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

Jay-Hyun Jo1, Tae-Moon Chung2, Hyewon Youn3

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

Nature Communications
|November 13, 2014
PubMed

Insights

The parafibromin/hCdc73 protein regulates p53 mRNA stability, controlling apoptosis and cell proliferation. Mutations in hCdc73 can lead to tumor progression by disrupting this crucial mechanism.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • The parafibromin/hCdc73 protein is part of the PAFc complex, essential for RNA polymerase II transcription.
  • Mutations in hCdc73 are linked to parathyroid carcinoma and HPT-JT syndrome, but the mechanism of its oncogenic action is unclear.

Purpose of the Study:

  • To elucidate the role of hCdc73 in regulating p53 mRNA stability and its implications in cancer.
  • To investigate the molecular interactions of hCdc73 with p53 mRNA and associated proteins.

Main Methods:

  • Investigated hCdc73's effect on p53 mRNA stability and p53-mediated apoptosis.
  • Performed co-immunoprecipitation to identify interacting proteins of hCdc73 in the cytoplasm.
  • Analyzed the impact of a cancer-associated hCdc73 mutant (K34Q) on p53 mRNA and cell proliferation.

Main Results:

  • hCdc73 directly binds to mature p53 mRNA in the cytoplasm, promoting its degradation.
  • hCdc73 interacts with eEF1Bγ and hSki8 to destabilize p53 mRNA.
  • Overexpression of the hCdc73(K34Q) mutant enhances p53 mRNA association, reduces p53 expression, and increases cell proliferation.

Conclusions:

  • hCdc73 acts as a direct regulator of p53 mRNA stability, thereby controlling p53 expression and apoptosis.
  • Aberrant regulation of the hCdc73-p53 mRNA interaction contributes to tumor progression in parathyroid diseases.

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