hyperplasia to neoplasia in NRP-152 and NRP-154 rat prostatic epithelial cells. BMC Cancer 2001, 1:19.
28. Huang F, Tong X, Fu L,et al. Knockdown of Stat3 by shRNA inhibits the growth of CAOV3 ovarian cancer cell line in vitro and in vivo [J]. Acta Biochim BiophysSin,2008, 40(6):519-525.
29.孙楠,田大,赵翔,等. STAT 3在非小细胞肺癌中的表达及与预后的关系[J].中国现代医学杂志,2006,19(16): 2906-2909.
30. Zhang X, Choe MS, Lee JE, et al. Grim-19 expression and its correlation with clinical outcomes of an induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) [J].J Clin Oncol, 2005, 23(16S):5519.
31. Maria TL, Dario C, Melissa R, et al. Environment and Genetics in Lung cancer Etiology (EAGLE) study: An integrative population-based case-control study of lung cancer [J]. BMC Public Health, 2008, 8:203-212
1. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to Interferon. Annu Rev Immunol 1997;15:749–95.
2. Sen GC. Novel functions of interferon-induced proteins. Semin Cancer Biol 2000;10(2):93–101.
3. Kalvakolanu DV. Interferons and cell growth control. Histol Histopathol 2000;15:523–537.
4. Taniguchi T, Takaoka A. A weak signal for strong responses: interferon-alpha/beta revisited. Nat Rev Mol Cell Biol 2001;2(5):378–386.
5. Sarasin-Filipowicz M, Oakeley EJ, Duong FH, et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci USA. 2008;105(19):7034-7039.
6. Borden EC, Lindner D, Dreicer R, Hussein M, Peereboom D.Second-generation interferons for cancer: clinical targets. Semin Cancer Biol 2000;10(2):125–144.
7. Jonasch E, Haluska FG. Interferon in oncological practice: of interferon biology, clinical applications, and toxicities. Oncologist 2001;6(1):34–55.
8. Kalvakolanu DV, Choi K, Borden EC. Interferons and hematopoeitic cytokines. In: Mendelsohn J, Howley PM, Israel MA, Liotta LA, editors. The molecular basis of cancer. Philadelphia: Saunders; 2001. p. 503–534.
9. Sporn MB, Suh N. Chemoprevention of cancer. Carcinogenesis 2000;21(3):525–530.
10. Kuwata T, Wang IM, Tamura T, Ponnamperuma RM, Levine R,Holmes KL, et al. Vitamin A deficiency in mice causes a systemic expansion of myeloid cells. Blood 2000;95(11):3349–3356.
11. Tanaka T, Dancheck BL, Trifiletti LC, et al. Altered localization of retinoid X receptor alpha coincides with loss of retinoid responsiveness in human breast cancer MDA-MB-231 cells. Mol Cell Biol. 2004;24(9):3972-3982.
12. Lobato JV, Maurício AC, Rodrigues JM, et al. Jaw avascular osteonecrosis after treatment of multiple myeloma with zoledronate. J Plast Reconstr Aesthet Surg. 2008;61(1):99-106.
13. Lindner DJ, Borden EC, Kalvakolanu DV. Synergistic anti-tumor effects of a combination of interferons and retinoic acid on human tumor cells in vitro and in vivo. Clin Cancer Res 1997;3(6):931–937.
14. Hofmann ER, Boyanapalli M, Lindner DJ, Weihua X, Hassel BA, Jagus R, et al. Thioredoxin reductase mediates cell death effects of the combination of beta interferon and retinoic acid. Mol Cell Biol 1998;18(11):6493–6504.
15. Adamson PC, Matthay KK, O'Brien M, et al.A phase 2 trial of all-trans-retinoic acid in combination with interferon-alpha2a in children with recurrent neuroblastoma or Wilms tumor: A Pediatric Oncology Branch, NCI and Children's Oncology Group Study. Pediatr Blood Cancer. 2007;49(5):661-665.
16. Moore DM, Kalvakolanu DV, Lippman SM, Kavanagh JJ, Hong WK, Borden EC, et al. Retinoic acid and interferon in human cancer: mechanistic and clinical studies. Semin Hematol 1994;31 (4 Suppl 5):31–37.
17. Ruotsalainen T, Halme M, Isokangas OP, Pyrhonen S, Mantyla M, Pekonen M, et al. Interferon-alpha and 13-cis-retinoic acid as maintenance therapy after high-dose combination chemotherapy with growth factor support for small cell lung cancer—a feasibility study. Anticancer Drugs 2000;11(2):101–108.
