Oncogenes Mitogenic Signals

In recent years, it has become apparent that strong mitogenic stimuli also can induce normal mammalian cells to express a senescentlike phenotype. This phenomenon was first described for overexpression of the oncogenic (mutated) form of RAS-HA in rodent or human cells (22,88). Oncogenic RAS was known to transform immortal human and rodent cells and facilitate their conversion to tu-morigenicity. However, in normal cells, overexpression of the RAS oncoprotein induced a senescence growth arrest. This senescence response was not induced if mutations or the expression of viral oncogenes inactivated the p53 and pRb tumor suppressor pathways. Consistent with this result, activated forms of two downstream effectors of RAS function—the RAF and MEK signaling protein kinases—also induce a senescence response when overexpressed in normal mammalian cells (23,25,89). In addition, overexpression of E2F1, a transcription factor important for regulating cell cycle progression into the S phase, elicits a senescent response in normal human fibroblasts (90). The E2F1-induced senescence response is also p53 dependent and is specifically mediated by the p14 tumor suppressor gene. Thus, when faced with certain supraphysiological mitogenic signals, which have the potential to cause neoplastic growth, normal cells permanently arrest growth with a senescent phenotype.

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