The Role of Wip1 in Regulating the Protumorigenic Senescence‐Associated Secretory Phenotype

Abstract

Senescent cells are known to accumulate in tissues with age. They are often characterized by a permanent cell cycle arrest and altered secretory profile referred to as the senescence‐associated secretory phenotype (SASP). The release of SASP factors—which include proinflammatory cytokines and growth factors—creates a milieu that can promote preneoplastic cell growth. The mitogen‐activated protein kinase p38 (p38MAPK) is a transcriptional and post‐transcriptional regulator of various SASP factors. Relative to its activation in response to lipopolysaccharide treatment, p38MAPK phosphorylation due to senescence stimuli is dramatically slower. To elucidate the mechanism of these slow kinetics, we focused on wild‐type p53‐induced phosphatase 1 (Wip1), which inactivates p38MAPK by dephosphorylating a conserved threonine residue. The loss of p53 function results in a more rapid and robust activation of p38MAPK in response to senescence. Additionally, Wip1 is rapidly induced by senescent stimuli, with expression decreasing over time, mirroring p38 activation kinetics. Therefore we hypothesize that senescent stimuli induces p53 to activate Wip1, which dephosphorylates p38MAPK, thereby delaying p38MAPK induction. Preliminary results from immunoblot analysis of senescent fibroblasts indicate a delay in phosphorylated p38MAPK induction on the first day after bleomycin treatment followed by robust activation in subsequent days. Further studies are focused on using the CRISPR‐Cas system to knock out Wip1 expression in order to investigate its role as a regulator of p38MAPK and the SASP in response to senescence.