Regulation of cell proliferation and differentiation by p38 MAPK in distinct physiopathological processes

The p38 mitogen activated protein kinase (MAPK) has a crucial role in cells’ stress adaptation and survival. It also plays a role in physiological processes such as differentiation of skeletal muscle or in pathologies such as cancer. In response to environmental stresses, a delay in cell cycle progression is required for cell adaptation. In the present study, we demonstrate that p38 MAPK maximizes cell survival upon stress by downregulating the E2F transcriptional program through the direct targeting of Retinoblastoma (RB) protein, a key regulator of the G1/S transition. p38 phosphorylation of RB at specific sites in the N terminus increases its affinity towards E2F, represses E2F-driven gene expression, and delays cell-cycle progression. These phosphorylation events render RB insensitive to CDK regulation, converting it into a strong suppressor of cell proliferation. Remarkably, the expression of a phosphomimetic RB mutant in cancer cell lines reduces colony formation and decreases their proliferative and tumorigenic potential in a mouse xenograft model. The p38 MAPK signaling pathway is also a major regulator of myogenesis (the process whereby quiescent muscle stem cells -satellite cells- expand and differentiate to form muscle fibers), by inducing cell cycle withdrawal and the expression of the muscle-specific transcriptional program. RB is also a regulator of the myogenic differentiation process. We explored the possible role of p38 in muscle cell differentiation using normal myoblasts and rhabdomyosarcoma (RMS) cells (which are defective in p38 MAPK activation), via RB phosphorylation. Our results strongly suggest that, despite the important role of p38 for differentiation of both myogenic models, this function does not depend on p38-phosphorylated RB. p38 MAPK has also been associated to aging of muscle stem cells. Aged satellite cells have a cell-autonomous increase in the activity of p38, thus contributing to defective control of quiescence, expansion and self-renewal capacities. In this study we show ...