SKI promotes Smad3 linker phosphorylations associated with the tumor-promoting trait of TGFbeta.
The transcriptional co-regulator SKI is a potent inhibitor of TGFbeta-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 TGFbeta 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 TGFbeta 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 TGFbeta signaling in melanoma cells.
Lin
Qiushi
Q
Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.
Chen
Dahu
D
Timchenko
Nikolai A
NA
Medrano
Estela E
EE
D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D017395:Plasminogen Activator Inhibitor 1; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C060614:SKI protein, human
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