Induction of p21WAF1/CIP1 and inhibition of Cdk2 mediated by the tumor suppressor p16INK4a

Mitra, Jayashree ; Dai, Charlotte Y. ; Somasundaram, Kumaravel ; El-Deiry, Wafik S. ; Satyamoorthy, Kapaettu ; Herlyn, Meenhard ; Enders, Greg H. (1999) Induction of p21WAF1/CIP1 and inhibition of Cdk2 mediated by the tumor suppressor p16INK4a Molecular and Cellular Biology, 19 (5). pp. 3916-3928. ISSN 0270-7306

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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.

Item Type:Article
Source:Copyright of this article belongs to American Society for Microbiology.
ID Code:49713
Deposited On:20 Jul 2011 13:51
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