Nuclear TP53: An unraveled function as transcriptional repressor of PINK1
| Autor: | Cristine Alves da Costa, Thomas Goiran, Frédéric Checler |
|---|---|
| Přispěvatelé: | Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Programmed cell death Transcription Genetic endocrine system diseases [SDV]Life Sciences [q-bio] Down-Regulation PINK1 Biology Gene Expression Regulation Enzymologic Mice 03 medical and health sciences Cytosol 0302 clinical medicine Downregulation and upregulation Neoplasms Mitophagy Autophagy Transcriptional regulation Animals Humans neoplasms Molecular Biology Loss function ComputingMilieux_MISCELLANEOUS Cell Nucleus Mice Knockout Cell Biology Phenotype Autophagic Punctum Mitochondria 3. Good health Cell biology Gene Expression Regulation Neoplastic HEK293 Cells 030104 developmental biology [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Tumor Suppressor Protein p53 Protein Kinases 030217 neurology & neurosurgery |
| Zdroj: | Autophagy Autophagy, Taylor & Francis, 2018, pp.1-3. ⟨10.1080/15548627.2018.1450022⟩ |
| ISSN: | 1554-8627 1554-8635 |
| DOI: | 10.1080/15548627.2018.1450022⟩ |
| Popis: | p53 is a transcription factor that is implicated in the control of both apoptotic and autophagic cell death. This tumor suppressor elicits both pro-autophagic and anti-autophagic phenotypes depending of its intracellular localization. The ability of p53 to repress autophagy has been exclusively associated to its cytoplasmic localization. Here, we show that transcriptional activity of p53 also contributes to autophagy down-regulation. Thus, nuclear p53 controls PINK1, a key protein involved in the control of mitophagy, by repressing its promoter activity, protein and mRNA levels, ex-vivo and in vivo. We establish that deletion of an identified p53 responsive element on PINK1 promoter impacts p53-mediated PINK1 transcriptional repression and we demonstrate a p53-PINK1 physical interaction by chromatin immunoprecipitation. Accordingly, we show that only nuclear p53 accounts for its ability to repress PINK1 gene transcription. Further, we demonstrate ex-vivo and in vivo that p53 invalidation in human cells increases LC3 maturation as well as optineurin and NDP52 autophagy receptors expression and down-regulates TIM23, TOM20 and HSP60 mitophagy markers. Importantly, this phenotype is mimicked by TP53 invalidation in mice brain. Finally, by combining pharmacological and genetic approaches, we show that the p53-mediated negative regulation of autophagy is PINK1-dependent. Thus pifithrin-α-mediated blockade of p53 transcriptional activity enhances LC3 maturation and reduces p62, TIM23, TOM20 and HSP60 protein levels. This pifithrin-α-associated pro-mitophagy phenotype is fully abolished by PINK1 depletion. This data unravels a novel pathway by which nuclear p53 can repress autophagy/mitophagy that could underlie important dysfunctions in both neurodegenerative and cancer diseases. |
| Databáze: | OpenAIRE |
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