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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Recent Advances on Mutant p53: Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions
Marco Cordani1,2, Alessia Garufi3, Rossella Benedetti4
1Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain.
Abstract:
The p53 protein is the master regulator of cellular integrity, primarily due to its tumor-suppressing functions. Approximately half of all human cancers carry mutations in the TP53 gene, which not only abrogate the tumor-suppressive functions but also confer p53 mutant proteins with oncogenic potential. The latter is achieved through so-called gain-of-function (GOF) mutations that promote cancer progression, metastasis, and therapy resistance by deregulating transcriptional networks, signaling pathways, metabolism, immune surveillance, and cellular compositions of the microenvironment. Despite recent progress in understanding the complexity of mutp53 in neoplastic development, the exact mechanisms of how mutp53 contributes to cancer development and how they escape proteasomal and lysosomal degradation remain only partially understood. In this review, we address recent findings in the field of oncogenic functions of mutp53 specifically regarding, but not limited to, its implications in metabolic pathways, the secretome of cancer cells, the cancer microenvironment, and the regulating scenarios of the aberrant proteasomal degradation. By analyzing proteasomal and lysosomal protein degradation, as well as its connection with autophagy, we propose new therapeutical approaches that aim to destabilize mutp53 proteins and deactivate its oncogenic functions, thereby providing a fundamental basis for further investigation and rational treatment approaches for TP53-mutated cancers.
Insights
Mutant p53 proteins drive cancer progression and therapy resistance. This review explores their oncogenic functions and proposes targeting protein degradation for new cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The p53 protein is a key tumor suppressor, crucial for cellular integrity.
- Mutations in the TP53 gene are found in about half of human cancers, leading to loss of tumor suppression and gain of oncogenic functions.
- Mutant p53 proteins (mutp53) promote cancer progression, metastasis, and therapy resistance through various cellular mechanisms.
Purpose of the Study:
- To review recent findings on the oncogenic functions of mutp53.
- To elucidate the mechanisms by which mutp53 contributes to cancer development.
- To explore how mutp53 evades degradation and to propose novel therapeutic strategies targeting mutp53 stability.
Main Methods:
- Literature review focusing on recent advancements in understanding mutp53.
- Analysis of proteasomal and lysosomal protein degradation pathways, including autophagy.
- Examination of mutp53's role in metabolic pathways, cancer secretome, and the tumor microenvironment.
Main Results:
- Mutp53 proteins possess gain-of-function (GOF) properties, actively promoting cancer.
- Mutp53 deregulates critical cellular processes including metabolism, immune surveillance, and the tumor microenvironment.
- Aberrant regulation of proteasomal and lysosomal degradation pathways contributes to mutp53 stability and oncogenic activity.
Conclusions:
- Understanding mutp53's multifaceted oncogenic roles is crucial for cancer therapy.
- Targeting the degradation pathways of mutp53 presents a promising therapeutic avenue for TP53-mutated cancers.
- Further research into mutp53 stability and degradation mechanisms can pave the way for rational treatment strategies.
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