Smad pathway-specific transcriptional regulation of the cell cycle inhibitor p21WAF1/Cip1
Smad pathway-specific transcriptional regulation of the cell cycle inhibitor p21WAF1/Cip1
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DOI：
10.1002/jcp.20304
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发表时间：
2005-07-01
影响因子：
5.6
通讯作者：
Moustakas, A
中科院分区：
文献类型：
--
作者：
Pardali, K;Kowanetz, M;Moustakas, A
转化生长因子-β（TGF-β）抑制上皮细胞生长，部分通过转录诱导细胞周期抑制因子p21（WAF 1/Cip 1）（p21）。我们发现，骨形态发生蛋白（BMP）-7诱导更高的p21比TGF-β 1在各种上皮细胞的表达。尽管如此，BMP-7仅微弱地抑制上皮细胞增殖，因为细胞周期促进因子ld 2被BMP-7伴随诱导。用TGF-β超家族的所有I型受体进行的信号传导研究表明，BMP受体比TGF-β/激活素受体诱导更高的p21表达。Smad 4通过所有受体途径对p21调节是必需的。基于先前已知的c-Myc阻断p21表达和上皮细胞生长停滞对TGF-β 1的反应的能力，我们证明异位c-Myc表达可以消除所有TGF-β和BMP受体对Smad介导的p21诱导。此外，通过所有受体途径的p21诱导可以被TGF-β超家族的天然抑制剂阻断。Smad 7抑制所有通路，而Smad 6选择性地抑制BMP通路。观察到的途径特异性反映了BMP Smads与TGF-β Smads相比反式激活p21启动子的效率。此外，BMP-特异性Smads、Smad 1、Smad 5，尤其是Smad 8，可诱导内源性p21 mRNA和蛋白水平，而与TGF-β受体磷酸化Smads（R-Smads）、Smad 2和Smad 3相比，它们不能诱导上皮生长抑制。因此，p21是所有TGF-β超家族通路的共同靶标。然而，TGF-β超家族成员诱导细胞生长停滞的能力取决于其他基因靶点的调节。
Transforming growth factor-beta (TGF-beta) inhibits epithelial cell growth, in part via transcriptional induction of the cell cycle inhibitor p21(WAF1/Cip1) (p21). We show that bone morphogenetic protein (BMP)-7 induces higher p21 expression than TGF-beta 1 in various epithelial cells. Despite this, BMP-7 only weakly suppresses epithelial cell proliferation, as ld2, a cell cycle-promoting factor, becomes concomitantly induced by BMP-7. Signaling studies with all type I receptors of the TGF-beta superfamily show that BMP receptors induce higher p21 expression than TGF-beta/activin receptors. Smad4 is essential for p21 regulation by all receptor pathways. Based on the previously known ability of c-Myc to block p21 expression and epithelial growth arrest in response to TGF-beta 1, we demonstrate that ectopic c-Myc expression can abrogate Smad-mediated p21 induction by all TGF-beta and BMP receptors. Furthermore, p21 induction by all receptor pathways can be blocked by the natural inhibitors of the TGF-beta superfamily. Smad7 inhibits all pathways whereas Smad6 selectively inhibits the BMP pathways. The observed pathway specificity reflects the efficiency by which BMP Smads, compared to TGF-beta Smads, transactivate the p21 promoter. In addition, BMP-specific Smads, Smad1, Smad5, and especially Smad8, induce enclogenous p21 rnRNA and protein levels, while they fail to induce epithelial growth inhibition when compared to TGF-beta receptor-phosphorylated Smads (R-Smads), Smad2 and Smad3. Thus, p21 is a common target of all TGF-beta superfamily pathways. However, the ability of TGF-beta superfamily members to induce cell growth arrest depends on the regulation of additional gene targets.