The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor
The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor
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DOI：
10.1074/jbc.m110901200
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发表时间：
2002-04-19
影响因子：
4.8
通讯作者：
Lasky, LA
中科院分区：
文献类型：
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作者：
Tang, TTL;Dowbenko, D;Lasky, LA
(T)he通过突变PTEN脂质磷酸酶激活AKT/蛋白激酶B激酶导致多种肿瘤的存活率提高。这种对凋亡的抗性部分是通过抑制由叉头转录因子亚家族（包括AFX）诱导的遗传程序来实现的。在这里，我们描述了一个AFX调节的途径，似乎占至少一部分，这种凋亡调控系统。被诱导合成活性形式AFX的细胞通过激活凋亡性死亡途径而死亡。对AFX调控基因的分析表明，转录抑制因子BCL-6的表达上调了4 -7倍。对BCL-6启动子的检查表明AFX结合到可以激活转录的特异性靶位点。BCL-X-L是一种抗凋亡蛋白，在其启动子中含有潜在的BCL-6靶位点。对表达AFX的细胞中内源性BCL-X-L水平的分析显示转录物和蛋白质的下调增强（类似于1.3 -1.7倍），并且BCL-6直接结合并抑制BCL-XL启动子。最后，从BCL-6-/-小鼠中分离的巨噬细胞在体外显示出增强的存活。这些结果表明AFX通过转录抑制因子BCL-6抑制抗凋亡BCL-XL的水平来部分地调节凋亡。
(T)he activation of the AKT/protein kinase B kinases by mutation of the PTEN lipid phosphatase results in enhanced survival of a diversity of tumors. This resistance to apoptosis is partly accomplished by the inhibition of genetic programs induced by a subfamily of forkhead transcription factors including AFX. Here we describe an AFX-regulated pathway that appears to account for at least part of this apoptotic regulatory system. Cells induced to synthesize an active form of AFX die by activating the apoptotic death pathway. An analysis of genes regulated by AFX demonstrated that BCL-6, a transcriptional repressor, is up-regulated similar to4-7-fold. An examination of the BCL-6 promoter demonstrated that AFX bound to specific target sites that could activate transcription. BCL-X-L, an anti-apoptotic protein, contains potential BCL-6 target sites in its promoter. An analysis of endogenous BCL-X-L levels in AFX-expressing cells revealed enhanced down-regulation of the transcript (similar to1.3-1.7-fold) and protein, and BCL-6 directly binds to and suppresses the BCL-XL promoter. Finally, macrophages isolated from BCL-6-/- mice show enhanced survival in vitro. These results suggest that AFX regulates apoptosis in part by suppressing the levels of anti-apoptotic BCL-XL through the transcriptional repressor BCL-6.