18. Majewski S, Szmurlo A, Marczak M, Jablonska S, Bollag W. Synergistic effect of retinoids and interferon alpha on tumor-induced angiogenesis: anti-angiogenic effect on HPV-harboring tumor-cell lines. Int J Cancer 1994;57(1):81–85.
19. Brewster AM, Lee JJ, Clayman GL,et al. Randomized trial of adjuvant13-cis-retinoic acid and interferon alfa for patients with aggressive skin squamous cell carcinoma. J Clin Oncol. 2007;25(15):1974-1978.
20. Shin DM, Khuri FR, Murphy B, Garden AS, Clayman G, Francisco M, et al. Combined interferon-alfa, 13-cis-retinoic acid, and alpha-tocopherol in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase ii trial. J Clin Oncol 2001;19(12):3010–3017.
21. Boorjian SA, Milowsky MI, Kaplan J, et al. Phase 1/2 clinical trial of interferon alpha2b and weekly liposome-encapsulated all-trans retinoic acid in patients with advanced renal cell carcinoma.. J Immunother 2007;30(6):655-662.
22. D.V. Kalvakolanu. The GRIMs: a new interface between cell death regulation and interferon/retinoid induced growth suppression Cytokine & Growth Factor Reviews 2004 ;15(2-3):169-194.
23. Angell JE, Lindner DJ, Shapiro PS, et al. Identification of Grim-19,a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach. J Biol Chem 2000;275(43): 33416–33426.
24. Murray JG, Zhang B, Taylor SW, Oglesbee D, Fahy E, Marusich MF, et al. The subunit composition of the human NADH dehydrogenase obtained by rapid one step immunopurification. J Biol Chem 2003;278(16):13619–13622.
25. Fearnley IM, Carroll J, Shannon RJ, Runswick MJ, Walker JE, Hirst J. Grim-19, a cell death regulatory gene product, is a subunit of bovine mitochondrial NADH: ubiquinone oxidoreductase (complex J Biol Chem 2001;276:38345–8.
26. zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002;2(5):342–350.
27. Munger K, Howley PM. Human papillomavirus immortalization and transformation functions. Virus Res 2002;89(2):213–228.
28. hidambaram NV, Angell JE, Ling W, et al. Chromosomal localization of human Grim-19,a novel IFN-beta and retinoic acid-activated regulator of cell death. JInterferon Cytokine Res 2000;20(7):661–665.
29. Singh A, Misra V, Thimmulappa RK, et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006;3(10):1865-1876.
30. Claveria C, Caminero E, Martinez-A C, et al.GH3,a novel proapoptotic domain in Drosophila Grim, promotes a mitochondrial death pathway. EMBO J, 2002;21(13):3327-3336.
31. Ma X, Karra S, Guo W, et al. Regulation of interferon and retinoic acid-induced cell death activation through thioredoxin reductase. J Biol Chem 2001; 276(27):24843-24854.
32. Maximo V, Bothelo T, Capela J, Soares P, Lima J, Taveira A, Amaro T, Barbosa AP, Preto A, Harach HR, Williams D, Sobrinho-Simoes M Somatic and germline mutation in Grim-19, a dual function gene involved in mithocondrial metabolism and cell death, is linked to mithocondrion-rich (Hurthle cell) tumorurs of the thyroid. Br J Cancer 2005;92(10):1892– 1898.
33. I Alchanati1, SC Nallar, P Sun, L Gao, J Hu, A Stein, E Yakirevich, DKonforty , I Alroy,X Zhao, SP Reddy, MB Resnick and DV Kalvakolanu A proteomic analysis reveals the loss of expression of the cell death regulatory gene Grim-19 in human renal cell carcinomas Oncogene 2006;25(54):7138-7147.
34. Zhang J, Yang J, Roy SK, et al. The cell death regulator Grim-19 is an inhibitor of signal transducer and activator of transcription 3. Proc Natl Acad Sci U S A 2003;100(16):9342–9347.
35. Schroder M, Kroeger KM, Volk HD, et al. Preassociation of nonactivated Stat3 molecules demonstrated in living cells using bioluminescence resonance energy transfer: a new model of STAT activation J Leukoc Biol 2004;75(5):792-797.
