The p38MAPK-MK2-HSP27 Pathway Regulates the mRNA Stability of the Senescence-Associated Secretory Phenotype
Moore, H. R.; Alspach, E.; Hirsch, J. L.; Monahan, J.; Stewart, S. A.
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Age is a significant risk factor for the development of cancer. Both age-dependent accumulation of cell autonomous mutations within preneoplastic cells and increases in senescent stromal cells within the tumor microenvironment are thought to collaborate to drive tumorigenesis. Senescent cells express pro-tumorigenic factors termed the senescence-associated secretory phenotype (SASP), subject to a variety of regulatory mechanisms that are not fully elucidated. Previous work demonstrated that p38 mitogen-activated protein kinase (p38MAPK)-dependent regulation of AUF1 occupancy on SASP factor mRNAs post-transcriptionally stabilizes many SASP mRNAs and contributes to their increased expression. Here, we address the mechanism by which p38MAPK regulates AUF1s occupancy and activity on SASP factor mRNAs. We found that the p38MAPK-MK2-HSP27 pathway regulates both mRNA stability and AUF1 occupancy in cells induced to senesce. Furthermore, the tumor-promoting abilities of senescent stromal cells were lost upon inhibition of MK2, suggesting that this pathway is a viable therapeutic target within the tumor microenvironment.
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