Title:
Mechanisms of senescence induction and their implications in tumorigenesis

Makoto Nakanishi
Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University

Abstract:
Senescence is a state of permanent growth arrest and is a pivotal part of the anti-tumorigenic barrier in vivo. Although the tumor suppressor activities of p53 and pRb family proteins are essential for the induction of senescence, molecular mechanisms by which these proteins induce senescence are still not clear.　Very recently, we have uncovered the molecular basis underlying senescence induction in which mitosis skipping plays an essential role. Our findings indicate that the regulatory mechanisms of the timing and level of p53 activation play a key role in senescent processes. Thus, the duration of Chk1-dependent G2 checkpoint regulates p53 activation timing and is a key factor that determines whether or not cells undergo senescence. We also identify SCF^Fbxo22-KDM4A as a senescence-associated E3 ligase targeting methylated p53 for degradation. The down-regulation of p53 by SCF^Fbxo22-KDM4A is critical for the induction of p16 and senescence-associated secretory phenotypes at the late phase of senescence. In this talk, I would like to introduce details of cellular senescence and discuss about their potential use as therapeutic targets for malignant tumors.