36. Kretzschmar AK, Dinger MC, Henze C, et al. Analysis of Stat3(signal transducer and activator of transcription 3)dimerization by fluorescence resonance energy transfer in living cells. Biochem J 2004;377(Pt 2): 289-297.Interferon Cytokine Res 2000;20(7):661–665.
29. Singh A, Misra V, Thimmulappa RK, et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006;3(10):1865-1876.
30. Claveria C, Caminero E, Martinez-A C, et al.GH3,a novel proapoptotic domain in Drosophila Grim, promotes a mitochondrial death pathway. EMBO J, 2002;21(13):3327-3336.
31. Ma X, Karra S, Guo W, et al. Regulation of interferon and retinoic acid-induced cell death activation through thioredoxin reductase. J Biol Chem 2001; 276(27):24843-24854.
32. Maximo V, Bothelo T, Capela J, Soares P, Lima J, Taveira A, Amaro T, Barbosa AP, Preto A, Harach HR, Williams D, Sobrinho-Simoes M Somatic and germline mutation in Grim-19, a dual function gene involved in mithocondrial metabolism and cell death, is linked to mithocondrion-rich (Hurthle cell) tumorurs of the thyroid. Br J Cancer 2005;92(10):1892– 1898.
33. I Alchanati1, SC Nallar, P Sun, L Gao, J Hu, A Stein, E Yakirevich, DKonforty , I Alroy,X Zhao, SP Reddy, MB Resnick and DV Kalvakolanu A proteomic analysis reveals the loss of expression of the cell death regulatory gene Grim-19 in human renal cell carcinomas Oncogene 2006;25(54):7138-7147.
34. Zhang J, Yang J, Roy SK, et al. The cell death regulator Grim-19 is an inhibitor of signal transducer and activator of transcription 3. Proc Natl Acad Sci U S A 2003;100(16):9342–9347.
35. Schroder M, Kroeger KM, Volk HD, et al. Preassociation of nonactivated Stat3 molecules demonstrated in living cells using bioluminescence resonance energy transfer: a new model of STAT activation J Leukoc Biol 2004;75(5):792-797.
36. Kretzschmar AK, Dinger MC, Henze C, et al. Analysis of Stat3(signal transducer and activator of transcription 3)dimerization by fluorescence resonance energy transfer in living cells. Biochem J 2004;377(Pt 2): 289-297.
2. Peto R,Darby S,Deo H,等.1950年以来英国的吸烟、戒烟和肺癌状况:全国统计和两项病例对照研究的综合报告.英国医学杂志中文版,2000,3(4)∶169.
3. Brantley EC, Nabors LB, Gillespie GY, et al. Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression. Clin Cancer Res, 2008,14(15):4694-4704.
4. Chun-Liang Chen, Ling Cen, Jennifer Kohout, et al. Signal transducer and activator of transcription3 activation is associated with bladder cancer cell growth and survival. Molecular Cancer, 2008, (7):78-89.
5. Bowman T, Garcia R, Turkson J, et al. STATs in oncogeoesis [J]. Oncogene, 2000 ,19 (21) :2 474-2488.
6. Spiekermann K, Biet hahn S, Wilde S, et al. Constitutive activation of STAT transcription factors in acute myelogenous leukemia [J] .Eur J Haematol , 2001 ,67 (2) :63-71.
7. Angell JE, Lindner DJ, Shapiro PS, Hofmann ER, Kalvakolanu DV. Identification of Grim-19, a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach. J Biol Chem 2000;275:33416-33426
8. Zhang J, Yang J, Roy SK, Tininini S, Hu J, Bromberg JF, Poli V, Stark GR, Kalvakolanu DV, The cell death regulator Grim-19 is an inhibitor of signal transducer and activator of transcription 3. Proc Natl Acad Sci USA 2003;100:9342-9347
9. Lufei C, Ma J, Huang G, Zhang T, Novotny-Diermayr V, Ong CT, Cao X. Grim-19,a death-regulatory gene product, suppresses Stat3 activity via functional interaction. EMBO J 2003;22:1325-1335
10. Huang G, Lu H, Hao A, Ng DC, Ponniah S, Guo K, Lufei C, Zeng Q, Cao X.Grim-19,a cell death regulatory protein, is essential for assembly and function of mitochondrial complex I. Mol Cell Biol 2004;24:8447-8456
11. Kalvakolanu DV.The GRIMs:a new interferface between cell death regulation and interferon/retinoid induced growth suppression.Cytokine Growth Factor Rev,2004,15(2-3):169-194
12. Leong PL, Andrews GA, Johnson DE, et al .Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc Natl Acad Sci USA , 2003 , 100 ( 7) :4138-4143.
