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Cytoplasmic parafibromin/hCdc73 targets and destabilizes p53 mRNA to control p53-mediated apoptosis

Nature Communications volume 5, Article number: 5433 (2014) | Download Citation

Abstract

The parafibromin/hCdc73 is a component of the PAFc, which controls RNA polymerase II-mediated general transcription. In parathyroid carcinoma and familial autosomal dominant hyperparathyroidism-jaw tumour (HPT-JT), hCdc73 mutations are heavily implicated, yet the underlying mechanism of its carcinogenic action is poorly understood. Here we demonstrate that hCdc73 specifically controls messenger RNA stability of p53 and p53-mediated apoptosis. hCdc73 is associated with mature p53 mRNA in the cytoplasm and facilitates its degradation. Cytoplasmic hCdc73 physically interacts with eEF1Bγ and hSki8, and this interaction is required to bind and destabilize p53 mRNA. Furthermore, enhanced association of p53 mRNA with a cancer-driven hCdc73(K34Q) mutant was also observed. As a result, reduced p53 expression as well as enhanced cell proliferation was acquired in the hCdc73 (K34Q)-overexpressed cells. Altogether, our findings indicate that hCdc73 directly targets p53 mRNA to repress p53 expression, and aberrant regulation of this interaction may lead to tumour progression.

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Acknowledgements

We thank Dr D. Hwang (DGIST, Korea) for the technical support on microarray analysis, and Drs G.-O. Ahn, C.S. Hwang and K.-H. Lee (Postech, Korea) for the advice on solid tumour model, column chromatography and RNA-pull down assay, respectively. This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIP) (NO. NRF-2012R1A2A2A01007525 and NRF-2012R1A4A1028200).

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Affiliations

  1. Department of Life Sciences, Pohang University of Science and Technology, Life Science Building 208, POSTECH, Nam-Gu, Pohang, Gyungbuk 790-784, Korea

    • Jay-Hyun Jo
    •  & Joo-Yeon Yoo
  2. Department of Nuclear Medicine, Cancer Imaging Center, Seoul National University Cancer Hospital, Seoul 110-744, Korea

    • Tae-Moon Chung
    •  & Hyewon Youn
  3. Tumor Microenvironment Global Core Research Center, Cancer Research Institute, Seoul National University, Seoul 110-799, Korea

    • Hyewon Youn

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Contributions

J.-H.J. and J.-Y.Y. designed the study and wrote the paper. J.-H.J. performed most of the experiments. T.-M.C. performed the in vivo solid tumour studies. J.-Y.Y. and H.Y. supervised the experiments and project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Joo-Yeon Yoo.

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https://doi.org/10.1038/ncomms6433

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