Recent Advances on Mutant p53 - Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions

Sep 21, 2026

Uploaded by Maeve

The p53 protein is a master regulator of cellular integrity, and about half of human cancers carry TP53 mutations that remove tumor-suppressive activity while endowing mutant p53 with oncogenic gain-of-function. These mutants promote cancer progression, metastasis, and resistance by disrupting transcriptional programs, signaling, metabolism, immune surveillance, and microenvironmental cell composition. Although progress has been made, the precise mechanisms linking mutant p53 to tumor development and its escape from proteasomal and lysosomal degradation remain incompletely resolved. This review synthesizes recent findings on oncogenic functions, including metabolic pathways, cancer secretome, microenvironment effects, and aberrant proteasomal degradation, and proposes therapeutic strategies to destabilize mutp53 and shut down oncogenic activity, supporting rational treatment of TP53-mutated cancers.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages24

Reading Time1 h 0 min

AccessFree to download

Introduction

Oncogenic gain-of-function of mutant p53

Clinical impact of TP53 mutations

Scope of the review

biomolecules Review Recent Advances on Mutant p53: Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions Marco Cordani 1,2, *, Alessia Garufi 3, Rossella Benedetti 4, Marco Tafani 4, Michele Aventaggiato 4, Gabriella D’Orazi 3,5, * and Mara Cirone 4 Citation: Cordani, M.; Garufi, A.; Benedetti, R.; Tafani, M.; Aventaggiato, M.; D’Orazi, G.; Cirone, M. Recent Advances on Mutant p53: Unveiling Novel Oncogenic Roles, Degradation Pathways, and Therapeutic Interventions. Biomolecules 2024, 14, 649. [https://](https://)[ ](https://)[doi.org/10.3390/biom14060649](doi.org/10.3390/biom14060649) Academic Editor: Hang Fai (Henry) Kwok Received: 7 May 2024 Revised: 24 May 2024 Accepted: 28 May 2024 Published: 31 May 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040 Madrid, Spain 2 Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain 3 Unit of Cellular Networks and Molecular Therapeutic Targets, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; [alessia.garufi@ifo.it](alessia.garufi@ifo.it) 4 Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy; [rossella.benedetti@uniroma1.it](rossella.benedetti@uniroma1.it) (R.B.); [marco.tafani@uniroma1.it](marco.tafani@uniroma1.it) (M.T.); [michele.aventaggiato@uniroma1.it](michele.aventaggiato@uniroma1.it) (M.A.); [mara.cirone@uniroma1.it](mara.cirone@uniroma1.it) (M.C.) 5 Department of Neurosciences, Imaging and Clinical Sciences, University G. D’Annunzio, 00131 Chieti, Italy * Correspondence: mcordani@ucm.es (M.C.); [gdorazi@unich.it](gdorazi@unich.it) (G.D.) Abstract: The p53 protein is the master regulator of cellular integrity, primarily due to its tumorsuppressing 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. Keywords: mutant p53; cancer secretome; extracellular vesicles; tumor microenvironment; MDM2; proteasome; ubiquitination; chaperone-mediated autophagy (CMA); heat shock proteins (HSP) 1. Introduction The p53 protein, often referred to as “the guardian of the genome”, plays a crucial role in maintaining cellular integrity by regulating a variety of cellular processes such as DNA repair, cell cycle arrest

FAQs

How do TP53 mutations affect p53 and cancer behavior?

TP53 mutations abolish normal tumor-suppressive p53 functions and produce mutant p53 proteins with oncogenic gain-of-function, promoting progression, metastasis, and therapy resistance.

What mechanisms are highlighted as drivers of mutant p53 gain-of-function?

Mutant p53 gain-of-function is described as affecting transcriptional networks, signaling pathways, metabolism, immune evasion, and tumor microenvironment composition.

Why is proteasomal and lysosomal degradation important in this context?

The review emphasizes that the mechanisms by which mutant p53 escapes proteasomal and lysosomal degradation are only partially understood and that proteasomal/lysosomal degradation pathways are central to proposed therapeutic strategies.

Sep 21, 2026

Uploaded by Maeve