A family of LIM-only transcriptional coactivators: Tissue-specific expression and selective activation of CREB and CREM
A family of LIM-only transcriptional coactivators: Tissue-specific expression and selective activation of CREB and CREM
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DOI：
10.1128/mcb.20.22.8613-8622.2000
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发表时间：
2000-11-01
影响因子：
5.3
通讯作者：
Sassone-Corsi, P
中科院分区：
文献类型：
--
作者：
Fimia, GM;De Cesare, D;Sassone-Corsi, P
CREB家族的转录因子响应于各种信号传导途径控制大量基因的表达。CREB家族成员介导的调节与多种生理功能有关。经典地，CREB的激活已知发生在必需调节位点（CREB中的Ser133）的磷酸化以及随后与普遍存在的共激活因子CREB结合蛋白（CBP）的相互作用之后。然而，在靶基因的识别中实现选择性的机制以及为确保组织特异性激活而采用的途径仍然未被认识。我们最近描述了CREB家族转录因子的第一个组织特异性共激活因子，ACT（睾丸CREM激活因子）。ACT是一种仅与男性生殖细胞中CREM相关的LIM蛋白，并提供独立于磷酸化和CBP的激活功能。在这里，我们的特点是一个家庭的LIM只有蛋白质共享共同的结构组织与ACT。这些被称为四个半LIM结构域（FHL）蛋白，并显示组织特异性和发育调节表达。FHL蛋白显示不同程度的内在激活潜力。当在酵母或哺乳动物细胞中共表达时，它们为CREB和CREM提供强大的激活功能，特定的组合引发选择性激活。ACT蛋白的缺失分析表明，激活功能取决于LIM结构域的特定排列，这对反式激活和相互作用特性都是必不可少的。这项研究揭示了存在一个家庭的组织特异性辅激活因子，通过新的，CBP独立的路线，引发CREB和CREM的转录激活。PHL蛋白的其他合作伙伴的未来鉴定可能会揭示组织特异性转录调控的不受重视的方面。
Transcription factors of the CREB family control the expression of a large number of genes in response to various signaling pathways. Regulation mediated by members of the CREB family has been linked to various physiological functions. Classically, activation by CREB is known to occur upon phosphorylation at an essential regulatory site (Ser133 in CREB) and the subsequent interaction with the ubiquitous coactivator CREB-binding protein (CBP). However, the mechanism by which selectivity is achieved in the identification of target genes, as well as the routes adopted to ensure tissue-specific activation, remains unrecognized. We have recently described the first tissue-specific coactivator of CREB family transcription factors, ACT (activator of CREM in testis). ACT is a LIM-only protein which associates with CREM in male germ cells and provides an activation function which is independent of phosphorylation and CBP. Here we characterize a family of LIM-only proteins which share common structural organization with ACT. These are referred to as four-and-a-half-LIM-domain (FHL) proteins and display tissue-specific and developmentally regulated expression. FHL proteins display different degrees of intrinsic activation potential. They provide powerful activation function to both CREB and CREM when coexpressed either in yeast or in mammalian cells, specific combinations eliciting selective activation. Deletion analysis of the ACT protein shows that the activation function depends on specific arrangements of the LIM domains, which are essential for both transactivation and interaction properties. This study uncovers the existence of a family of tissue-specific coactivators that operate through novel, CBP-independent routes to elicit transcriptional activation by CREB and CREM. The future identification of additional partners of PHL proteins is likely to reveal unappreciated aspects of tissue-specific transcriptional regulation.