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标题：p63 supports aerobic respiration through hexokinase II
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作者：Guiditta Viticchiè ; Massimiliano Agostini ; Anna Maria Lena 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：37
页码：11577-11582
DOI：10.1073/pnas.1508871112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe importance of {Delta}Np63 in controlling metabolism has not been investigated so far. We identified a regulatory pathway involving {Delta}Np63 and the glycolytic enzyme hexokinase 2 (HK2). {Delta}Np63 direct-dependent regulation of HK2 expression contributes to the coupling between glucose metabolism and oxidative phosphorylation, providing the energy necessary to sustain cell proliferation and protecting cells from oxidative stress. The {Delta}Np63-HK2axis is also present in epithelial cancer cells, suggesting that {Delta}Np63 could participate in cancer metabolic reprogramming. Short p63 isoform, {Delta}Np63, 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 {Delta}Np63 depletion in human keratinocytes impairs mitochondrial basal respiration and increases mitochondrial membrane polarization and intracellular reactive oxygen species. We show {Delta}Np63-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 {Delta}Np63 as a master regulator in epithelial cells of a combined subset of molecular mechanisms, including cellular energy metabolism and respiration. The {Delta}Np63-HK2 axis is also present in epithelial cancer cells, suggesting that {Delta}Np63 could participate in cancer metabolic reprogramming.
关键词：p63 ; HK2 ; keratinocytes ; oxidative metabolism ; mitochondria