13. Jochen Wilhelm, Alfred Pingoud. Real - Time Polymerase Chain Reaction Chem.Bio.Chem.2003,4,1120-1128.
14. Michael Liew,Robert Pryor,Robert Palais,Cindy Meadows,Maria Erali, Elaine Lyon,Carl Wittwer. Genotyping of Single-Nucleotide Polymorphisms By Hihg-Resolution Melting of Small Amplicons. Clinical Chemistry 2004,50:71156-1164.
15. Rasola A, Bernardi P. The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis.Apoptosis, 2007,12(5):815-833.
16. Lowe SW,Lin AW. Apoptosis in cancer. Carcinogenesis.2000, 21(3):485-95.
17. Lovegrove FE,Gharib SA, Patel SN, et al. Expression microarray analysis implicates apoptosis and interferon-responsive mechanisms in susceptibility to experimental cerebral malaria. Am J Pathol, 2007,171(6):1894-1903.
18. Murray J, Zhang B, Taylor SW, et al. The subunit composition of the human NADH dehydrogenase obtained by rapid one-step immunopurification [J]. J Biol Chem, 2003, 278(16): 13619-22.
19. Fearnley IM, Carroll J, Shannon RJ,et al. Grim-19, a cell death regulatory gene product, is a subunit of bovine mitochondrial NADH:ubiquinone oxidoreductase (complex I) [J]. J Biol Chem, 2001, 276(42): 38345-8.
20. Alchanati I, Nallar SC, Sun P, et al. A proteomic analysis reveals the loss of expression of the cell death regulatory gene Grim-19 in human renal cell carcinomas [J]. Oncogene, 2006, 25(54): 7138-47.
21. Máximo V, Botelho T, Capela J,et al. Somatic and germline mutation in Grim-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hurthle cell) tumours of the thyroid [J]. Br J Cancer, 2005, 92(10): 1892-8.
22. GONG Long -Bo, LUO Xue -Lai, LIU Shuang -You, et al. Correlations of Grim-19 and Its Target Gene Product Stat3 to Malignancy of Human Colorectal Carcinoma [J]. Ai Zheng, 2007,26(7): 683-687
23. Mora LB, Buettner R, Seigne J, et al. Constitutive activation of Stat3 inhuman prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Research, 2002, 62(22):6659-6666.
24. Ni Z, Lou W, Leman ES, et al. Inhibition of constitutively activated Stat3 signaling pathway suppresses growth of prostate cancer cells. Cancer Res, 2000, 60(5):1225-1228.
25. Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res,2002,8(4):945-954.
26. Barton BE, Karras JG, Murphy TF, et al. Signal transducer and activator of transcription 3(Stat3) activation in prostate cancer: Direct Stat3 inhibition induces apoptosis in prostate cancer lines. Mol Cancer Ther 2004, 3(1):11-20.
27. Barton BE, Murphy TF, Adem P, et al. IL-6 signaling by Stat3 participates in the change from hyperplasia to neoplasia in NRP-152 and NRP-154 rat prostatic epithelial cells. BMC Cancer 2001, 1:19.
28. Huang F, Tong X, Fu L,et al. Knockdown of Stat3 by shRNA inhibits the growth of CAOV3 ovarian cancer cell line in vitro and in vivo [J]. Acta Biochim BiophysSin,2008, 40(6):519-525.
29.孙楠,田大,赵翔,等. STAT 3在非小细胞肺癌中的表达及与预后的关系[J].中国现代医学杂志,2006,19(16): 2906-2909.
30. Zhang X, Choe MS, Lee JE, et al. Grim-19 expression and its correlation with clinical outcomes of an induction chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) [J].J Clin Oncol, 2005, 23(16S):5519.
31. Maria TL, Dario C, Melissa R, et al. Environment and Genetics in Lung cancer Etiology (EAGLE) study: An integrative population-based case-control study of lung cancer [J]. BMC Public Health, 2008, 8:203-212
1. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to Interferon. Annu Rev Immunol 1997;15:749–95.
