The Ski Protein Family Is Required for MeCP2-mediated Transcriptional Repression

Kokura, Kenji; Kaul, Sunil C.; Wadhwa, Renu; Nomura, Takuji; Khan, Matiullah; Shinagawa, Toshie; Yasukawa, Takashi; Colmenares, Clemencia; Ishii, Shunsuke

doi:10.1074/jbc.m105747200

Cited by 195 publications

(141 citation statements)

References 51 publications

Supporting

Mentioning

140

Contrasting

Order By: Relevance

“…Of relevance, MeCP2 directly interacts with SMRT, N-CoR1, mSin3A and Ski, all of which are core components of CBF1 corepressor complexes and are removed upon interaction of NotchIC with CBF-1. 27,36,37 NotchIC prevented MeCP2 repression of IkBa transcription and that this effect was lost in mutant NotchIC proteins unable to bind CBF-1. We conclude that MeCP2 forms a key component of the CBF1 corepressor complex at the IkBa promoter.…”

Section: Discussionmentioning

confidence: 96%

Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis

et al. 2006

View full text Add to dashboard Cite

Myofibroblasts are critical cellular elements of wound healing generated at sites of injury by transdifferentiation of resident cells. A paradigm for this process is conversion of hepatic stellate cells (HSC) into hepatic myofibroblasts. Treatment of HSC with DNA methylation inhibitor 5-aza-2 0 -deoxycytidine (5-azadC) blocked transdifferentiation. 5-azadC also prevented loss of IjBa and PPARc expression that occurs during transdifferentiation to allow acquisition of proinflammatory and profibrogenic characteristics. ChIP analysis revealed IjBa promoter is associated with transcriptionally repressed chromatin that converts to an active state with 5-azadC treatment. The methyl-CpG-binding protein MeCP2 which promotes repressed chromatin structure is selectively detected in myofibroblasts of diseased liver. siRNA knockdown of MeCP2 elevated IjBa promoter activity, mRNA and protein expression in myofibroblasts. MeCP2 interacts with IjBa promoter via a methyl-CpG-dependent mechanism and recruitment into a CBF1 corepression complex. We conclude that MeCP2 and DNA methylation exert epigenetic control over hepatic wound healing and fibrogenesis

show abstract

Section: Discussionmentioning

confidence: 96%

Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis

et al. 2006

View full text Add to dashboard Cite

show abstract

“…However, upregulation of cdc25A gene may be one of the multiple mechanisms for tumor formation by loss of c-Ski. Recently, we found that c-Ski is required for methyl CpG-dependent gene silencing via directly interacting with methyl-CpG-binding protein, MeCP2 (Kokura et al, 2001). If expression of some protooncogenes is repressed by methylation of their promoter regions, loss of c-Ski would enhance expression of those oncogenes, leading to transformation.…”

Section: Discussionmentioning

confidence: 99%

Increased susceptibility to tumorigenesis of ski-deficient heterozygous mice

Shinagawa¹,

Nomura²,

Colmenares

et al. 2001

Oncogene

Self Cite

View full text Add to dashboard Cite

“…The stoichiometry between N-CoR and SKI appears to be important for repression, as overexpression of SKI partly abrogates such function. SKI is also required for transcriptional repression mediated by MeCP2, a member of the family of methyl-CpG-binding proteins ( Figure 1) (Kokura et al, 2001). Except for the mouse studies, it is important to mention, though, that the SKI activities described above were observed in vitro by overexpression of SKI and other proteins.…”

Section: The Ski Proteinmentioning

confidence: 99%

“…SKI has been recently reassigned to chromosome 1 p36 Kokura et al, 2001), a common region of alterations in human cancers including melanomas (Kaghad et al, 1997). The human SKI produces multiple forms of mRNAs, with two major species of 6.8 and 5.3 kb which are not due to alternative splicing, within the coding region.…”

Section: The Ski Proteinmentioning

confidence: 99%

Repression of TGF-β signaling by the oncogenic protein SKI in human melanomas: consequences for proliferation, survival, and metastasis

Medrano

2003

Oncogene

View full text Add to dashboard Cite

Transforming growth factor-b (TGF-b) has dual and paradoxical functions as a tumor suppressor and promoter of tumor progression and metastasis. TGF-b-mediated growth inhibition is gradually lost during melanoma tumor progression, but there are no measurable defects at the receptor level. Furthermore, melanoma cells release high levels of TGF-b to the microenvironment, which upon activation induces matrix deposition, angiogenesis, survival, and transition to more aggressive phenotypes. The SKI and SnoN protein family associate with and repress the activity of Smad2, Smad3, and Smad4, three members of the TGF-b signaling pathway. SKI also facilitates cellcycle progression by targeting the RB pathway by at least two ways: it directly associates with RB and represses its activity when expressed at high levels, and indirectly, it represses Smad-mediated induction of p21 Waf-1 . This results in increased CDK2 activity, RB phosphorylation, and inactivation. Therefore, high levels of SKI result in lesions to the RB pathway in a manner similar to p16 INK4a loss. SKI mRNA and protein levels dramatically increase during human melanoma tumor progression. In addition, the SKI protein shifts from nuclear localization in intraepidermal melanoma cells to nuclear and cytoplasmic in invasive and metastatic melanomas. Here, I discuss the basis for repression of intracellular TGF-b signaling by SKI, some additional activities of this protein, and propose that by disrupting multiple tumor suppressor pathways, SKI functions as a melanoma oncogene.

show abstract

The Ski Protein Family Is Required for MeCP2-mediated Transcriptional Repression

Cited by 195 publications

References 51 publications

Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis

Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis

Increased susceptibility to tumorigenesis of ski-deficient heterozygous mice

Repression of TGF-β signaling by the oncogenic protein SKI in human melanomas: consequences for proliferation, survival, and metastasis

Contact Info

Product

Resources

About