THE division cycle of eukaryotic cells is regulated by a family of protein kinases known as the cyclin-dependent kinases (CDKs)1,2. The sequential activation of individual members of this family and their consequent phosphorylation of critical substrates promotes orderly progression through the cell cycle3,4. The complexes formed by CDK4 and the D-type cyclins have been strongly implicated in the control of cell proliferation during the G1 phase3–6. CDK4 exists, in part, as a multi-protein complex with a D-type cyclin, proliferating cell nuclear antigen and a protein, p21 (refs 7–9). CDK4 associates separately with a protein of Mr 16K, particularly in cells lacking a functional retinoblastoma protein9. Here we report the isolation of a human p16 complementary DNA and demonstrate that p16 binds to CDK4 and inhibits the catalytic activity of the CDK4/cyclin D enzymes. p16 seems to act in a regulatory feedback circuit with CDK4, D-type cyclins and retinoblastoma protein.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Solomon, M., J. Curr. Opin. Cell Biol. 5, 180–186 (1993).
Nigg, E. A. Curr. Opin. Cell Biol. 5, 187–193 (1993).
Motokura, T. & Arnold, A. Biochim. biophys. Acta 1155, 63–78 (1993).
Sherr, C. J. Cell 73, 1059–1065 (1993).
Matsushime, H., Roussel, M. F., Ashmun, R. A. & Sherr, C. J. Cell 65, 701–713 (1991).
Matsushime, H. et al. Cell 71, 323–334 (1992).
Xiong, Y., Shang, H. & Beach, D. Cell 71, 505–514 (1992).
Zhang, H., Xiong, Y. & Beach, D. Molec. biol. Cell 4, 897–906 (1993).
Xiong, Y., Zhang, H. & Beach, D. Genes Dev. 7, 1572–1583 (1993).
Fields, S. & Song, O. Nature 340, 245–246 (1989).
Meyerson, M. et al. EMBO J. 11, 2909–2917 (1992).
Kato, J.-Y., Matsushime, H., Hiebert, S. W., Ewen, M. E. & Sherr, C. J. Genes Dev. 7, 331–342 (1993).
Ewen, M. E. et al. Cell 73, 487–497 (1993).
Zhu, L. et al. Genes Dev. 7, 1111–1125 (1993).
Hannon, G. J., Demetrick, D. & Beach, D. Genes Dev. 7, 2378–2391 (1993).
Li, Y., Graham, C., Lacy, S., Duncan, A. M. V. & Whyte, P. Genes Dev. 7, 2366–2377 (1993).
Lukas, J., Pagano, M., Staskova, Z., Draetta, G. & Bartek, J. Oncogene (in the press).
Xiong, Y. et al. Nature 366, 701–704 (1993).
Lees, E. M. & Harlow, E. Molec. cell. Biol. 13, 1194–1201 (1993).
Zheng, X.-F. & Ruderman, J. V. Cell 75, 155–164 (1993).
Michaely, P. & Bennet, V. Trends Cell Biol. 2, 127–129 (1992).
Harlow, E. & Lane, D. Antibodies: A Laboratory Manual (Cold Spring Habor Laboratory Press, New York, 1988).
Chen, X.-S., Brash, A. R. & Funk, C. D. Eur. J. Biochem. 214, 845–852 (1993).
About this article
Cite this article
Serrano, M., Hannon, G. & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707 (1993). https://doi.org/10.1038/366704a0
Genes and Environment (2022)
SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response
Nature Aging (2022)
p16INK4A-deficiency predicts response to combined HER2 and CDK4/6 inhibition in HER2+ breast cancer brain metastases
Nature Communications (2022)
Genomic alterations drive metastases formation in pancreatic ductal adenocarcinoma cancer: deciphering the role of CDKN2A and CDKN2B in mediating liver tropism
Journal of Hematology & Oncology (2021)