Cabin1 restrains p53 activity on chromatin

Abstract

The tumor suppressor p53 has been proposed to bind target promoters upon genotoxic stress. However, recent evidence shows that p53 occupies some target promoters without such stress, suggesting that a negative regulator might render p53 transcriptionally inactive on these promoters. Here we show that calcineurin binding protein 1 (Cabin1) is a negative regulator of p53. Downregulation of Cabin1 induces activation of a subset of p53 target genes. Cabin1 physically interacts with p53 on these target promoters and represses p53 transcriptional activity in the absence of genotoxic stress, by regulating histone modification and p53 acetylation marks. Knockdown of Cabin1 retards cell growth and promotes cell death after DNA damage in a p53-dependent manner. Thus, Cabin1 inhibits p53 function on chromatin in the quiescent state; the presence of inactive p53 on some promoters might allow a prompt response upon DNA damage.

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Figure 1: Cabin1 regulates the mRNA level of a subset of p53 target genes.
Figure 2: CABIN1 physically interacts with p53.
Figure 3: CABIN1 occupies a subset of p53 target promoters in the absence of genotoxic stress.
Figure 4: CABIN1 dissociates from promoters upon genotoxic stress.
Figure 5: CABIN1 regulates both histone marks on p53 target promoters and the acetylation of p53.
Figure 6: Knockdown of CABIN1 retards cell growth and promotes cell death on DNA damage.
Figure 7: Mechanism of negative regulation of p53 by Cabin1.

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Acknowledgements

We are grateful to S.T. Kim (Sungkyunkwan University) for the KDM1 expression vector and K.L. Wright (University of South Florida) for the EHMT2 expression vector. We thank B. Vogelstein (The Johns Hopkins University Medical Institutions) for the HCT116 (TP53+/+) and HCT116 (TP53−/−) lines. This work was supported by KOSEF grants from the Korean National Research Laboratory (ROA-2007-000-20002-0) and the Center for Functional Analysis for Human Genome (3344-20060070) to H.-D.Y. and Korean Research Foundation grants (KRF-C00257) to H.-D.Y. and E.-J.C. S.-Y.C. was supported by the Seoul Science Fellowship.

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H.J. planned the research, performed almost all the experiments and wrote the manuscript; S.-Y.C. performed some of the immunoprecipitation experiments; E.-J.C. supervised the research; H.-D.Y. planned and supervised the research and wrote the manuscript.

Corresponding author

Correspondence to Hong-Duk Youn.

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Supplementary Figures 1–6 and Supplementary Tables 1 and 2 (PDF 640 kb)

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Jang, H., Choi, SY., Cho, EJ. et al. Cabin1 restrains p53 activity on chromatin. Nat Struct Mol Biol 16, 910–915 (2009). https://doi.org/10.1038/nsmb.1657

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