title: SKI promotes Smad3 linker phosphorylations associated with the tumor-promoting trait of TGFbeta.
abstract: 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.
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Lin
authors.forename: Dahu
authors.initials: D
authors.lastname: Chen
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Timchenko
authors.forename: Estela E
authors.initials: EE
authors.lastname: Medrano
mesh_terms: 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
chemical_list: 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
references.citation: Cancer Sci. 2009 Oct;100(10):1809-16
references.pmid: 19594546
references.citation: Clin Cancer Res. 2007 Aug 15;13(16):4817-24
references.pmid: 17699860
references.citation: Histol Histopathol. 2006 Jun;21(6):645-62
references.pmid: 16528675
references.citation: J Biol Chem. 2003 Jul 4;278(27):24858-64
references.pmid: 12716897
references.citation: Carcinogenesis. 2009 Sep;30(9):1497-506
references.pmid: 19546161
references.citation: Cancer Metastasis Rev. 2005 Jun;24(2):265-72
references.pmid: 15986136
references.citation: J Biol Chem. 2007 Jul 13;282(28):20492-501
references.pmid: 17510063
references.citation: Cell. 2009 Apr 17;137(2):369-79
references.pmid: 19379700
references.citation: Leukemia. 2006 Mar;20(3):437-43
references.pmid: 16424870
references.citation: J Biol Chem. 2009 Jul 24;284(30):19808-16
references.pmid: 19458083
references.citation: Mol Cell Biol. 1991 Feb;11(2):1167-70
references.pmid: 1846665
references.citation: Oncogene. 2003 May 19;22(20):3123-9
references.pmid: 12793438
references.citation: J Biol Chem. 2000 Dec 29;275(52):40710-7
references.pmid: 11018029
references.citation: Oncogene. 2001 Dec 6;20(56):8100-8
references.pmid: 11781823
references.citation: Cancer Res. 2008 Feb 1;68(3):650-6
references.pmid: 18245463
references.citation: Mol Cell. 2009 Nov 13;36(3):457-68
references.pmid: 19917253
references.citation: Cancer Res. 2001 Nov 15;61(22):8074-8
references.pmid: 11719430
references.citation: Cell. 2003 May 16;113(4):495-506
references.pmid: 12757710
references.citation: Cancer Res. 2008 May 1;68(9):3277-85
references.pmid: 18451154
references.citation: Ann Epidemiol. 2009 Jul;19(7):455-61
references.pmid: 19282200
references.citation: Int J Oncol. 2008 Jun;32(6):1221-6
references.pmid: 18497983
references.citation: J Dermatol Sci. 2009 Jan;53(1):26-33
references.pmid: 18782659
references.citation: Biochem Biophys Res Commun. 2009 May 22;383(1):119-24
references.pmid: 19341714
references.citation: Cancer Res. 2009 Jul 1;69(13):5321-30
references.pmid: 19531654
references.citation: Oncogene. 2005 Jun 23;24(27):4321-9
references.pmid: 15806149
references.citation: Cell Oncol. 2009;31(1):41-51
references.pmid: 19096149
references.citation: Mol Biol Cell. 2008 Dec;19(12):5446-55
references.pmid: 18843049
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5924-9
references.pmid: 10811875
references.citation: Cancer Cell. 2007 May;11(5):447-60
references.pmid: 17482134
references.citation: Cell Signal. 2008 Sep;20(9):1579-91
references.pmid: 18387785
references.citation: J Biol Chem. 2009 Apr 10;284(15):9663-73
references.pmid: 19218245
references.citation: J Biol Chem. 2009 Jan 30;284(5):3334-3344
references.pmid: 19049980
references.citation: Cancer Res. 2007 Jun 1;67(11):5090-6
references.pmid: 17545585
references.citation: Pigment Cell Melanoma Res. 2009 Dec;22(6):761-72
references.pmid: 19845874
references.citation: Cancer Res. 2003 Oct 15;63(20):6626-34
references.pmid: 14583455
references.citation: Genes Dev. 1999 Feb 15;13(4):412-23
references.pmid: 10049357