The physiology of p16INK4A-mediated G1 proliferative arrest
- 185 Downloads
Phosphorylation of the product of the retinoblastoma susceptibility gene (Rb) physiologically inactivates its growth-suppressive properties. Rb phosphorylation is mediated by cyclin-dependent kinases (CDKs), whose activity is enhanced by cyclins and inhibited by CDK inhibitors. p16INK4A is a member of a family of inhibitors specific for CDK4 and CDK6. p16INK4A is deleted and inactivated in a wide variety of human malignancies, including familial melanomas and pancreatic carcinoma syndromes, indicating that it is an authentic human tumor suppressor. Although one mechanism for its tumor suppression may be prevention of Rb phosphorylation, thereby causing G1 arrest, many normal cell types express p16INK4A, and are still able to traverse the cell cycle. In a search for other mechanisms, we have found that p16INK4A is required for p53-independent G1 arrest in response to DNA-damaging agents, including topoisomerase I and II inhibitors. Thus, like other tumor suppressors, p16INK4A plays an essential role in a DNA-damage checkpoint that leads to cell cycle arrest.
Index Entriesp16 INK4A ARF cell cycle cancer
Unable to display preview. Download preview PDF.
- 4.Slebos, R. J., Lee, M. H., Plunkett, B. S., Kessis, T. D., Williams, B. O., Jacks, T., Hedrick, L., Kastan, M. B. and Cho, K. R. (1994) p53-dependent G1 arrest involves pRB-related proteins and is disrupted by the human papillomavirus 16 E7 oncoprotein. Proc. Natl. Acad. Sci. USA 91, 5320–5324.PubMedCrossRefGoogle Scholar
- 8.Carnero, A. and Hannon, G. J. (1998) The INK4 family of CDK inhibitors. Curr. Topics Microbiol. Immunol. 227, 43–55.Google Scholar
- 23.Goldstein, A. M., Fraser, M. C., Struewing, J. P., Hussussian, C. J., Ranade, K., Zametkin, D. P., Fontaine, L. S., Organic, S. M., Dracopoli, N. C., Clark, W. H. J. and Tucker, M. A. (1995) Increased risk of pancreatic cancer in melanoma-prone kindreds with p16 INK4 mutations. N. Engl. J. Med. 333, 970–974.PubMedCrossRefGoogle Scholar
- 40.Sedlacek, H. H., Czech, J., Naik, R., Kaur, G., et al. (1996) Flavopiridol (L868275;NSC 649890), a new kinase inhibitor for tumor therapy. Int. J. Oncol. 9, 1143–1168.Google Scholar