The Ski oncoprotein interacts with Skip, the human homolog of Drosophila Bx42

Dahl, Richard; Wani, Bushra; Hayman, Michael J.

doi:10.1038/sj.onc.1201687

Cited by 96 publications

(76 citation statements)

References 21 publications

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“…We also know little regarding protein complex formation and activity between endogenous SKI and members of its own family such as SnoN, and with proteins that might interfere with its activity such as the SKI-interacting protein Skip (Dahl et al, 1998b). Skip is particularly interesting as its overexpression partially overcomes Ski/Sno-dependent repression.…”

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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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: 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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“…Skip was originally identi®ed as a binding partner of the viral oncogene, v-Ski (Dahl et al, 1998), and Skip has recently been shown to possess the characteristics of a transcriptional co-activator on a number of cellular promoters (Baudino et al, 1998;Zhou et al, 2000). Using a variety of assays, we show a strong and direct interaction between HPV-16 E7 and Skip.…”

Section: Introductionmentioning

confidence: 87%

“…The HPV-16 E7 oncoprotein was fused in-frame to the GAL4 DNA binding domain in the vector pAS1, and this was used to screen a lymphoid cDNA library that was constructed in pACT (Durfee et al, 1993). The two-hybrid screen with E7 identi®ed three clones of the same cDNA clone encoding Skip, which was originally identi®ed as a v-Ski-interacting protein (Dahl et al, 1998). To further con®rm a speci®c interaction of Skip with HPV-16 E7, the isolated clones (pACT-Skip) were rescued in E. coli and retransformed into yeast containing pAS-E7 and selected E7 mutants, together with additional GAL4-DNA binding domain fusion constructs as controls.…”

Section: Identification Of Skip As a New Interacting Partner Of Hpv-1mentioning

confidence: 99%

The HPV-16 E7 oncoprotein binds Skip and suppresses its transcriptional activity

2001

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E7 is the major transforming protein of human papillomavirus (HPV), which is implicated in the development of cervical cancer. The transforming activity of E7 has been attributed in part to its interaction with the retinoblastoma (Rb) tumour suppressor; however, the Rb interaction alone is not su cient for transformation by E7. In a screen for cellular targets of HPV E7, we identi®ed the Ski interacting protein, Skip, as a new interacting partner of E7. We show that HPV-16 E7 associates with Skip via sequences in its carboxy terminal region, and the evolutionarily conserved proline rich sequences (PRS) of the SNW domain of Skip. E7 functionally targets Skip in vivo and inhibits its transcriptional activation activity. Two transformation defective mutants of E7 were identi®ed that failed both to bind Skip and to inhibit its transcriptional activity. These results suggest that inhibition of Skip function may contribute to cell transformation by HPV-16 E7. Oncogene (2001) 20, 7677 ± 7685.

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“…Recent evidence suggests that SkiP, like its Drosophila counterpart, plays an important role in transcriptional regulation and is widely expressed in many tissues. It was first described as a nuclear protein that interacted with the oncoprotein v-Ski to mediate its transforming activities (Dahl et al, 1998). Recent studies demonstrate that SkiP interacts with many transcriptional regulators to modulate transcription.…”

Section: Estrogen-regulated Genes Expression In Ovarian Cancer Cells mentioning

confidence: 99%

“…SkiP is the human homolog of Drosophila melanogaster nuclear protein Bx42 (Folk et al, 1996;Dahl et al, 1998). Recent evidence suggests that SkiP, like its Drosophila counterpart, plays an important role in transcriptional regulation and is widely expressed in many tissues.…”

Section: Estrogen-regulated Genes Expression In Ovarian Cancer Cells mentioning

confidence: 99%

Profiling estrogen-regulated gene expression changes in normal and malignant human ovarian surface epithelial cells

et al. 2005

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Estrogens regulate normal ovarian surface epithelium (OSE) cell functions but also affect epithelial ovarian cancer (OCa) development. Little is known about how estrogens play such opposing roles. Transcriptional profiling using a cDNA microarray containing 2400 named genes identified 155 genes whose expression was altered by estradiol-17b (E2) in three immortalized normal human ovarian surface epithelial (HOSE) cell lines and 315 genes whose expression was affected by the hormone in three established OCa (OVCA) cell lines. All but 19 of the genes in these two sets were different. Among the 19 overlapping genes, five were found to show discordant responses between HOSE and OVCA cell lines. The five genes are those that encode clone 5.1 RNAbinding protein (RNPS1), erythrocyte adducin a subunit (ADD1), plexin A3 (PLXNA3 or the SEX gene), nuclear protein SkiP (SKIIP), and Rap-2 (rap-2). RNPS1, ADD1, rap-2, and SKIIP were upregulated by E2 in HOSE cells but downregulated by estrogen in OVCA cells, whereas PLXNA3 showed the reverse pattern of regulation. The estrogen effects was observed within 6-18 h of treatment. In silicon analyses revealed presence of estrogen response elements in the proximal promoters of all five genes. RNPS1, ADD1, and PLXNA3 were underexpressed in OVCA cell lines compared to HOSE cell lines, while the opposite was true for rap-2 and SKIIP. Functional studies showed that RNPS1 and ADD1 exerted multiple antitumor actions in OVCA cells, while PLXNA3 only inhibited cell invasiveness. In contrast, rap-2 was found to cause significant oncogenic effects in OVCA cells, while SKIIP promotes only anchorageindependent growth. In sum, gene profiling data reveal that (1) E2 exerts different actions on HOSE cells than on OVCA cells by affecting two distinct transcriptomes with few overlapping genes and (2) among the overlapping genes, a set of putative oncogenes/tumor suppressors have been identified due to their differential responses to E2 between the two cell types. These findings may explain the paradoxical roles of estrogens in regulating normal and malignant OSE cell functions.

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The Ski oncoprotein interacts with Skip, the human homolog of Drosophila Bx42

Cited by 96 publications

References 21 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

The HPV-16 E7 oncoprotein binds Skip and suppresses its transcriptional activity

Profiling estrogen-regulated gene expression changes in normal and malignant human ovarian surface epithelial cells

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