Oncogene-induced cellular senescence.

ABSTRACT

Oncogene-induced senescence (OIS) is a robust and sustained antiproliferative response brought about by oncogenic signaling resulting from an activating mutation of an oncogene, or the inactivation of a tumor-suppressor gene. The pathways mediating OIS are complex and incompletely elucidated but, the proliferative arrest involves activation of both the RB and p53 pathways. In addition, whereas there are indications that at least in some situations, negative feedback loops abolish the increased mitogenic signaling resulting from the oncogenic mutations, also an unexpected contribution of interleukin-mediated signaling has recently been found. OIS brings about cessation of growth of some benign tumors, including melanocytic nevi and several other lesions, including pituitary and thyroid adenomas. It protects against progression to cancer, and in this way complements oncogene-induced apoptosis. Perhaps, OIS has evolved as an alternative to apoptosis especially regarding long-lived cell types that are not replaceable in large numbers. Contrary to the earlier belief, OIS is not entirely irreversible, at least in some well documented in vitro systems. This means that its induction does not entirely eliminate the oncogenic threat resulting from the mutated cell. It also means that OIS, or related phenomena that may affect a proportion of the tumor cells of some cancers, may have an influence on responsiveness to cytotoxic cancer therapies, because OIS is associated with an antiapoptosis phenotype.