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p53-R273H Sustains ROS, Pro-Inflammatory Cytokine Release and mTOR Activation While Reducing Autophagy, Mitophagy and UCP2 Expression, Effects Prevented by wtp53

p53 is the most frequently mutated or inactivated gene in cancer, as its activity is not reconcilable with tumor onset and progression. Moreover, mutations in the p53 gene give rise to mutant proteins such as p53-R273H that, besides losing the wild type p53 (wtp53) capacity to safeguard genome integ...

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Detalles Bibliográficos
Autores principales: Romeo, Maria Anele, Gilardini Montani, Maria Saveria, Benedetti, Rossella, Arena, Andrea, D’Orazi, Gabriella, Cirone, Mara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996167/
https://www.ncbi.nlm.nih.gov/pubmed/33668399
http://dx.doi.org/10.3390/biom11030344
Descripción
Sumario:p53 is the most frequently mutated or inactivated gene in cancer, as its activity is not reconcilable with tumor onset and progression. Moreover, mutations in the p53 gene give rise to mutant proteins such as p53-R273H that, besides losing the wild type p53 (wtp53) capacity to safeguard genome integrity, may promote carcinogenesis, mainly due to its crosstalk with pro-oncogenic pathways. Interestingly, the activation of oncogenic pathways is interconnected with reactive oxygen species (ROS) and the release of pro-inflammatory cytokines that contribute to create an inflammatory/pro-tumorigenic milieu. In this study, based on experiments involving p53-R273H silencing and transfection, we showed that this mutant p53 (mutp53) promoted cancer cell survival by increasing intracellular ROS level and pro-inflammatory/immune suppressive cytokine release, activating mTOR, reducing autophagy and mitophagy and downregulating uncoupling protein 2 (UCP2). Interestingly, p53-R273H transfection into cancer cells carrying wtp53 induced none of these effects and resulted in p21 upregulation. This suggests that wtp53 may counteract several pro-tumorigenic activities of p53-R273H and this could explain the lower aggressiveness of cancers carrying heterozygous mutp53 in comparison to those harboring homozygous mutp53.