p38α and p38γ Mediate Oncogenic ras-induced Senescence through Differential Mechanisms

Oncogene-induced senescence is a tumor-suppressive defense mechanism triggered upon activation of certain oncogenes in normal cells. Recently, the senescence response to oncogene activation has been shown to act as a bona fide barrier to cancer development in vivo. Multiple previous studies have implicated the importance of the p38 MAPK pathway in oncogene-induced senescence. However, the contribution of each of the four p38 isoforms (encoded by different genes) to senescence induction is unclear. In the current study, we demonstrated that p38 alpha and p38 gamma, but not p38 beta, play an essential role in oncogenic ras-induced senescence. Both p38 alpha and p38 gamma are expressed in primary human fibroblasts and are activated upon transduction of oncogenic ras. Small hairpin RNA-mediated silencing of p38 alpha or p38 gamma expression abrogated ras-induced senescence, whereas constitutive activation of p38 alpha and p38 gamma caused premature senescence. Furthermore, upon activation by oncogenic ras, p38 gamma stimulated the transcriptional activity of p53 by phosphorylating p53 at Ser33, suggesting that the ability of p38 gamma to mediate senescence is at least partly achieved through p53. However, p38 alpha contributed to ras-inducted senescence via a p53-indepdendent mechanism in cells by mediating ras-induced expression of p16(INK4A), another key senescence effector. These findings have identified p38 alpha and p38 gamma as essential components of the signaling pathway that regulates the tumor-suppressing senescence response, providing insights into the molecular mechanisms underlying the differential involvement of the p38 isoforms in senescence induction.