2. Sen GC. Novel functions of interferon-induced proteins. Semin Cancer Biol 2000;10(2):93–101.
3. Kalvakolanu DV. Interferons and cell growth control. Histol Histopathol 2000;15:523–537.
4. Taniguchi T, Takaoka A. A weak signal for strong responses: interferon-alpha/beta revisited. Nat Rev Mol Cell Biol 2001;2(5):378–386.
5. Sarasin-Filipowicz M, Oakeley EJ, Duong FH, et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci USA. 2008;105(19):7034-7039.
6. Borden EC, Lindner D, Dreicer R, Hussein M, Peereboom D.Second-generation interferons for cancer: clinical targets. Semin Cancer Biol 2000;10(2):125–144.
7. Jonasch E, Haluska FG. Interferon in oncological practice: of interferon biology, clinical applications, and toxicities. Oncologist 2001;6(1):34–55.
8. Kalvakolanu DV, Choi K, Borden EC. Interferons and hematopoeitic cytokines. In: Mendelsohn J, Howley PM, Israel MA, Liotta LA, editors. The molecular basis of cancer. Philadelphia: Saunders; 2001. p. 503–534.
9. Sporn MB, Suh N. Chemoprevention of cancer. Carcinogenesis 2000;21(3):525–530.
10. Kuwata T, Wang IM, Tamura T, Ponnamperuma RM, Levine R,Holmes KL, et al. Vitamin A deficiency in mice causes a systemic expansion of myeloid cells. Blood 2000;95(11):3349–3356.
11. Tanaka T, Dancheck BL, Trifiletti LC, et al. Altered localization of retinoid X receptor alpha coincides with loss of retinoid responsiveness in human breast cancer MDA-MB-231 cells. Mol Cell Biol. 2004;24(9):3972-3982.
12. Lobato JV, Maurício AC, Rodrigues JM, et al. Jaw avascular osteonecrosis after treatment of multiple myeloma with zoledronate. J Plast Reconstr Aesthet Surg. 2008;61(1):99-106.
13. Lindner DJ, Borden EC, Kalvakolanu DV. Synergistic anti-tumor effects of a combination of interferons and retinoic acid on human tumor cells in vitro and in vivo. Clin Cancer Res 1997;3(6):931–937.
14. Hofmann ER, Boyanapalli M, Lindner DJ, Weihua X, Hassel BA, Jagus R, et al. Thioredoxin reductase mediates cell death effects of the combination of beta interferon and retinoic acid. Mol Cell Biol 1998;18(11):6493–6504.
15. Adamson PC, Matthay KK, O'Brien M, et al.A phase 2 trial of all-trans-retinoic acid in combination with interferon-alpha2a in children with recurrent neuroblastoma or Wilms tumor: A Pediatric Oncology Branch, NCI and Children's Oncology Group Study. Pediatr Blood Cancer. 2007;49(5):661-665.
16. Moore DM, Kalvakolanu DV, Lippman SM, Kavanagh JJ, Hong WK, Borden EC, et al. Retinoic acid and interferon in human cancer: mechanistic and clinical studies. Semin Hematol 1994;31 (4 Suppl 5):31–37.
17. Ruotsalainen T, Halme M, Isokangas OP, Pyrhonen S, Mantyla M, Pekonen M, et al. Interferon-alpha and 13-cis-retinoic acid as maintenance therapy after high-dose combination chemotherapy with growth factor support for small cell lung cancer—a feasibility study. Anticancer Drugs 2000;11(2):101–108.
18. Majewski S, Szmurlo A, Marczak M, Jablonska S, Bollag W. Synergistic effect of retinoids and interferon alpha on tumor-induced angiogenesis: anti-angiogenic effect on HPV-harboring tumor-cell lines. Int J Cancer 1994;57(1):81–85.
19. Brewster AM, Lee JJ, Clayman GL,et al. Randomized trial of adjuvant13-cis-retinoic acid and interferon alfa for patients with aggressive skin squamous cell carcinoma. J Clin Oncol. 2007;25(15):1974-1978.
20. Shin DM, Khuri FR, Murphy B, Garden AS, Clayman G, Francisco M, et al. Combined interferon-alfa, 13-cis-retinoic acid, and alpha-tocopherol in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase ii trial. J Clin Oncol 2001;19(12):3010–3017.
21. Boorjian SA, Milowsky MI, Kaplan J, et al. Phase 1/2 clinical trial of interferon alpha2b and weekly liposome-encapsulated all-trans retinoic acid in patients with advanced renal cell carcinoma.. J Immunother 2007;30(6):655-662.
