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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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Mutant p53 Gains Its Function via c-Myc Activation upon CDK4 Phosphorylation at Serine 249 and Consequent PIN1

Peng Liao1, Shelya X Zeng1, Xiang Zhou1

  • 1Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.

Molecular Cell
|December 12, 2017
PubMed

Insights

A novel pathway involving CDK4, PIN1, and c-Myc drives the gain of function in the p53-R249S mutant, promoting hepatocellular carcinoma development. This discovery sheds light on cancer progression mechanisms.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • TP53 missense mutations contribute to cancer development through gain of function (GOF).
  • The p53-R249S mutant is frequently found in hepatocellular carcinoma (HCC), linked to hepatitis B and aflatoxin B1 exposure.

Purpose of the Study:

  • To elucidate a unique mechanism for the gain of function (GOF) of the p53-R249S mutant in hepatocellular carcinoma (HCC).

Main Methods:

  • Investigated the interaction of CDK4 with p53-R249S and its effect on nuclear translocation.
  • Examined the role of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) binding to p53-R249S.
  • Assessed the impact of p53-R249S on c-Myc interaction and rDNA transcription.

Main Results:

  • CDK4 phosphorylates and enhances the nuclear localization of p53-R249S in HCC cells.
  • PIN1 specifically binds to p53-R249S, distinct from wild-type p53 binding sites.
  • p53-R249S interacts with c-Myc, boosting c-Myc-dependent rDNA transcription essential for ribosomal biogenesis.

Conclusions:

  • A novel CDK4-PIN1-p53-R249S-c-Myc pathway facilitates the GOF of p53-R249S in HCC.
  • This pathway represents a new mechanism contributing to hepatocellular carcinoma progression.
Keywords:
CDK4FBW7aGOFPIN1c-Myccell proliferationgain of functionp53-R249Sphosphorylationribosomal biogenesistranscription

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