title: The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis.
abstract: The p53 tumor suppressor protein, a transcription factor, induces cell cycle arrest and apoptosis via the upregulation of downstream target genes. Ferredoxin Reductase (protein, FR; gene, FDXR) transfers electron from NADPH to cytochrome P450 via ferredoxin in mitochondria. Here, we identified FDXR as a target gene of the p53 family, that is, p53, p63, and p73. We found that FDXR can be induced by DNA damage in cells in a p53-dependent manner and by a mutated form of p53 that is competent in inducing apoptosis. In addition, we identified a p53 response element located within the FDXR promoter that is responsive to wild-type p53, p63alpha, p63gamma, p73alpha, and p73beta. Furthermore, we showed that p53, p63alpha and p73alpha directly bind to the p53 response element in vivo and promote the accessibility of the FDXR promoter by increasing the acetylation of histones H3 and H4. To determine the role of FR in p53 tumor suppression, we generated cell lines that express FR using a tetracycline-regulated promoter. We found that over-expression of FR in lung H1299, breast MCF7, and colorectal HCT116 carcinoma cells have no effect on cell proliferation. However, we showed that FR increases the sensibility of H1299 and HCT116 cells to 5-fluorouracil-, doxorubicin- and H(2)O(2)- mediated apoptosis. Our data support a model of feed-forward loop for p53 activity, that is, various cellular stresses, including reactive oxygen species (ROS), activate p53, which induces the expression of FDXR; and the FDXR gene product, FR, in turn sensitizes cells to ROS-mediated apoptosis.
authors.affiliation: Department of Cell Biology, UAB Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama, AL 35294, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Xinbin
authors.initials: X
authors.lastname: Chen
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle; D004268:DNA-Binding Proteins / Q000502:physiology; D004317:Doxorubicin / Q000494:pharmacology; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008565:Membrane Proteins; D009687:Nuclear Proteins / Q000502:physiology; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000502:physiology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020218:Response Elements; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins
chemical_list: C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; D005287:Ferredoxin-NADP Reductase; D005472:Fluorouracil