Zhu Jidong, Blenis John, Yuan Junying
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2008 May 6;105(18):6584-9. doi: 10.1073/pnas.0802785105. Epub 2008 May 1.
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.
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。
