An ARF/CtBP2 complex regulates BH3-only gene expression and p53-independent apoptosis.
An ARF/CtBP2 complex regulates BH3-only gene expression and p53-independent apoptosis.
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DOI：
10.1038/cdd.2009.140
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发表时间：
2010-03
影响因子：
12.4
通讯作者：
Grossman, S. R.
中科院分区：
文献类型：
--
作者：
Kovi, R. C.;Paliwal, S.;Pande, S.;Grossman, S. R.
选择性阅读框架(ARF)抑癌基因同时发挥着P53依赖和P53非依赖的功能。辅阻遏子C末端结合蛋白(CtBP)与ARF相互作用，导致蛋白酶体介导的CtBP降解。ARF可通过ARF与CtBP的相互作用诱导P53缺失的结肠癌细胞的凋亡。在一个凋亡基因阵列中，BIK被唯一鉴定为在CtBP2基因敲除或ARF过表达后在结肠癌细胞中协同上调。验证了阵列的发现，ARF诱导了Bik mRNA和蛋白的表达，这一活性需要完整的CtBP结合域。当同时沉默Bik的表达时，CtBP缺乏诱导的细胞凋亡显著减弱。对BiK启动子的分析揭示了CtBP相互作用的碱性Kruppel样因子(BKLF)的结合位点。BKLF和CtBP2抑制了Bik启动子荧光素酶的表达，ARF逆转了CtBP相关的抑制作用。染色质免疫沉淀分析表明，CtBP主要被BKLF募集到BiK启动子中。在ARF表达或CtBP缺陷的细胞中，BH3-only基因的表达谱显示，Bik在结肠癌细胞中唯一受ARF/CtBP调控，而其他BH3-only蛋白(Bim，Bmf)在骨肉瘤细胞中表现出CtBP依赖的抑制。ARF拮抗CtBP对Bik和其他BH3-only基因的抑制作用可能在ARF诱导的P53非依赖性细胞凋亡和肿瘤抑制中起关键作用。
The alternative reading frame (ARF) tumor suppressor exerts both p53-dependent and p53-independent functions. The corepressor C-terminal binding protein (CtBP) interacts with ARF, resulting in proteasome-mediated degradation of CtBP. ARF can induce apoptosis in p53-null colon cancer cells, in a manner dependent on ARF interaction with CtBP. Bik was uniquely identified in an apoptotic gene array as coordinately upregulated in colon cancer cells after either CtBP2 knockdown or ARF overexpression. Validating the array findings, ARF induced Bik mRNA and protein expression, and this activity required an intact CtBP binding domain. Apoptosis induced by CtBP deficiency was substantially impaired when Bik expression was simultaneously silenced. An analysis of the Bik promoter revealed binding sites for the CtBP-interacting basic Kruppel-like factor (BKLF). A Bik promoter luciferase reporter was repressed by BKLF and CtBP2, and ARF reversed CtBP-associated repression. Chromatin immunoprecipitation analyses showed that CtBP was recruited to the Bik promoter largely by BKLF. Expression profiling of BH3-only gene expression in ARF-expressing or CtBP-deficient cells revealed that Bik was uniquely regulated by ARF/CtBP in colon cancer cells, whereas additional BH3-only proteins (Bim, Bmf) showed CtBP-dependent repression in osteosarcoma cells. ARF antagonism of CtBP repression of Bik and other BH3-only genes may have a critical role in ARF-induced p53-independent apoptosis and tumor suppression.
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影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B
DOI：
10.1073/pnas.0830998100
发表时间：
2003-04-15
影响因子：
11.1
作者：
Grooteclaes, M;Deveraux, Q;Frisch, SM
通讯作者：
Frisch, SM
DOI：
10.1083/jcb.200703040
发表时间：
2007-11-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gillissen B;Essmann F;Hemmati PG;Richter A;Richter A;Oztop I;Chinnadurai G;Dörken B;Daniel PT
通讯作者：
Daniel PT
影响因子：
4.8
作者：
Mathai, JP;Germain, M;Shore, GC
通讯作者：
Shore, GC
影响因子：
5.3
作者：
Quinlan, Kate G. R.;Verger, Alexis;Crossley, Merlin
通讯作者：
Crossley, Merlin