Wild type- and mutant p53 proteins in mitochondrial dysfunction: emerging insights in cancer disease Academic Article uri icon

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abstract

  • Deregulated cell metabolism is one of the cancer hallmarks. Mitochondrial DNA mutations and enzyme defects, aberrant tumor suppressor or oncogenic activities cause mitochondrial dysfunction leading to deregulated cellular energetics. The tumor suppressor protein, p53 is a tetrameric transcription factor that in response to diverse genotoxic and non-genotoxic insults activates a plethora of target genes to preserve genome integrity. In the last two decades the discovery of cytoplasmic p53 localization focused intense research on its extra-nuclear functions. The ability of p53 to induce apoptosis acting directly at mitochondria and the related mechanisms of p53 localization and translocation in the cytoplasm have been investigated. A role of cytoplasmic p53 in autophagy, pentose phosphate pathway, fatty acid synthesis and oxidation, and drug response has been proposed. TP53 gene is mutated in more than half of human cancers. In parallel to loss of tumor suppressive functions, mutant p53 proteins often gain new tumorigenic activities (GOF, gain of function). It has been recently shown that mutant p53 proteins mediate metabolic changes thereby promoting cancer development and metastases. Here we review the contribution of either wild-type p53 or mutant p53 proteins to the fine-tuning of mitochondrial metabolism of both normal and cancer cells. Greater knowledge at the mechanistic level might provide insights to develop new cancer therapeutic approaches.

publication date

  • May 2019