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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
P53 mutations and cancer: a tight linkage
Francesco Perri1, Salvatore Pisconti1, Giuseppina Della Vittoria Scarpati1
1Medical Oncology Unit, POC SS Annunziata, Taranto (Italy), Italy.
Abstract:
P53 is often mutated in solid tumors, in fact, somatic changes involving the gene encoding for p53 (TP53) have been discovered in more than 50% of human malignancies and several data confirmed that p53 mutations represent an early event in cancerogenesis. Main p53 functions consist in cell cycle arrest, DNA repair, senescence and apoptosis induction in response to mutagenic stimuli, and, to exert those functions, p53 acts as transcriptional factor. Recent data have highlighted another very important role of p53, consisting in regulate cell metabolism and cell response to oxidative stress. Majority of tumor suppressor genes, such as adenomatous polyposis coli (APC), retinoblastoma-associated protein (RB) and Von-Hippel-Lindau (VHL) are inactivated by deletion or early truncation mutations in tumors, resulting in the decreased or loss of expression of their proteins. Differently, most p53 mutations in human cancer are missense mutations, which result in the production of full-length mutant p53 proteins. It has been reported that mutant p53 proteins and wild type p53 proteins often regulate same cellular biological processes with opposite effects. So, mutant p53 has been reported to supply the cancer cells of glucose and nutrients, and, to avoid reactive oxygen species (ROS) mediated damage during oxidative stress. These last features are able to render tumor cells resistant to ionizing radiations and chemotherapy. A future therapeutic approach in tumors bearing p53 mutations may be to deplete cancer cells of their energy reserves and antioxidants.
Insights
Mutant p53 (TP53) proteins, found in over 50% of cancers, support tumor growth by regulating metabolism and resisting oxidative stress. Targeting these energy reserves may offer new cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The TP53 gene is mutated in over 50% of human malignancies, often representing an early event in cancerogenesis.
- While tumor suppressor genes like APC, RB, and VHL are typically inactivated by deletions or truncations, TP53 mutations are frequently missense, producing full-length mutant proteins.
- Mutant p53 proteins can exert functions opposite to wild-type p53, influencing cancer cell metabolism and stress responses.
Purpose of the Study:
- To review the dual role of p53, encompassing its canonical tumor suppressor functions and its newly recognized roles in regulating cell metabolism and oxidative stress response.
- To highlight the distinct mutational patterns of TP53 compared to other tumor suppressor genes and the functional consequences of these mutations.
- To explore the potential of targeting metabolic pathways and antioxidant defenses in p53-mutated cancers.
Main Methods:
- Literature review and synthesis of existing research on p53 function, mutation patterns, and cancer biology.
- Analysis of the differential effects of wild-type versus mutant p53 on cellular processes.
- Exploration of emerging therapeutic strategies based on metabolic vulnerabilities and oxidative stress.
Main Results:
- Mutant p53 proteins can promote cancer cell survival by enhancing glucose and nutrient uptake.
- Mutant p53 contributes to resistance against oxidative stress by mitigating reactive oxygen species (ROS) damage.
- These pro-tumorigenic functions of mutant p53 confer resistance to conventional therapies like ionizing radiation and chemotherapy.
Conclusions:
- Mutant p53 plays a critical role in cancer progression by altering cellular metabolism and stress responses.
- The distinct functional outcomes of mutant p53 present unique therapeutic vulnerabilities.
- Future cancer treatment strategies may involve depleting energy reserves and antioxidants in p53-mutated tumors.
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