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miR-29 miRNAs activate p53 by targeting p85α and CDC42

Abstract

The tumor suppressor p53 is central to many cellular stress responses. Although numerous protein factors that control p53 have been identified, the role of microRNAs (miRNAs) in regulating p53 remains unexplored. In a screen for miRNAs that modulate p53 activity, we find that miR-29 family members (miR-29a, miR-29b and miR-29c) upregulate p53 levels and induce apoptosis in a p53-dependent manner. We further find that miR-29 family members directly suppress p85α (the regulatory subunit of PI3 kinase) and CDC42 (a Rho family GTPase), both of which negatively regulate p53. Our findings provide new insights into the role of miRNAs in the p53 pathway.

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Figure 1: miR-29 miRNAs positively regulate p53.
Figure 2: miR-29 miRNAs induce apoptosis in a p53-dependent manner.
Figure 3: Inhibition of miR-29 downregulates p53 activity.
Figure 4: p85α and CDC42 are directly targeted by miR-29 miRNAs.
Figure 5: Ectopic expression of CDC42 and p85α rescues cellular apoptosis.

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Acknowledgements

We thank J. Chung (Korea Advanced Institute of Science and Technology (KAIST)) for the pG13-luc plasmid, D. Park (School of Biological Sciences, Seoul National University) for the CDC42 expression plasmid, H.-D. Youn (College of Medicine, Seoul National University) for the HCT116 cell lines and S. Hee Baek (School of Biological Sciences, Seoul National University) for helpful discussion. We are grateful to the members of our laboratory, particularly C. Joo, W. Jones, J. Han and Y.-K. Kim for critical reading of the manuscript. This work was supported by the Creative Research Initiatives Program (V.N.K.) and by BK21 Research Fellowships (S.-Y.P. and M.H.) from the Ministry of Education, Science and Technology of the Republic of Korea.

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S.-Y.P., J.H.L. and M.H. performed the experiments and analyzed the data; J.-W.N. performed bioinformatic analyses and helped with editing of the manuscript; S.-Y.P., J.H.L. and V.N.K. designed the study and wrote the paper.

Corresponding author

Correspondence to V Narry Kim.

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Supplementary Figures 1–9 and Supplementary Table 1 (PDF 302 kb)

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Park, SY., Lee, J., Ha, M. et al. miR-29 miRNAs activate p53 by targeting p85α and CDC42. Nat Struct Mol Biol 16, 23–29 (2009). https://doi.org/10.1038/nsmb.1533

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