The RNA-binding protein KSRP promotes decay of beta-catenin mRNA and is inactivated by PI3K-AKT signaling.
The RNA-binding protein KSRP promotes decay of beta-catenin mRNA and is inactivated by PI3K-AKT signaling.
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DOI：
10.1371/journal.pbio.0050005
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发表时间：
2006-12
期刊：
影响因子：
9.8
通讯作者：
Briata P
中科院分区：
文献类型：
--
作者：
Gherzi R;Trabucchi M;Ponassi M;Ruggiero T;Corte G;Moroni C;Chen CY;Khabar KS;Andersen JS;Briata P
β-catenin在细胞命运决定、细胞增殖和转化等生物学过程中起着重要作用。在这里，我们报道β-catenin由一个不稳定的转录物编码，其半衰期被Wnt和磷脂酰肌醇3-激酶- akt信号延长。AKT磷酸化mRNA衰变促进因子KSRP的独特丝氨酸残基，诱导其与多功能蛋白14-3-3的关联，并阻止KSRP与外核糖核分解复合物外泌体的相互作用。这削弱了KSRP促进mRNA快速衰变的能力。我们的研究结果揭示了β-catenin表达的一个意想不到的控制水平，指出KSRP是确保β-catenin在未刺激细胞中快速降解所需的因子。我们提出KSRP磷酸化是磷脂酰肌醇3-激酶- akt信号传导和β-连环蛋白积累之间的联系。在哺乳动物发育和成年期间，β-catenin调节一系列基因的转录，这些基因在细胞增殖和分化中起着多种重要作用。当β-catenin携带突变导致β-catenin功能失控时，它也在癌症中发挥作用。在这里，我们报道β-catenin编码转录物的寿命受到调控控制。我们发现，与哺乳动物正常发育相关并与肿瘤形成有关的特定细胞信号可以延长β-catenin转录物的半衰期，从而导致β-catenin蛋白的积累。我们通过显示负责β-连环蛋白转录不稳定性（从而降解）的蛋白质因子被磷酸化（一种化学修饰）破坏，确定了这种延长的分子机制。当该因子受损时，β-catenin mRNA和蛋白会积累。我们的研究结果表明，通过调节β-catenin转录物的半衰期来响应与增殖和分化相关的信号，β-catenin水平得到了意想不到的控制。作者发现，PI3K-AKT信号通路延长了β-catenin mRNA的半衰期，揭示了β-catenin调控的新水平。
β-catenin plays an essential role in several biological events including cell fate determination, cell proliferation, and transformation. Here we report that β-catenin is encoded by a labile transcript whose half-life is prolonged by Wnt and phosphatidylinositol 3-kinase–AKT signaling. AKT phosphorylates the mRNA decay-promoting factor KSRP at a unique serine residue, induces its association with the multifunctional protein 14-3-3, and prevents KSRP interaction with the exoribonucleolytic complex exosome. This impairs KSRP's ability to promote rapid mRNA decay. Our results uncover an unanticipated level of control of β-catenin expression pointing to KSRP as a required factor to ensure rapid degradation of β-catenin in unstimulated cells. We propose KSRP phosphorylation as a link between phosphatidylinositol 3-kinase–AKT signaling and β-catenin accumulation. During mammalian development and adulthood, β-catenin regulates the transcription of a family of genes with multiple essential roles in cell proliferation and differentiation. β-catenin also plays a role in cancer when it carries mutations that result in uncontrolled β-catenin function. Here, we report that the lifetime of the β-catenin–encoding transcript is under regulatory control. We show that specific cellular signals relevant to proper mammalian development and implicated in tumor formation can prolong β-catenin transcript half-life, leading to the accumulation of β-catenin protein. We identify a molecular mechanism for this prolongation by showing that a protein factor responsible for β-catenin transcript instability (and thus degradation) is impaired by phosphorylation, a chemical modification. When this factor is impaired, β-catenin mRNA and protein accumulate. Our results point to an unanticipated control of β-catenin levels through regulation of its transcript half-life in response to signals related to proliferation and differentiation. The authors show that the half-life of β-catenin mRNA is prolonged by PI3K-AKT signaling, revealing a new level of control on β-catenin.
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影响因子：
14.9
作者：
Bakheet T;Williams BR;Khabar KS
通讯作者：
Khabar KS
影响因子：
2.7
作者：
Hedgepeth, CM;Conrad, LJ;Klein, PS
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DOI：
10.1073/pnas.96.15.8745
发表时间：
1999-07-20
影响因子：
11.1
作者：
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通讯作者：
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8
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Desbois-Mouthon, C;Cadoret, A;Capeau, J
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Capeau, J