Wang H, Song K, Krebs T L, Yang J, Danielpour D
Department of Pharmacology, Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Oncogene. 2008 Nov 20;27(54):6791-805. doi: 10.1038/onc.2008.291. Epub 2008 Sep 1.
We recently reported that hydrogen peroxide-inducible clone-5 (Hic-5, also named androgen receptor-associated protein 55) can bind to the transforming growth factor-beta (TGF-beta)-signaling regulator Smad3, thereby inhibiting certain Smad3-dependent TGF-beta responses. We now show that Hic-5 can also control TGF-beta responses through an alternative mechanism involving Smad7, a key negative regulator of TGF-beta signaling. Hic-5 binds directly to Smad7. This interaction requires the LIM3 domain of Hic-5, and enhances TGF-beta signaling through causing loss of Smad7 protein but not mRNA. Enforced expression of Hic-5 reverses the ability of Smad7 to suppress TGF-beta-induced phosphorylation of Smads 2 and 3 and activation of the plasminogen activator inhibitor-1 promoter (in NRP-154 and PC3 prostate carcinoma and WPMY-1 prostate myofibroblast cell lines). Lentiviral-mediated small-hairpin RNA silencing of endogenous Hic-5 reduced TGF-beta responses in PC3 and WPMY-1 cells. Further work suggests that the level of Smad7 is modulated by its physical interaction with Hic-5 and targeted to a degradation pathway not likely to be proteasomal. Our findings support that Hic-5 functions as a cell-type-specific activator of TGF-beta signaling through its ability to physically interact with and neutralize Smad7.
我们最近报道，过氧化氢诱导克隆-5（Hic-5，也称为雄激素受体相关蛋白55）可与转化生长因子-β（TGF-β）信号调节因子Smad3结合，从而抑制某些Smad3依赖的TGF-β反应。我们现在表明，Hic-5还可通过涉及Smad7（TGF-β信号的关键负调节因子）的另一种机制来控制TGF-β反应。Hic-5直接与Smad7结合。这种相互作用需要Hic-5的LIM3结构域，并通过导致Smad7蛋白而非mRNA的丢失来增强TGF-β信号。Hic-5的强制表达可逆转Smad7抑制TGF-β诱导的Smads 2和3磷酸化以及纤溶酶原激活物抑制剂-1启动子激活的能力（在NRP-154和PC3前列腺癌细胞系以及WPMY-1前列腺肌成纤维细胞系中）。慢病毒介导的内源性Hic-5小发夹RNA沉默降低了PC3和WPMY-1细胞中的TGF-β反应。进一步的研究表明，Smad7的水平通过其与Hic-5的物理相互作用受到调节，并靶向一条不太可能是蛋白酶体的降解途径。我们的研究结果支持，Hic-5通过其与Smad7物理相互作用并使其失活的能力，作为TGF-β信号的细胞类型特异性激活剂发挥作用。
