Notch1 oncoprotein antagonizes TGF-β/Smad-mediated cell growth suppression via sequestration of coactivator p300
Notch1 oncoprotein antagonizes TGF-β/Smad-mediated cell growth suppression via sequestration of coactivator p300
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DOI：
10.1111/j.1349-7006.2005.00048.x
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发表时间：
2005-05-01
期刊：
影响因子：
5.7
通讯作者：
Chiba, S
中科院分区：
文献类型：
--
作者：
Masuda, S;Kumano, K;Chiba, S
Notch蛋白构成跨膜受体家族，其在细胞分化、增殖和凋亡中起关键作用。尽管已经认识到过量的Notch信号传导是潜在的致瘤性的，但是关于Notch信号传导失调诱导肿瘤转化的精确机制知之甚少。在这里，我们证明了Notch信号传导与转化生长因子-β（TGF-β）信号传导具有转录串扰，其特征在于其抗增殖作用。TGF-β介导的转录反应被组成型活性Notch 1抑制，并且这种抑制作用通过引入转录辅激活因子p300而被取消。我们进一步表明，这种TGF-β信号传导的阻断是通过从Smad 3中螯合p300来执行的。此外，在Notch 1自发激活的人宫颈癌细胞系CaSki中，用小干扰RNA抑制Notch 1表达显著恢复了对TGF-β的反应性。综上所述，我们认为Notch癌蛋白促进细胞生长和癌症发展的部分原因是通过从Smad 3中分离p300来抑制TGF-β的生长抑制作用。
The Notch proteins constitute a family of transmembrane receptors that play a pivotal role in cellular differentiation, proliferation and apoptosis. Although it has been recognized that excess Notch signaling is potentially tumorigenic, little is known about precise mechanisms through which dysregulated Notch signaling induces neoplastic transformation. Here we demonstrate that Notch signaling has a transcriptional cross-talk with transforming growth factor-beta (TGF-beta) signaling, which is well characterized by its anti proliferative effects. TGF-beta-mediated transcriptional responses are suppressed by constitutively active Notch1, and this inhibitory effect is canceled by introduction of transcriptional coactivator p300. We further show that this blockade of TGF-beta signaling is executed by the sequestration of p300 from Smad3. Moreover, in a human cervical carcinoma cell line, CaSki, in which Notch1 is spontaneously activated, suppression of Notch1 expression with small interfering RNA significantly restores the responsiveness to TGF-beta. Taken together, we propose that Notch oncoproteins promote cell growth and cancer development partly by suppressing the growth inhibitory effects of TGF-beta through sequestrating p300 from Smad3.