Activation of cAMP response element-mediated gene expression by regulated nuclear transport of TORC proteins
Activation of cAMP response element-mediated gene expression by regulated nuclear transport of TORC proteins
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DOI：
10.1016/j.cub.2004.11.002
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发表时间：
2004-12-14
期刊：
影响因子：
9.2
通讯作者：
Labow, M
中科院分区：
文献类型：
--
作者：
Bittinger, MA;McWhinnie, E;Labow, M
CREB蛋白家族是响应细胞外信号的基因表达的关键介质，也是适应性行为和长期记忆形成的重要调节因子[1-4]。TORC蛋白最近被描述为有效的CREB共激活因子，但其在CREB活性调控中的作用尚不清楚[5,6]。发现TORC蛋白以依赖于crm1的方式从细胞核中输出。开发了一种基于高通量显微镜的筛选方法来鉴定能够诱导核TORC积累的基因和途径。PKA催化亚基和钙通道TRPV6的表达将TORC1重新定位到细胞核。三种人类TORC蛋白的核积累是通过增加细胞内cAMP或钙水平诱导的。TORC1和TORC2对钙而非cAMP的易位是由钙调神经磷酸酶介导的，并且TORC1被钙调神经磷酸酶直接去磷酸化。研究表明，TORC功能对于cAMP、钙或GPCR激活诱导的cre介导的基因表达至关重要，TORC1的核转运足以激活cre依赖性转录。果蝇TORC也被证明在体内响应钙调磷酸酶激活而易位。因此，TORC核易位是激活camp反应基因的一个必要的、保守的步骤。
The CREB family of proteins are critical mediators of gene expression in response to extracellular signals and are essential regulators of adaptive behavior and long-term memory formation [1-4]. The TORC proteins were recently described as potent CREB coactivators, but their role in regulation of CREB activity remained unknown [5, 6]. TORC proteins were found to be exported from the nucleus in a CRM1-dependent fashion. A high-throughput microscopy-based screen was developed to identify genes and pathways capable of inducing nuclear TORC accumulation. Expression of the catalytic subunit of PKA and the calcium channel TRPV6 relocalized TORC1 to the nucleus. Nuclear accumulation of the three human TORC proteins was induced by increasing intracellular cAMP or calcium levels. TORC1 and TORC2 translocation in response to calcium, but not cAMP, was mediated by calcineurin, and TORC1 was shown to be directly dephosphorylated by calcineurin. TORC function was shown to be essential for CRE-mediated gene expression induced by cAMP, calcium, or GPCR activation, and nuclear transport of TORC1 was sufficient to activate CRE-dependent transcription. Drosophila TORC was also shown to translocate in response to calcineurin activation in vivo. Thus, TORC nuclear translocation is an essential, conserved step in activation of cAMP-responsive genes.