PREMATURE SENESCENCE INVOLVING P53 AND P16 IS ACTIVATED IN RESPONSE TO CONSTITUTIVE MEK MAPK MITOGENIC SIGNALING/

Oncogenic Pas transforms immortal rodent cells to a tumorigenic state, in part, by constitutively transmitting mitogenic signals through the mitogen-activated protein kinase (MAPK) cascade. In primary cells, Pa s is initially mitogenic but eventually induces premature senescence i nvolving the p53 and p16(INK4a) tumor suppressors. Constitutive activa tion of MEK (a component of the MAPK cascade) induces both p53 and p16 , and is required for Ras-induced senescence of normal human fibroblas ts. Furthermore, activated MEK permanently arrests primary murine fibr oblasts but forces uncontrolled mitogenesis and transformation in cell s lacking either p53 or INK4a. The precisely opposite response of norm al and immortalized cells to constitutive activation of the MAPK casca de implies that premature senescence acts as a fail-safe mechanism to limit the transforming potential of excessive Pas mitogenic signaling. Consequently, constitutive MAPK signaling activates p53 and p16 as tu mor suppressors.