Signaling-dependent and coordinated regulation of transcription, splicing, and translation resides in a single coregulator, PCBP1
Signaling-dependent and coordinated regulation of transcription, splicing, and translation resides in a single coregulator, PCBP1
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DOI：
10.1073/pnas.0701065104
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发表时间：
2007-04-03
影响因子：
11.1
通讯作者：
Kumar, Rakesh
中科院分区：
文献类型：
--
作者：
Meng, Qingchang;Rayala, Suresh K.;Kumar, Rakesh
转录、剪接和翻译可能以时空依赖的方式协调调节，尽管支持这一概念的实验证据很少。酵母双杂交筛选乳腺cDNA文库与人类p21激活激酶1（Pak 1）作为诱饵确定聚C-RNA结合蛋白1（PCBP 1），它控制翻译的mRNA含有DICE（分化控制元件）。人细胞的促有丝分裂刺激以Pak 1敏感的方式磷酸化苏氨酸60和127上的PCBP 1。Pak 1依赖性磷酸化PCBP 1释放其结合和翻译抑制从DICE-小基因。PCBP 1的过表达也抑制了内源性L1细胞粘附分子mRNA的翻译，其在3'非翻译区含有两个DICE基序。我们还发现，Pak 1激活导致PCBP 1的核保留增加，真核翻译起始因子4 E（elF 4 E）启动子的招募，并以Pak 1敏感的方式刺激elF 4 E表达。此外，促有丝分裂刺激促进Pak 1和PCBP 1依赖的选择性剪接和外显子列入从CD 44小基因。PCBF 1的选择性剪接功能反过来又通过其与Caper α的内在相互作用介导，Caper α是一种先前参与RNA剪接的U2 snRNP辅助因子相关蛋白。这些发现确立了这样的原则：单个辅调节因子可以作为转录、剪接和翻译的信号依赖性和协调调节因子发挥作用。
Transcription, splicing, and translation are potentially coordinately regulatable in a temporospatial-dependent manner, although supporting experimental evidence for this notion is scarce. Yeast two-hybrid screening of a mammary gland cDNA library with human p21-activated kinase 1 (Pak1) as bait identified polyC-RNA-binding protein 1 (PCBP1), which controls translation from mRNAs containing the DICE (differentiation control element). Mitogenic stimulation of human cells phosphorylated PCBP1 on threonines 60 and 127 in a Pak1-sensitive manner. Pak1-dependent phosphorylation of PCBP1 released its binding and translational inhibition from a DICE-minigene. Overexpression of PCBP1 also inhibited the translation of the endogenous L1 cell adhesion molecule mRNA, which contains two DICE motifs in the 3' untranslated region. We also found that Pak1 activation led to an increased nuclear retention of PCBP1, recruitment to the eukaryotic translation initiation factor 4E (elF4E) promoter, and stimulation of elF4E expression in a Pak1-sensitive manner. Moreover, mitogenic stimulation promoted Pak1- and PCBP1-dependent alternative splicing and exon inclusion from a CD44 minigene. The alternative splicing functions of PCBF1 were in turn mediated by its intrinsic interaction with Caper alpha, a U2 snRNP auxiliary factor-related protein previously implicated in RNA splicing. These findings establish the principle that a single coregulator can function as a signal-dependent and coordinated regulator of transcription, splicing, and translation.