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Molecular and Cellular Biology, May 1999, p. 3916-3928, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Induction of p21WAF1/CIP1 and Inhibition of Cdk2 Mediated by the Tumor Suppressor p16INK4a

Jayashree Mitra,1,2,3 Charlotte Y. Dai,1,2,3 Kumaravel Somasundaram,1,2,3,4 Wafik S. El-Deiry,1,2,3,4 Kapaettu Satyamoorthy,5 Meenhard Herlyn,5 and Greg H. Enders1,2,3,*

Departments of Medicine1 and Genetics,2 Cancer Center,3 and Howard Hughes Medical Institute,4 University of Pennsylvania School of Medicine, and The Wistar Institute,5 Philadelphia, Pennsylvania 19104

Received 15 October 1998/Returned for modification 14 November 1998/Accepted 22 February 1999

The tumor suppressor p16INK4a inhibits cyclin-dependent kinases 4 and 6. This activates the retinoblastoma protein (pRB) and, through incompletely understood events, arrests the cell division cycle. To permit biochemical analysis of the arrest, we generated U2-OS osteogenic sarcoma cell clones in which p16 transcription could be induced. In these clones, binding of p16 to cdk4 and cdk6 abrogated binding of cyclin D1, p27KIP1, and p21WAF1/CIP1. Concomitantly, the total cellular level of p21 increased severalfold via a posttranscriptional mechanism. Most cyclin E-cdk2 complexes associated with p21 and became inactive, expression of cyclin A was curtailed, and DNA synthesis was strongly inhibited. Induction of p21 alone, in a sibling clone, to the level observed during p16 induction substantially reproduced these effects. Overexpression of either cyclin E or A prevented p16 from mediating arrest. We then extended these studies to HCT 116 colorectal carcinoma cells and a p21-null clone derived by homologous recombination. In the parental cells, p16 expression also augmented total cellular and cdk2-bound p21. Moreover, p16 strongly inhibited DNA synthesis in the parental cells but not in the p21-null derivative. These findings indicate that p21-mediated inhibition of cdk2 contributes to the cell cycle arrest imposed by p16 and is a potential point of cooperation between the p16/pRB and p14ARF/p53 tumor suppressor pathways.

* Corresponding author. Mailing address: Penn/GI Division, 600 CRB, 415 Curie Blvd., Philadelphia, PA 19104-6144. Phone: (215) 898-0159. Fax: (215) 573-2024. E-mail: endersgh{at}mail.med.upenn.edu.

Molecular and Cellular Biology, May 1999, p. 3916-3928, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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