Expression of the c-ski proto-oncogene in human melanoma cell lines

Fumagalli, Stefano; Doneda, Luisa; Nomura, Nobuo; Larizza, Lidia

doi:10.1097/00008390-199304000-00004

Cited by 60 publications

(57 citation statements)

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“…During mouse development, Ski is expressed at relatively high levels in neural crest-derived cells (Lyons et al, 1994), and SKI transcripts are expressed at high levels in human melanoma cell lines compared to normal melanocytes (Fumagalli et al, 1993). Overexpression of SKI in melanomas results from yet to be defined transcriptional and/or post-transcriptional events, as Southern blot analysis did not find alterations in restriction enzyme patterns or increase in gene dosage (Fumagalli et al, 1993). Recently, we demonstrated that SKI is overexpressed in vivo in all melanomas studied (n ¼ 44) (Reed et al, 2001).…”

Section: Ski Overexpression Localization and Function During Melanomentioning

confidence: 99%

“…We have learned of numerous activities regulated by these proteins, and yet, numerous unanswered questions remain. For example, what signals upregulate SKI transcription in melanomas (Fumagalli et al, 1993). Is such an event necessary and sufficient for melanoma tumor progression as the pattern of SKI protein expression appears to indicate (Reed et al, 2001)?…”

Section: Perspectives and Future Directionsmentioning

confidence: 99%

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

Medrano

2003

Oncogene

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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.

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Section: Ski Overexpression Localization and Function During Melanomentioning

confidence: 99%

Section: Perspectives and Future Directionsmentioning

confidence: 99%

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

Medrano

2003

Oncogene

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“…Several studies indicate that the levels of c-ski are significantly higher in human tumor cell lines derived from neuroblastoma, melanoma and prostate cancers (Nomura et al, 1989;Fumagalli et al, 1993;Reed et al, 2001;Zhang et al, 2003). These studies support the notion that the transforming activity of Ski may be attributable to variable levels of expression and may provide a basis for human tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Control of cell cycle-dependent degradation of c-Ski proto-oncoprotein by Cdc34

et al. 2004

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It is known that excess amounts of Ski, or any member of its proto-oncoprotein family, causes disruption of the transforming growth factor beta signal transduction pathway, thus causing oncogenic transformation of cells. Previous studies indicate that Ski is a relatively unstable protein whose expression levels can be regulated by ubiquitin-mediated proteolysis. Here, we investigate the mechanism by which the stability of Ski is regulated. We show that the steady-state levels of Ski protein are controlled post-translationally by cell cycle-dependent proteolysis, wherein Ski is degraded during the interphase of the cell cycle but is relatively stable during mitosis. Furthermore, we demonstrate that the ubiquitin-conjugating enzyme Cdc34 mediates cell cycle-dependent Ski degradation both in vitro and in vivo. Overexpression of dominant-negative Cdc34 stabilizes Ski and enhances its ability to antagonize TGF-b signaling. Our data suggest that regulated proteolysis of Ski is one of the key mechanisms that control the threshold levels of this proto-oncoprotein, and thus prevents epithelial cells from becoming TGF-b resistant.

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“…Overexpression of c-Ski abolished TGF-␤-induced growth inhibition (Luo et al, 1999;Sun et al, 1999;Xu et al, 2000). High levels of expression of c-Ski were reported in several tumor cell lines (Nomura et al, 1989;Fumagalli et al, 1993) and in melanomas in vivo (Reed et al, 2001). Inhibition of TGF-␤ signaling is thus regarded as a part of the mechanism of oncogenesis by Ski proteins (He et al, 2003).…”

mentioning

confidence: 98%

Interaction with Smad4 Is Indispensable for Suppression of BMP Signaling by c-Ski

Takeda

Mizuide

Oka³

et al. 2004

MBoC

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c-Ski is a transcriptional corepressor that interacts strongly with Smad2, Smad3, and Smad4 but only weakly with Smad1 and Smad5. Through binding to Smad proteins, c-Ski suppresses signaling of transforming growth factor-␤ (TGF-␤) as well as bone morphogenetic proteins (BMPs). In the present study, we found that a mutant of c-Ski, termed c-Ski (ARPG) inhibited TGF-␤/activin signaling but not BMP signaling. Selectivity was confirmed in luciferase reporter assays and by determination of cellular responses in mammalian cells (BMP-induced osteoblastic differentiation of C2C12 cells and TGF-␤-induced epithelial-to-mesenchymal transdifferentiation of NMuMG cells) and Xenopus embryos. The ARPG mutant recruited histone deacetylases 1 (HDAC1) to the Smad3-Smad4 complex but not to the Smad1/5-Smad4 complex. c-Ski (ARPG) was unable to interact with Smad4, and the selective loss of suppression of BMP signaling by c-Ski (ARPG) was attributed to the lack of Smad4 binding. We also found that c-Ski interacted with Smad3 or Smad4 without disrupting Smad3-Smad4 heteromer formation. c-Ski (ARPG) would be useful for selectively suppressing TGF-␤/activin signaling. INTRODUCTIONCytokines of the transforming growth factor-␤ (TGF-␤) superfamily are multifunctional proteins that regulate growth, differentiation, apoptosis, and morphogenesis of a wide variety of cell types. TGF-␤ and related factors bind to two different types of serine/threonine kinase receptors, termed type I and type II (Derynck et al., 1998;Attisano and Wrana, 2000;Shi and Massagué, 2003). Type I receptor is activated by type II receptor upon ligand binding and transduces signals into cytoplasm through phosphorylation of receptorregulated Smads (R-Smads). Phosphorylated R-Smads interact with Co-Smad (Smad4) and translocate into the nucleus. Nuclear Smad complexes regulate transcription of target genes in cooperation with transcriptional activators/repressors as well as with coactivators/corepressors . Of the eight different mammalian Smad proteins, Smad1, Smad5, and Smad8 are R-Smads activated by BMP family members, whereas Smad2 and Smad3 are R-Smads activated by TGF-␤ and activin.Transcription of target genes by TGF-␤ is upregulated by binding of Smads to transcriptional coactivators, including p300 and CBP, which induce acetylation of histones and loosen chromatin structure (Massagué and Chen, 2000;Miyazono et al., 2001). In contrast, transcriptional corepressors, including TGIF, c-Ski, and SnoN, physically interact with Smads, and repress TGF-␤ signaling through recruitment of histone deacetylases (HDACs) (Massagué and Chen, 2000;Liu et al., 2001).c-Ski was originally identified as a cellular counterpart of a retroviral oncogene product, v-Ski (Li et al., 1986). c-Ski physically interacts with Smad2, Smad3, and Smad4, thus antagonizing signal transduction in the TGF-␤ pathway (Akiyoshi et al., 1999;Luo et al., 1999;Sun et al., 1999;Xu et al., 2000). Overexpression of c-Ski abolished TGF-␤-induced growth inhibition (Luo et al., 1999;Sun et al., 1999;Xu et al., 200...

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Expression of the c-ski proto-oncogene in human melanoma cell lines

Cited by 60 publications

References 0 publications

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

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

Control of cell cycle-dependent degradation of c-Ski proto-oncoprotein by Cdc34

Interaction with Smad4 Is Indispensable for Suppression of BMP Signaling by c-Ski

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