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It takes a team: a gain-of-function story of p53-R249S
Huai Wang 1,2,3, Peng Liao1, Shelya X. Zeng1, and Hua Lu 1,*
1 Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
2 School of Public Health, Nanchang University, Nanchang 330006, China
3 Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang 330006, China
*Correspondence to:Hua Lu, E-mail: hlu2@tulane.edu
J Mol Cell Biol, Volume 11, Issue 4, April 2019, Pages 277-283  https://doi.org/10.1093/jmcb/mjy086
Keyword: p53-R249S, Liver cancer, HCC, CDK4/cyclin D1, PIN1, c-Myc, FBW7a

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.