Induction of p21(WAF1/CIP1) and inhibition of Cdk2 mediated by the tumor suppressor p16(INK4α)

Jayashree Mitra, Charlotte Y. Dai, Kumaravel Somasundaram, Wafik S. El-Deiry, Kapaettu Satyamoorthy, Meenhard Herlyn, Greg H. Enders

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    Abstract

    The tumor suppressor p16(INK4α) 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, p27(KIP1), and p21(WAF1/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 p14(ARF)/p53 tumor suppressor pathways.

    Original languageEnglish
    Pages (from-to)3916-3928
    Number of pages13
    JournalMolecular and Cellular Biology
    Volume19
    Issue number5
    Publication statusPublished - 05-1999

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    All Science Journal Classification (ASJC) codes

    • Molecular Biology
    • Genetics
    • Cell Biology

    Cite this

    Mitra, J., Dai, C. Y., Somasundaram, K., El-Deiry, W. S., Satyamoorthy, K., Herlyn, M., & Enders, G. H. (1999). Induction of p21(WAF1/CIP1) and inhibition of Cdk2 mediated by the tumor suppressor p16(INK4α). Molecular and Cellular Biology, 19(5), 3916-3928.