p53-Mediated transactivation of LIMK2b links actin dynamics to cell cycle checkpoint control.
The p53 tumor suppressor protein is widely known for its role as a sequence-specific transcription factor that regulates the expression of stress response genes. Here, we report the identification of LIMK2, which encodes a kinase that regulates actin dynamics through phosphorylation of cofilin, as a p53 target upregulated by DNA damage. Interestingly, the splice variant LIMK2b, but not LIMK2a, was induced in a p53-dependent manner through an intronic consensus p53-binding site. Depletion of LIMK2b leads to early exit of G2/M arrest after DNA damage, whereas its overexpression prolongs the arrest. These responses are recapitulated by ectopic expression of the active cofilin S3A mutant and the inactive cofilin S3D mutant, respectively, suggesting that LIMK2b may modulate G2/M arrest through cofilin phosphorylation. Furthermore, in support of its potential role as a tumor suppressor, LIMK2b was downregulated in esophageal and thyroid cancers, as well as in a number of established cancer cell lines, and its expression suppresses cancer cell migration. Taken together, our results unveil a novel pathway whereby LIMK2b, acting downstream of p53, ensures proper execution of checkpoint arrest by modulating the dynamics of actin polymerization.
Hsu
F-F
FF
Institute of Biochemistry and Molecular Biology, Molecular Medicine Program, National Yang-Ming University, Taipei, Taiwan.
Lin
T-Y
TY
Chen
J-Y
JY
Shieh
S-Y
SY
D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D048749:Cytokinesis / Q000235:genetics; D004249:DNA Damage; D016195:G2 Phase / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D054461:Lim Kinases / Q000235:genetics* / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D011003:Ploidies; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
D051339:Actin Depolymerizing Factors; D000199:Actins; D016159:Tumor Suppressor Protein p53; C102895:LIMK2 protein, human; D054461:Lim Kinases