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Physical and functional interaction between p53 mutants and different isoforms of p73
S Strano1, E Munarriz, M Rossi
1Molecular Oncogenesis Laboratory, Regina Elena Cancer Center, Via delle Messi d'Oro 156, Rome 00158, Italy.
The Journal of Biological Chemistry
|July 8, 2000
Summary
Mutant tumor suppressor p53 protein physically and functionally interacts with p73 protein. This interaction may help cancer cells survive and grow.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The tumor suppressor gene p53 is frequently inactivated in human cancers.
- p53 homologue p73 can induce apoptosis or growth arrest in p53-null cells.
- Some p53 mutants exhibit gain-of-function activity, but the mechanism is unclear.
Purpose of the Study:
- To investigate the molecular mechanism behind the gain-of-function activity of tumor-derived p53 mutants.
- To determine if p53 mutants interact with p73.
Main Methods:
- In vitro and in vivo association studies using p53 mutants (p53His175, p53Gly281) and p73 isoforms.
- Verification of association under physiological conditions in breast cancer cell lines (T47D, SKBR3).
- Analysis of protein domains involved in the p53-p73 interaction and p73 transcriptional activity assays.
Main Results:
- Tumor-derived p53 mutants (p53His175, p53Gly281) associate with all tested p73 isoforms (alpha, beta, gamma, delta).
- The core domain of mutant p53 and specific domains of p73 are crucial for this association.
- Mutant p53 significantly inhibits the transcriptional activity of p73 isoforms.
Conclusions:
- Tumor-derived p53 mutants physically and functionally interact with p73.
- This interaction creates a network involving mutant p53 and p73 isoforms.
- This network may provide a survival advantage to tumor cells.