Cordani, MarcoGarufi, AlessiaBenedetti, RossellaTafani, MarcoAventaggiato, MicheleD’Orazi, GabriellaCirone, Mara2025-03-122025-03-122024Cordani, 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:// doi.org/10.3390/biom140606492218-273X10.3390/biom14060649https://hdl.handle.net/20.500.14352/118713Marco Cordani was supported by grant RYC2021-031003I funded by MICIU/AEI/10.13039/501100011033 and, by European Union NextGenerationEU/PRTR. Marco Tafani was supported by grant Ateneo 2023 from Sapienza University. Mara Cirone was funded by the Italian Association for Cancer Research (AIRC; grant IG 2019-23040).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.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal articlehttps://doi.org/10.3390/biom14060649https://www.mdpi.com/2218-273X/14/6/649open access577.2616-006.6Mutant p53Cancer secretomeExtracellular vesiclesTumor microenvironmentMDM2ProteasomeUbiquitinationChaperone-mediated autophagy (CMA)Heat shock proteins (HSP)Bioquímica (Biología)Biología molecular (Biología)Oncología2403 Bioquímica2415 Biología Molecular3201.01 Oncología