Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression
Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression
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DOI：
10.1038/sj.emboj.7601715
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发表时间：
2007-06-20
期刊：
影响因子：
11.4
通讯作者：
Montminy, Marc
中科院分区：
文献类型：
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作者：
Ravnskjaer, Kim;Kester, Henri;Montminy, Marc
许多激素和生长因子通过促进CREB（P-CREB）的磷酸化刺激基因表达，从而增强了其与组蛋白乙酰基酶旁系同源物P300和CBP（CBP/P300）的关联。相对于cAMP，应力信号触发可比量的CREB磷酸化，但对CRE依赖性转录的影响最小。在这里，我们表明，潜在的细胞质共激活因子TORC2通过与CBP/P300关联并将其募集到CREB靶基因的子集来介导靶基因激活，以响应cAPC信号传导。但是，torc2不会因应力信号而被激活。在缺席的情况下，由于CBP募集的阻滞，P-CREB无法刺激CRE依赖性转录。 TORC2对CBP/P300启动子占用率的影响似乎是关键的，因为功能突变体CREB多肽的增益与CBP的亲和力增加，CBP恢复了CRE介导的转录在暴露于应力信号的细胞中。综上所述，这些结果表明TORC2是介导cAMP和应力途径对CREB靶基因表达的差异作用的长期追求的辅助因子。
A number of hormones and growth factors stimulate gene expression by promoting the phosphorylation of CREB (P-CREB), thereby enhancing its association with the histone acetylase paralogs p300 and CBP (CBP/p300). Relative to cAMP, stress signals trigger comparable amounts of CREB phosphorylation, but have minimal effects on CRE-dependent transcription. Here, we show that the latent cytoplasmic coactivator TORC2 mediates target gene activation in response to cAMP signaling by associating with CBP/p300 and increasing its recruitment to a subset of CREB target genes. TORC2 is not activated in response to stress signals, however; and in its absence, P-CREB is unable to stimulate CRE-dependent transcription, due to a block in CBP recruitment. The effect of TORC2 on CBP/p300 promoter occupancy appears pivotal because a gain of function mutant CREB polypeptide with increased affinity for CBP restored CRE-mediated transcription in cells exposed to stress signals. Taken together, these results indicate that TORC2 is one of the long sought after cofactors that mediates the differential effects of cAMP and stress pathways on CREB target gene expression.