PI3K/Akt和MAPK信号通路的激活通过磷酸化并促进Mad1的降解来调节Myc介导的转录。
Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1.
作者信息
Zhu Jidong, Blenis John, Yuan Junying
机构信息
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Proc Natl Acad Sci U S A. 2008 May 6;105(18):6584-9. doi: 10.1073/pnas.0802785105. Epub 2008 May 1.
Abstract
Mad1, a member of the Myc/Max/Mad family, suppresses Myc-mediated transcriptional activity by competing with Myc for heterodimerization with its obligatory partner, Max. The expression of Mad1 suppresses Myc-mediated cell proliferation and transformation. The levels of Mad1 protein are generally low in many human cancers, and Mad1 protein has a very short half-life. However, the mechanism that regulates the turnover of Mad1 protein is poorly understood. In this study, we showed that Mad1 is a substrate of p90 ribosomal kinase (RSK) and p70 S6 kinase (S6K). Both RSK and S6K phosphorylate serine 145 of Mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of Mad1 accelerates the ubiquitination and degradation of Mad1 through the 26S proteasome pathway, which in turn promotes the transcriptional activity of Myc. Our study provides a direct link between the growth factor signaling pathways regulated by PI3 kinase/Akt and MAP kinases with Myc-mediated transcription.
摘要
Mad1是Myc/Max/Mad家族的成员之一，它通过与Myc竞争与其必需伴侣Max形成异二聚体，从而抑制Myc介导的转录活性。Mad1的表达可抑制Myc介导的细胞增殖和转化。在许多人类癌症中，Mad1蛋白水平通常较低，且Mad1蛋白的半衰期非常短。然而，调节Mad1蛋白周转的机制却知之甚少。在本研究中，我们发现Mad1是p90核糖体激酶（RSK）和p70 S6激酶（S6K）的底物。在血清或胰岛素刺激下，RSK和S6K都会使Mad1的丝氨酸145磷酸化。Mad1的Ser-145磷酸化通过26S蛋白酶体途径加速Mad1的泛素化和降解，进而促进Myc的转录活性。我们的研究在由PI3激酶/Akt和MAP激酶调节的生长因子信号通路与Myc介导的转录之间建立了直接联系。
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2
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Curr Top Microbiol Immunol. 2006;302:63-122. doi: 10.1007/3-540-32952-8_4.
3
Mnt-Max to Myc-Max complex switching regulates cell cycle entry.Mnt-Max 复合体向 Myc-Max 复合体的转换调控细胞周期进入。
J Cell Biol. 2005 May 9;169(3):405-13. doi: 10.1083/jcb.200411013. Epub 2005 May 2.
4
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5
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6
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Mol Cell Biol. 2004 Jan;24(1):200-16. doi: 10.1128/MCB.24.1.200-216.2004.
7
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8
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