期刊
CELL CYCLE
卷 9, 期 9, 页码 1684-1689出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.9.9.11292
关键词
melanoma; SKI protein complexes; Smad3 linker phosphorylations
类别
资金
- NIH [R01 CA084282, R01 AG032135, RC2 AG036562, RO1 AG20752, RO1 CA100070, RO1 GM55188]
- Baylor/M.D. Anderson Cancer Center
The transcriptional co-regulator SKI is a potent inhibitor of TGF beta-growth inhibitory signals. SKI binds to receptor-activated Smads in the nucleus, forming repressor complexes containing HDACs, mSin3, NCoR, and other protein partners. Alternatively, SKI binds to activated Smads in the cytoplasm, preventing their nuclear translocation. SKI is necessary for anchorage-independent growth of melanoma cells in vitro, and most important, for human melanoma xenograft growth in vivo. We recently identified a novel role of SKI in TGF beta signaling. SKI promotes the switch of Smad3 from repressor of proliferation to activator of oncogenesis by facilitating phosphorylations in the linker domain. High levels of endogenous SKI are required by the tumor promoting trait of TGF beta to induce expression of the plasminogen-activator inhibitor-1 (PAI-1), sustained expression of C-Myc and for aborting upregulation of p21(Waf-1). Here we discuss how SKI diversifies and amplifies its functions by associating with multiple protein partners and by promoting Smad3 linker phosphorylation(s) in response to TGF beta signaling in melanoma cells.
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