The MEK pathway is required for stimulation of p21WAF1/CIP1 by transforming growth factor-β
The MEK pathway is required for stimulation of p21WAF1/CIP1 by transforming growth factor-β
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DOI：
10.1074/jbc.274.50.35381
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发表时间：
1999-12-10
影响因子：
4.8
通讯作者：
Wang, XF
中科院分区：
文献类型：
--
作者：
Hu, PPC;Shen, X;Wang, XF
转化生长因子-β（TGF-β）可以诱导多种细胞类型中的细胞周期蛋白依赖性激酶抑制剂p21和p15。我们先前已经表明，Smad 3是TGF-β的生长抑制活性所必需的，而Smads的过表达不足以激活HaCaT细胞中p21的表达。这些数据表明，一个额外的信号通路可能参与刺激HaCaT细胞中的p21。鉴于最近发现丝裂原活化蛋白激酶（MAPK）通路可引起p21诱导和细胞停滞，我们检测了该通路参与TGF-β诱导的p21和p15。我们发现TGF-β可调节MAPK通路，导致转录因子Elk的反式激活能力增加，MAPK通路中的组成性活性成分激活pal表达，并且MAPK途径的抑制剂或显性负性构建体显著降低TGF-β对p21的诱导。组成型活性MEK和MEK抑制剂对Smad活性，包括DNA结合、定位和与辅激活因子p800/CBP的相互作用均无影响，这些发现表明MAPK通路可能是一个独立的通路，参与TGF-β诱导p21和p15。
Transforming growth factor-beta (TGF-beta)can induce the cyclin-dependent kinase inhibitors p21 and p15 in a variety of cell types. We have shown previously that Smad3 is required for the growth inhibitory activity of TGF-beta, whereas overexpression of Smads is not sufficient to activate the expression of p21 in HaCaT cells. These data suggest that an additional signaling pathway may be involved in stimulating p21 in HaCaT cells. Given the recent finding that the mitogen-activated protein kinase (MAPK) pathway can cause p21 induction and arrest cells, we examined the involvement of this pathway for p21 and p15 induction by TGF-beta, We found that TGF-beta can regulate the MAPK pathway, leading to the increased transactivation ability of transcription factor Elk, Constitutively active components in the MAPK pathway activate pal expression, and inhibitors or dominant negative constructs for the MAPK pathway significantly decrease p21 induction by TGF-beta, Both constitutively active MEK and inhibitors for MEK have no effect on Smad activity, including DNA binding, localization, and interaction with coactivator p800/CBP, These findings suggest that the MAPK pathway may be an independent pathway that is involved in p21 and p15 induction by TGF-beta.