It takes a team: a gain-of-function story of p53-R249S.

Abstract

Gain-of-function (GOF), the most malicious oncogenic activity of a cancer-promoting protein, is well illustrated to three hotspot p53 mutations at R248, R175, and R273 with distinct molecular mechanisms. Yet, less is known about another hotspot p53 mutant, R249S (p53-R249S). p53-R249S is the sole hotspot mutation in hepatocellular carcinoma (HCC) that is highly associated with chronic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin B1 (AFB1). Its GOF is suggested by the facts that this mutant is associated with earlier onset of HCC and poorer prognosis of cancer patients and that its overexpression drives HCC proliferation and tumorigenesis. By contrast, simply knocking in this mutant in normal mice did not show apparent GOF activity. Hence, the GOF activity for p53-R249S and its underlying mechanisms have been elusive until recent findings offered some new insights. This review will discuss these findings as well as their clinical significance and implications for the development of a strategy to target multiple molecules as a therapy for p53-R249S-harboring HCC.

• Authors: Huai Wang, Peng Liao, Shelya X Zeng, Hua Lu
• Journal: Journal of molecular cell biology (J Mol Cell Biol) Vol. 11 Issue 4 Pg. 277-283 (04 01 2019) ISSN: 1759-4685 [Electronic] United States
• PMID: 30608603 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: © The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.

Chemical References

• NIMA-Interacting Peptidylprolyl Isomerase
• Proto-Oncogene Proteins c-myc
• Tumor Suppressor Protein p53
• Cyclin D1

Topics

• Animals
• Carcinogenesis
• Carcinoma, Hepatocellular (metabolism, pathology)
• Cyclin D1 (metabolism)
• Gain of Function Mutation
• Humans
• Liver Neoplasms (metabolism, pathology)
• NIMA-Interacting Peptidylprolyl Isomerase (metabolism)
• Proto-Oncogene Proteins c-myc (metabolism)
• Tumor Suppressor Protein p53 (genetics, metabolism)