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.
Mesh Terms:
Animals, CDC2-CDC28 Kinases, Cell Differentiation, Cell Division, Cell Line, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinases, Cyclins, DNA, Complementary, DNA-Binding Proteins, Down-Regulation, Endosomal Sorting Complexes Required for Transport, Green Fluorescent Proteins, Humans, Keratinocytes, Luminescent Proteins, Mice, Oligonucleotides, Antisense, Phosphorylation, Precipitin Tests, Protein Binding, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Retinoblastoma Protein, S Phase, Time Factors, Transcription Factors, Transfection, Two-Hybrid System Techniques
Animals, CDC2-CDC28 Kinases, Cell Differentiation, Cell Division, Cell Line, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinases, Cyclins, DNA, Complementary, DNA-Binding Proteins, Down-Regulation, Endosomal Sorting Complexes Required for Transport, Green Fluorescent Proteins, Humans, Keratinocytes, Luminescent Proteins, Mice, Oligonucleotides, Antisense, Phosphorylation, Precipitin Tests, Protein Binding, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Retinoblastoma Protein, S Phase, Time Factors, Transcription Factors, Transfection, Two-Hybrid System Techniques
Proc. Natl. Acad. Sci. U.S.A.
Date: Apr. 16, 2002
PubMed ID: 11943869
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