Cyclin E and c-Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins

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Abstract
Retroviral expression of the cyclin‐dependent kinase (CDK) inhibitor p16INK4a in rodent fibroblasts induces dephosphorylation of pRb, p107 and p130 and leads to G1 arrest. Prior expression of cyclin E allows S‐phase entry and long‐term proliferation in the presence of p16. Cyclin E prevents neither the dephosphorylation of pRb family proteins, nor their association with E2F proteins in response to p16. Thus, cyclin E can bypass the p16/pRb growth‐inhibitory pathway downstream of pRb activation. Retroviruses expressing E2F‐1, ‐2 or ‐3 also prevent p16‐induced growth arrest but are ineffective against the cyclin E‐CDK2 inhibitor p27Kip1, suggesting that E2F cannot substitute for cyclin E activity. Thus, cyclin E possesses an E2F‐independent function required to enter S‐phase. However, cyclin E may not simply bypass E2F function in the presence of p16, since it restores expression of E2F‐regulated genes such as cyclin A or CDC2. Finally, c‐Myc bypasses the p16/pRb pathway with effects indistinguishable from those of cyclin E. We suggest that this effect of Myc is mediated by its action upstream of cyclin E‐CDK2, and occurs via the neutralization of p27Kip1 family proteins, rather than induction of Cdc25A. Our data imply that oncogenic activation of c‐Myc, and possibly also of cyclin E, mimics loss of the p16/pRb pathway during oncogenesis.