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首页> 外文期刊>Molecular and Cellular Biology >Regulation of Id3 cell cycle function by Cdk-2-dependent phosphorylation.
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Regulation of Id3 cell cycle function by Cdk-2-dependent phosphorylation.

机译：Cdk-2依赖性磷酸化对Id3细胞周期功能的调节。

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The functions of basic helix-loop-helix (bHLH) transcription factors in activating differentiation-linked gene expression and in inducing G1 cell cycle arrest are negatively regulated by members of the Id family of HLH proteins. These bHLH antagonists are induced during a mitogenic signalling response, and they function by sequestering their bHLH targets in inactive heterodimers that are unable to bind to specific gene regulatory (E box) sequences. Recently, cyclin E-Cdk2- and cyclin A-Cdk2-dependent phosphorylation of a single conserved serine residue (Ser5) in Id2 has been shown to occur during late G1-to-S phase transition of the cell cycle, and this neutralizes the function of Id2 in abrogating E-box-dependent bHLH homo- or heterodimer complex formation in vitro (E. Hara, M. Hall, and G. Peters, EMBO J. 16:332-342, 1997). We now show that an analogous cell-cycle-regulated phosphorylation of Id3 alters the specificity of Id3 for abrogating both E-box-dependent bHLH homo- or heterodimer complex formation in vitro and E-box-dependent reporter gene function in vivo. Furthermore, compared with wild-type Id3, an Id3 Asp5 mutant (mimicking phosphorylation) is unable to promote cell cycle S phase entry in transfected fibroblasts, whereas an Id3 Ala5 mutant (ablating phosphorylation) displays an activity significantly greater than that of wild-type Id3 protein. Cdk2-dependent phosphorylation therefore provides a switch during late G1-to-S phase that both nullifies an early G1 cell cycle regulatory function of Id3 and modulates its target bHLH specificity. These data also demonstrate that the ability of Id3 to promote cell cycle S phase entry is not simply a function of its ability to modulate bHLH heterodimer-dependent gene expression and establish a biologically important mechanism through which Cdk2 and Id-bHLH functions are integrated in the coordination of cell proliferation and differentiation.
机译：碱性螺旋-环-螺旋（bHLH）转录因子在激活分化相关基因表达和诱导G1细胞周期停滞中的功能受到HLH蛋白Id家族成员的负调控。这些bHLH拮抗剂是在促有丝分裂信号反应期间诱导的，它们通过将bHLH靶标螯合在无法结合特定基因调控（E box）序列的非活性异二聚体中而发挥作用。最近，已证明Id2中单个保守丝氨酸残基（Ser5）的细胞周期蛋白E-Cdk2-和细胞周期蛋白A-Cdk2依赖的磷酸化发生在细胞周期的G1-S期过渡后期，这中和了功能Id2在体外消除E-盒依赖性bHLH同二聚体或异二聚体复合物的形成中的作用（E. Hara，M. Hall，and G. Peters，EMBO J. 16：332-342，1997）。我们现在显示，Id3的类似细胞周期调节的磷酸化改变了Id3的特异性，以废除体外E-box依赖的bHLH同源或异源二聚体复合物的形成以及体内E-box依赖的报告基因的功能。此外，与野生型Id3相比，Id3 Asp5突变体（模仿磷酸化）不能促进转染的成纤维细胞中的细胞周期S期进入，而Id3 Ala5突变体（消融磷酸化）显示的活性明显高于野生型Id3蛋白。因此，依赖于Cdk2的磷酸化在G1到S晚期阶段提供了一个转换，既使Id3的早期G1细胞周期调节功能无效，又调节了其靶bHLH特异性。这些数据还表明，Id3促进细胞周期S期进入的能力不仅仅是其调节bHLH异二聚体依赖性基因表达并建立生物学重要机制的能力的函数，通过该机制，Cdk2和Id-bHLH功能可以整合到细胞中。细胞增殖和分化的协调。

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