p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21^Cip1 mRNA Mediates the G₁/S Checkpoint

ABSTRACT

Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the G₂/M cell cycle arrest induced by DNA damage, but little is known about the role of this signaling pathway in the G₁/S transition. Upregulation of the cyclin-dependent kinase inhibitor p21^Cip1 is thought to make a major contribution to the G₁/S cell cycle arrest induced by γ radiation. We show here that inhibition of p38 MAPK impairs p21^Cip1 accumulation and, as a result, the ability of cells to arrest in G₁ in response to γ radiation. We found that p38 MAPK induces p21^Cip1 mRNA stabilization, without affecting its transcription or the stability of the protein. In particular, p38 MAPK phosphorylates the mRNA binding protein HuR on Thr118, which results in cytoplasmic accumulation of HuR and its enhanced binding to the p21^Cip1 mRNA. Our findings help to understand the emerging role of p38 MAPK in the cellular responses to DNA damage and reveal the existence of p53-independent networks that cooperate in modulating p21^Cip1 levels at the G₁/S checkpoint.