Individual CREB-target genes dictate usage of distinct cAMP-responsive coactivation mechanisms
Individual CREB-target genes dictate usage of distinct cAMP-responsive coactivation mechanisms
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DOI：
10.1038/sj.emboj.7601734
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发表时间：
2007-06-20
期刊：
影响因子：
11.4
通讯作者：
Brindle, Paul K.
中科院分区：
文献类型：
--
作者：
Xu, Wu;Kasper, Lawryn H.;Brindle, Paul K.
CREB是营地和钙诱导型转录的关键介体，其中丝氨酸133在其激酶诱导型结构域（KID）中的磷酸化通常等于反式激活。 CREB在体外结合了同时激活剂CBP和p300（CBP/P300）的KIX结构域需要磷酸ser133，尽管该原型共激活因子相互作用对于内源基因表达的重要性尚不清楚。在这里，我们表明，与Kix的CREB相互作用仅对于CAMP诱导转录的一部分和CBP/P300招募是必需的。出人意料的是，在其启动子上与CREB结合的单个营地诱导基因在对Kix的依赖方面有所不同，没有检查显示完全依赖性。另外，我们发现CREB碱性拉链（BZIP）结构域中的精氨酸314（ARG314）有助于CBP/P300募集和非Kix独立的CREB反式激活函数。这意味着调节的CREB（TORC）的换能器，这是一种通过ARG314结合的无关cAMP响应共激活因子，可以在这些功能中结合CBP/P300。有趣的是，对于不需要CREB的基因的全部营地诱导也需要Kix。因此，单个Creb-target基因上下文决定了至少两种不同的营地响应共激活机制的相对贡献。
CREB is a key mediator of cAMP- and calcium-inducible transcription, where phosphorylation of serine 133 in its Kinase-Inducible Domain (KID) is often equated with transactivation. Phospho-Ser133 is required for CREB to bind the KIX domain of the coactivators CBP and p300 (CBP/p300) in vitro, although the importance of this archetype coactivator interaction for endogenous gene expression is unclear. Here, we show that the CREB interaction with KIX is necessary for only a part of cAMP-inducible transcription and CBP/p300 recruitment. Surprisingly, individual cAMP-inducible genes with CREB bound at their promoters differed in their reliance on KIX and none examined showed complete dependence. Alternatively, we found that arginine 314 (Arg314) in the CREB basic-leucine zipper (bZIP) domain contributed to CBP/p300 recruitment and KIX-independent CREB transactivation function. This implicates Transducer Of Regulated CREB (TORC), an unrelated cAMP-responsive coactivator that binds via Arg314, and which can bind CBP/p300, in these functions. Interestingly, KIX was also required for the full cAMP induction of a gene that did not require CREB. Thus, individual CREB-target gene context dictates the relative contribution of at least two different cAMP-responsive coactivation mechanisms.