Inhibition of smad antiproliferative function by CDK phosphorylation
Inhibition of smad antiproliferative function by CDK phosphorylation
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DOI：
10.4161/cc.4.1.1366
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发表时间：
2005-01-01
期刊：
影响因子：
4.3
通讯作者：
Matsuura, I
中科院分区：
文献类型：
--
作者：
Liu, F;Matsuura, I
Rb家族成员是CDK 4的唯一被证实的底物，直到最近显示在介导TGF-β抗增殖反应中起关键作用的Smad 3在体内和体外被CDK 4和CDK 2磷酸化。Smad 3的CDK磷酸化抑制其转录活性和抗增殖功能。Rb通路在几乎所有人类癌症中被破坏。由于p16肿瘤抑制因子的频繁失活或细胞周期蛋白D1的过度表达，大多数癌症含有高水平的CDK活性。因此，Rb途径的破坏不仅使Rb失活，而且可能减少Smad活性，这可能有助于肿瘤发生和对癌症中TGF-β生长抑制作用的抗性。虽然Smad 3的基因突变尚未报道，但Smad 3的CDK磷酸化可能提供了在肿瘤发生的早期阶段抑制Smad 3的肿瘤抑制功能的表观遗传机制。
Rb family members were the only demonstrated substrates of CDK4 until it was shown recently that Smad3, which plays a key role in mediating TGF-beta antiproliferative responses, is phosphorylated by both CDK4 and CDK2 in vivo and in vitro. CDK phosphorylation of Smad3 inhibits its transcriptional activity and antiproliferative function. The Rb pathway is disrupted in almost all human cancers. Most cancers contain high levels of CDK activity due to frequent inactivation of the p16 tumor suppressor or overexpression of cyclin D1. Therefore, disruption of the Rb pathway not only inactivates Rb, but also likely diminishes Smad activity, which may contribute to tumorigenesis and resistance to the TGF-beta growth-inhibitory effects in cancers. Although genetic mutation of Smad3 has not been reported, CDK phosphorylation of Smad3 may provide an epigenetic mechanism for inhibition of the tumor suppressive function of Smad3 during the early stages of tumorigenesis.