Mutant p53 oncogenicity: dominant-negative or gain-of-function?

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The p53 protein is a critical tumor suppressor, frequently mutated in human cancers.
• Mutant p53 can exhibit pro-oncogenic activities beyond the loss of its tumor-suppressive functions.

Purpose of the Study:

• To review evidence for dominant-negative effect (DNE) and gain-of-function (GOF) mechanisms of mutant p53.
• To discuss the context-dependent relevance of DNE and GOF in cancer development.

Main Methods:

• Review of in vitro and in vivo experimental models.
• Analysis of evidence for DNE and GOF activities of mutant p53.

Main Results:

• Both DNE and GOF mechanisms contribute to protumorigenic activities of mutant p53.
• The impact of DNE and GOF is highly dependent on the specific p53 mutation, genetic background, cellular environment, and assessed phenotype.

Conclusions:

• Mutant p53's protumorigenic effects are mediated by both DNE and GOF, with context-specific relevance.
• Understanding the balance between wild-type and mutant p53, and the factors governing DNE/GOF, is crucial for developing targeted cancer therapies.