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Different tumor-derived p53 mutants exhibit distinct biological activities
O Halevy1, D Michalovitz, M Oren
1Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
In its wild-type form, the protein p53 can interfere with neoplastic processes. Tumor-derived cells often express mutant p53. Full-length mutant forms of p53 isolated so far from transformed mouse cells exhibit three common properties in vitro: loss of transformation-suppressing activity, gain of pronounced transforming potential, and ability to bind the heat shock protein cognate hsc70. A tumor-derived mouse p53 variant is now described, whose site of mutation corresponds to a hot spot for p53 in human tumors. While absolutely nonsuppressing, it is only weakly transforming and exhibits no detectable hsc70 binding. The data suggest that the ability of a p53 mutant to bind endogenous p53 is not the sole determinant of its oncogenic potential. The data also support the existence of gain-of-function p53 mutants.
Insights
Mutant p53 proteins can promote tumor growth. This study identifies a specific p53 variant that, despite lacking tumor-suppressing activity, shows limited transforming potential and no heat shock cognate protein 70 binding, challenging current models of oncogenic p53.
Area of Science:
- Oncology
- Molecular Biology
- Protein Biochemistry
Background:
- The wild-type p53 protein is a crucial tumor suppressor.
- Tumor cells frequently express mutated forms of p53.
- Previously characterized mutant p53 proteins exhibit loss of tumor suppression, gain of transforming potential, and hsc70 binding.
Purpose of the Study:
- To characterize a novel tumor-derived mouse p53 variant.
- To investigate the relationship between p53 mutation site, transforming potential, and hsc70 binding.
- To explore the oncogenic mechanisms of p53 mutants.
Main Methods:
- Isolation and characterization of a specific tumor-derived mouse p53 variant.
- In vitro assays to assess transformation-suppressing activity.
- In vitro assays to evaluate transforming potential.
- Analysis of heat shock protein cognate hsc70 binding.
Main Results:
- The studied p53 variant, mutated at a human tumor hot spot, completely lacks tumor-suppressing activity.
- This variant displays only weak transforming potential.
- No detectable binding to hsc70 was observed for this p53 variant.
Conclusions:
- The ability of p53 mutants to bind hsc70 is not essential for their oncogenic potential.
- The data suggest that p53 mutants can possess oncogenic functions independent of hsc70 binding.
- The findings support the existence of "gain-of-function" p53 mutants.