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

Oncogene volume 22, pages 3123–3129 (2003)Cite this article

Abstract

Transforming growth factor-β (TGF-β) has dual and paradoxical functions as a tumor suppressor and promoter of tumor progression and metastasis. TGF-β-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-β 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-β signaling pathway. SKI also facilitates cell-cycle 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 p21Waf-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 p16INK4a 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-β signaling by SKI, some additional activities of this protein, and propose that by disrupting multiple tumor suppressor pathways, SKI functions as a melanoma oncogene.

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Acknowledgements

I thank Ed Stavnezer, Xin-Hua Feng, for critical comments and suggestions, and the contribution of colleagues and past and present members of my laboratory to the work discussed in this review. I also thank the National Cancer Institute for research support.

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  1. Huffington Center on Aging and Departments of Molecular and Cellular Biology and Dermatology, Baylor College of Medicine, Houston, TX, USA

    Estela E Medrano

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Medrano, E. Repression of TGF-β signaling by the oncogenic protein SKI in human melanomas: consequences for proliferation, survival, and metastasis. Oncogene 22, 3123–3129 (2003). https://doi.org/10.1038/sj.onc.1206452

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