VRK1 phosphorylates CREB and mediates CCND1 expression
VRK1 phosphorylates CREB and mediates CCND1 expression
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DOI：
10.1242/jcs.026757
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发表时间：
2008-09-15
影响因子：
4
通讯作者：
Kim, Kyong-Tai
中科院分区：
文献类型：
--
作者：
Kang, Tae-Hong;Park, Do-Young;Kim, Kyong-Tai
痘苗病毒B1K在病毒DNA复制中起着关键作用。同源的哺乳动物痘苗相关蛋白(VRK)也参与了DNA复制的调控，尽管直接证据仍然缺乏。在这里，我们发现VRK1通过诱导细胞周期蛋白D1(CCND1)的表达来调节DNA复制期的细胞周期进程。此外，人类癌细胞中VRK1的缺失减少了特定时间内处于S期的细胞的比例。VRK1通过促进磷酸化CREB的募集到CCND1启动子中的cAMP反应元件(CRE)的活性来特异性地增强该基因的活性。VRK1在体外使CREB在Ser133处磷酸化，而表达VRK1的激酶死亡突变体或用siRNA敲除VRK1不能激活CREB并随后激活CRE。最后，我们证明了VRK1是Myc过表达刺激的CCND1基因表达途径中的一个关键环节。我们的结果表明，VRK1是一种新的CCND1表达调控因子。
Vaccinia virus B1 kinase plays a key role in viral DNA replication. The homologous mammalian vaccinia-related kinases (VRKs) are also implicated in the regulation of DNA replication, although direct evidence remains elusive. Here we show that VRK1 regulates cell cycle progression in the DNA replication period by inducing cyclin D1 (CCND1) expression. Furthermore, depletion of VRK1 in human cancer cells reduces the fraction of cells in S phase at a given time. VRK1 specifically enhances activity of the cAMP-response element (CRE) in the CCND1 promoter by facilitating the recruitment of phospho-CREB to this locus. VRK1 phosphorylates CREB at Ser133 in vitro and the expression of a kinase-dead mutant of VRK1 or knockdown of VRK1 using siRNA fails to activate CREB and subsequently activate CRE. Finally, we show that VRK1 is a critical link in the CCND1 gene expression pathway stimulated by Myc overexpression. Our results indicate that VRK1 is a novel regulator of CCND1 expression.