P63 supports aerobic respiration through hexokinase II
| Autor: | Anna Maria Lena, Massimiliano Agostini, Gaelle Saintigny, Giuditta Viticchiè, Mara Mancini, David Dinsdale, Eleonora Candi, Huiqing Zhou, Lello Zolla, Gerry Melino |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Keratinocytes
HK2 Cellular respiration Oxidative phosphorylation Cell Separation Mitochondrion Biology Electron Oxidative Phosphorylation chemistry.chemical_compound Mice Oxygen Consumption oxidative metabolism Hexokinase Neoplasms Respiration Animals Humans Glycolysis Gene Silencing Cell adhesion Inner mitochondrial membrane Cell Proliferation keratinocytes mitochondria p63 Flow Cytometry Hydrogen Peroxide Microscopy Electron Mitochondria Mitochondrial Membranes NIH 3T3 Cells Oxidative Stress Oxygen Phenotype Transcription Factors Tumor Suppressor Protein p53 Tumor Suppressor Proteins Microscopy Multidisciplinary Settore BIO/11 Biological Sciences Cell biology Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10] chemistry Biochemistry |
| Zdroj: | Proceedings of the National Academy of Sciences USA, 112, 11577-82 Proceedings of the National Academy of Sciences USA, 112, 37, pp. 11577-82 |
| ISSN: | 0027-8424 |
| Popis: | Short p63 isoform, ΔNp63, is crucial for epidermis formation, and it plays a pivotal role in controlling the turnover of basal keratinocytes by regulating the expression of a subset of genes involved in cell cycle and cell adhesion programs. The glycolytic enzyme hexokinase 2 (HK2) represents the first step of glucose utilization in cells. The family of HKs has four isoforms that differ mainly in their tissue and subcellular distribution. The preferential mitochondrial localization of HK2 at voltage-dependent anion channels provides access to ATP generated by oxidative phosphorylation and generates an ADP/ATP recycling mechanism to maintain high respiration rates and low electron leak. Here, we report that ΔNp63 depletion in human keratinocytes impairs mitochondrial basal respiration and increases mitochondrial membrane polarization and intracellular reactive oxygen species. We show ΔNp63-dependent regulation of HK2 expression, and we use ChIP, validated by p63-Chip sequencing genomewide profiling analysis, and luciferase assays to demonstrate the presence of one p63-specific responsive element within the 15th intronic region of the HK2 gene, providing evidence of a direct interaction. Our data support the notion of ΔNp63 as a master regulator in epithelial cells of a combined subset of molecular mechanisms, including cellular energy metabolism and respiration. The ΔNp63-HK2 axis is also present in epithelial cancer cells, suggesting that ΔNp63 could participate in cancer metabolic reprogramming. |
| Databáze: | OpenAIRE |
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