22. D.V. Kalvakolanu. The GRIMs: a new interface between cell death regulation and interferon/retinoid induced growth suppression Cytokine & Growth Factor Reviews 2004 ;15(2-3):169-194.
23. Angell JE, Lindner DJ, Shapiro PS, et al. Identification of Grim-19,a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach. J Biol Chem 2000;275(43): 33416–33426.
24. Murray JG, Zhang B, Taylor SW, Oglesbee D, Fahy E, Marusich MF, et al. The subunit composition of the human NADH dehydrogenase obtained by rapid one step immunopurification. J Biol Chem 2003;278(16):13619–13622.
25. Fearnley IM, Carroll J, Shannon RJ, Runswick MJ, Walker JE, Hirst J. Grim-19, a cell death regulatory gene product, is a subunit of bovine mitochondrial NADH: ubiquinone oxidoreductase (complex J Biol Chem 2001;276:38345–8.
26. zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2002;2(5):342–350.
27. Munger K, Howley PM. Human papillomavirus immortalization and transformation functions. Virus Res 2002;89(2):213–228.
28. hidambaram NV, Angell JE, Ling W, et al. Chromosomal localization of human Grim-19,a novel IFN-beta and retinoic acid-activated regulator of cell death. JInterferon Cytokine Res 2000;20(7):661–665.
29. Singh A, Misra V, Thimmulappa RK, et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006;3(10):1865-1876.
30. Claveria C, Caminero E, Martinez-A C, et al.GH3,a novel proapoptotic domain in Drosophila Grim, promotes a mitochondrial death pathway. EMBO J, 2002;21(13):3327-3336.
31. Ma X, Karra S, Guo W, et al. Regulation of interferon and retinoic acid-induced cell death activation through thioredoxin reductase. J Biol Chem 2001; 276(27):24843-24854.
32. Maximo V, Bothelo T, Capela J, Soares P, Lima J, Taveira A, Amaro T, Barbosa AP, Preto A, Harach HR, Williams D, Sobrinho-Simoes M Somatic and germline mutation in Grim-19, a dual function gene involved in mithocondrial metabolism and cell death, is linked to mithocondrion-rich (Hurthle cell) tumorurs of the thyroid. Br J Cancer 2005;92(10):1892– 1898.
33. I Alchanati1, SC Nallar, P Sun, L Gao, J Hu, A Stein, E Yakirevich, DKonforty , I Alroy,X Zhao, SP Reddy, MB Resnick and DV Kalvakolanu A proteomic analysis reveals the loss of expression of the cell death regulatory gene Grim-19 in human renal cell carcinomas Oncogene 2006;25(54):7138-7147.
34. Zhang J, Yang J, Roy SK, et al. The cell death regulator Grim-19 is an inhibitor of signal transducer and activator of transcription 3. Proc Natl Acad Sci U S A 2003;100(16):9342–9347.
35. Schroder M, Kroeger KM, Volk HD, et al. Preassociation of nonactivated Stat3 molecules demonstrated in living cells using bioluminescence resonance energy transfer: a new model of STAT activation J Leukoc Biol 2004;75(5):792-797.
36. Kretzschmar AK, Dinger MC, Henze C, et al. Analysis of Stat3(signal transducer and activator of transcription 3)dimerization by fluorescence resonance energy transfer in living cells. Biochem J 2004;377(Pt 2): 289-297.Interferon Cytokine Res 2000;20(7):661–665.
29. Singh A, Misra V, Thimmulappa RK, et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006;3(10):1865-1876.
30. Claveria C, Caminero E, Martinez-A C, et al.GH3,a novel proapoptotic domain in Drosophila Grim, promotes a mitochondrial death pathway. EMBO J, 2002;21(13):3327-3336.
31. Ma X, Karra S, Guo W, et al. Regulation of interferon and retinoic acid-induced cell death activation through thioredoxin reductase. J Biol Chem 2001; 276(27):24843-24854.
32. Maximo V, Bothelo T, Capela J, Soares P, Lima J, Taveira A, Amaro T, Barbosa AP, Preto A, Harach HR, Williams D, Sobrinho-Simoes M Somatic and germline mutation in Grim-19, a dual function gene involved in mithocondrial metabolism and cell death, is linked to mithocondrion-rich (Hurthle cell) tumorurs of the thyroid. Br J Cancer 2005;92(10):1892– 1898.
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