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Updated: Dec 30, 2025
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
It takes a team: a gain-of-function story of p53-R249S
Huai Wang1,2,3, Peng Liao1, Shelya X Zeng1
1Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA.
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.
Insights
The p53-R249S mutation, linked to hepatitis B virus and aflatoxin B1, drives hepatocellular carcinoma (HCC) despite unclear gain-of-function (GOF) mechanisms. Recent insights reveal its GOF activity, offering new therapeutic targets for HCC.
Area of Science:
- Oncology
- Molecular Biology
- Hepatology
Background:
- Gain-of-function (GOF) mutations in the p53 protein are critical drivers of cancer, with known mechanisms for mutations at R248, R175, and R273.
- The p53-R249S hotspot mutation is uniquely prevalent in hepatocellular carcinoma (HCC), strongly associated with hepatitis B virus (HBV) infection and aflatoxin B1 (AFB1) exposure.
- Despite associations with earlier HCC onset and poorer prognosis, the precise GOF activity and molecular mechanisms of p53-R249S have remained largely elusive.
Purpose of the Study:
- To review recent findings elucidating the gain-of-function (GOF) activity of the p53-R249S mutant.
- To discuss the molecular mechanisms underlying p53-R249S-mediated oncogenesis in hepatocellular carcinoma (HCC).
- To explore the clinical significance and therapeutic implications for targeting p53-R249S-harboring HCC.
Main Methods:
- Literature review of recent studies on p53 mutations in cancer.
- Analysis of molecular mechanisms linking p53-R249S to hepatocellular carcinoma (HCC) pathogenesis.
- Evaluation of clinical data and prognostic indicators associated with p53-R249S.
Main Results:
- Recent research has provided new insights into the elusive gain-of-function (GOF) activity of the p53-R249S mutant.
- The p53-R249S mutation's GOF mechanisms are distinct and contribute to HCC proliferation and tumorigenesis.
- Understanding these mechanisms is crucial for developing targeted therapies.
Conclusions:
- Recent findings have shed light on the gain-of-function (GOF) activity of the p53-R249S mutant in hepatocellular carcinoma (HCC).
- The molecular mechanisms of p53-R249S are critical for HCC development and progression.
- These insights pave the way for developing novel multi-targeted therapeutic strategies for HCC patients with this specific mutation.
