P53 induces senescence through Lamin A/C stabilization-mediated nuclear deformation.

ABSTRACT: p53-mediated cellular senescence has been intensively investigated, because it is important for tumor suppressive function. In addition, p16/INK4A is well known to be critical for cellular senescence. However, detailed molecular mechanism or relevance between p53 and p16-mediated senescence has not been demonstrated yet. Here we show that p53 induces p16 through Lamin A/C stabilization via direct interaction. Stabilized Lamin A/C promotes degradation of BMI-1 and MEL-18 (Polycomb repressor complex 1, PRC1), which sequesters p16 promotor. Increased p53 can reduce BMI-1/MEL-18 and induce p16 expression via Lamin A/C. Elimination of Lamin A/C can abolish p53-induced p16 expression and BMI-1/MEL-18 reduction. As Lamin A/C expression is increased during cell differentiation, this mechanism seems to be very useful for selective induction of senescence in non-stem cells. Our results suggest that Lamin A/C-p53 network is important for p16/INK4A-mediated cellular senescence.

SUBMITTER: Yoon MH 

PROVIDER: S-EPMC6365587 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature