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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
p73 can suppress the proliferation of cells that express mutant p53
Amy C Willis1, Tara Pipes, Jianhui Zhu
1Department of Cell Biology and UAB Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Abstract:
Mutation of the p53 tumor suppressor gene is the most common genetic alteration in human cancer. p73, a member of the p53 family, has been found to exhibit activity similar to that of p53, including the ability to induce growth arrest and apoptosis. p53 and p73 have a high percentage of similarity at several domains, including the DNA binding domain. This domain in p53 is the location of missense mutations in many human cancers. Mutant p53, which cannot suppress cell proliferation, has been found to have a dominant-negative activity that inactivates wild-type p53. To determine the effects of mutant p53 on wild-type p73, we have established cell lines expressing both mutant p53 and wild-type p73 in a dual-inducible system. This system expresses mutant p53 in a tetracycline-repressible system and p73beta in an ecdysone-inducible system in a p53-null lung carcinoma parental cell line. We have found that wild-type p73beta, in the presence of mutant p53, retains the ability to transactivate p21 and suppresses cell growth through induction of both cell cycle arrest and apoptosis. In addition, in cell lines expressing wild-type p53 and wild-type p73beta, we have found that these proteins cooperate to additively transactivate p21 and suppress cell proliferation.
Insights
Mutant p53 does not inactivate wild-type p73, which retains its tumor-suppressing abilities. Wild-type p53 and p73 cooperate to suppress cell proliferation in cancer cells.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Cell Biology
Background:
- TP53 gene mutations are frequent in human cancers.
- p73, a p53 family member, shares functional similarities with p53, including growth arrest and apoptosis induction.
- Mutant p53 can exhibit dominant-negative activity, inhibiting wild-type p53 function.
Purpose of the Study:
- To investigate the effect of mutant p53 on wild-type p73 function.
- To analyze the interaction between mutant p53 and wild-type p73beta in a controlled cellular system.
Main Methods:
- Establishment of dual-inducible cell lines expressing mutant p53 and wild-type p73beta in a p53-null background.
- Utilized a tetracycline-repressible system for mutant p53 and an ecdysone-inducible system for p73beta.
- Assessed transactivation of p21, cell growth suppression, cell cycle arrest, and apoptosis.
Main Results:
- Wild-type p73beta maintained its ability to transactivate p21 and induce cell cycle arrest and apoptosis, even in the presence of mutant p53.
- Mutant p53 did not inactivate wild-type p73beta's tumor-suppressive functions.
- Wild-type p53 and wild-type p73beta showed cooperative, additive transactivation of p21 and suppression of cell proliferation.
Conclusions:
- Mutant p53 does not interfere with wild-type p73beta's tumor suppressor activity.
- Wild-type p53 and p73 can cooperate to inhibit cancer cell growth, suggesting potential therapeutic strategies targeting these pathways.
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