Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1).
TSG101 was discovered in a screen for tumor susceptibility genes and has since been shown to have a multiplicity of biological effects. However, the basis for TSG101's ability to regulate cell growth has not been elucidated. We report here that the TSG101 protein binds to the cyclin/ cyclin-dependent kinase ( CDK) inhibitor ( CKI) p21(Cip1/WAF1) and increases stability of the p21 protein in HEK293F cells and differentiating primary keratinocytes, suppressing differentiation in a p21-dependent manner. In proliferating keratinocytes where the p21 protein is relatively stable, TSG101 does not affect the stability or expression of p21 but shows p21-dependent recruitment to cyclin/ CDK complexes, inhibits cyclin/ CDK activity, and causes strong growth suppression to a much greater extent in p21+/+ than in p21-/- cells. Conversely, suppression of endogenous TSG101 expression by an antisense TSG101 cDNA causes doubling of the fraction of keratinocytes in the S phase of the cell cycle as occurs during p21 deficiency. Our results indicate that TSG101 has a direct role in the control of growth and differentiation in primary epithelial cells, and that p21 is an important mediator of these TSG101 functions.[1]References
- Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1). Oh, H., Mammucari, C., Nenci, A., Cabodi, S., Cohen, S.N., Dotto, G.P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
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