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p53-Mediated transactivation of LIMK2b links actin dynamics to cell cycle checkpoint control

Oncogene volume 29, pages 2864–2876 (2010)Cite this article

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Abstract

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.

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Acknowledgements

We thank Hsiu-Ting Lin for her expert technical assistance with the RT–PCR. This work was supported by funding from Academia Sinica to S-Y Shieh.

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Authors and Affiliations

  1. Institute of Biochemistry and Molecular Biology, Molecular Medicine Program, National Yang-Ming University, Taipei, Taiwan

    F-F Hsu

  2. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

    F-F Hsu, T-Y Lin, J-Y Chen & S-Y Shieh

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  1. F-F Hsu
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Correspondence to S-Y Shieh.

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Hsu, FF., Lin, TY., Chen, JY. et al. p53-Mediated transactivation of LIMK2b links actin dynamics to cell cycle checkpoint control. Oncogene 29, 2864–2876 (2010). https://doi.org/10.1038/onc.2010.40

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