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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The p53 target FDXR encodes a mitochondrial flavoprotein that initiates electron transport for cytochromes P450, which receive electrons from NADPH.
“The p53 target FDXR encodes a mitochondrial flavoprotein that initiates electron transport for cytochromes P450, which receive electrons from NADPH.202”
From Census and evaluation of p53 target genes (2017) · cites this paper as [202]
Cites
WAF1, a potential mediator of p53 tumor suppression
El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B. (1993) · Cell · doi:10.1016/0092-8674(93)90500-p · Cited by 8,321 · see citing works
p53 Mutations in Human Cancers
Hollstein, M., Sidransky, D., Vogelstein, B., & Harris, C. C. (1991) · Science · doi:10.1126/science.1905840 · Cited by 8,018 · see citing works
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607 · see citing works
The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
Wade Harper, J. (1993) · Cell · doi:10.1016/0092-8674(93)90499-g · Cited by 5,651 · see citing works
Tumor suppressor p53 is a direct transcriptional activator of the human bax gene
Toshiyuki, M., & Reed, J. C. (1995) · Cell · doi:10.1016/0092-8674(95)90412-3 · Cited by 4,063 · see citing works
p21 is a universal inhibitor of cyclin kinases
Xiong, Y., Hannon, G., Zhang, H., Casso, D., Kobayashi, R., & Beach, D. (1993) · Nature · doi:10.1038/366701a0 · Cited by 3,691 · see citing works
Requirement for p53 and p21 to Sustain G <sub>2</sub> Arrest After DNA Damage
Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J. P., Sedivy, J. M., Kinzler, K. W., & Vogelstein, B. (1998) · Science · doi:10.1126/science.282.5393.1497 · Cited by 2,803 · see citing works
p53: puzzle and paradigm.Preprint
Ko, L. J., & Prives, C. L. (1996) · Genes & Development · doi:10.1101/gad.10.9.1054 · Cited by 2,338 · see citing works
PUMA, a Novel Proapoptotic Gene, Is Induced by p53
Nakano, K., & Vousden, K. H. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00214-3 · Cited by 2,315 · see citing works
Yang, A., Kaghad, M., Wang, Y., Gillett, E. S., Fleming, M. D., Dötsch, V., Andrews, N. C., Caput, D., & McKeon, F. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80275-0 · Cited by 2,086 · see citing works
Triggering and modulation of apoptosis by oxidative stress
Chandra, J., Samali, A., & Orrenius, S. (2000) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(00)00302-6 · Cited by 1,335 · see citing works
Münger, K., Phelps, W. C., Bubb, V. J., Howley, P. M., & Schlegel, R. (1989) · Journal of Virology · doi:10.1128/jvi.63.10.4417-4421.1989 · Cited by 1,335 · see citing works
Oxidative stress and gene regulation
Allen, R. G., & Tresini, M. (2000) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(99)00242-7 · Cited by 1,297 · see citing works
PUMA Induces the Rapid Apoptosis of Colorectal Cancer Cells
Yu, J., Zhang, L., Hwang, P. M., Kinzler, K. W., & Vogelstein, B. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00213-1 · Cited by 1,282 · see citing works
Is a p53-Regulated Inhibitor of G2/M Progression
Hermeking, H., Lengauer, C., Polyak, K., He, T.-C., Zhang, L., Thiagalingam, S., Kinzler, K. W., & Vogelstein, B. (1997) · Molecular Cell · doi:10.1016/s1097-2765(00)80002-7 · Cited by 1,251 · see citing works
p21 is necessary for the p53-mediated G1 arrest in human cancer cells.
Waldman, T. A., Kinzler, K. W., & Vogelstein, B. (1995) · PubMed · Cited by 1,203 · see citing works
Nelson, W. G., & Kastan, M. B. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.3.1815 · Cited by 850 · see citing works
Chen, X., Ko, L. J., Jayaraman, L., & Prives, C. (1996) · Genes & Development · doi:10.1101/gad.10.19.2438 · Cited by 735 · see citing works
Self-citationChen, H.-W., Lin, R. J., Xie, W., Wilpitz, D. C., & Evans, R. M. (1999) · Cell · doi:10.1016/s0092-8674(00)80054-9 · Cited by 635 · see citing works
GADD45 induction of a G <sub>2</sub> /M cell cycle checkpoint
Wang, X. W., Zhan, Q., Coursen, J. D., Khan, M. A., Kontny, H. U., Yu, L., Hollander, M. C., O’Connor, P. M., Fornace, A. J., & Harris, C. C. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.7.3706 · Cited by 634 · see citing works
p63 and p73: p53 mimics, menaces and more
Yang, A., & McKeon, F. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35043127 · Cited by 504 · see citing works
On the shoulders of giants: p63, p73 and the rise of p53
Yang, A., Kaghad, M., Caput, D., & McKeon, F. (2002) · Trends in Genetics · doi:10.1016/s0168-9525(02)02595-7 · Cited by 486 · see citing works
Hwang, P. M., Bunz, F., Yu, J., Rago, C., Chan, T. A.-T., Murphy, M. P., Kelso, G. F., Smith, R. A. J., Kinzler, K. W., & Vogelstein, B. (2001) · Nature Medicine · doi:10.1038/nm1001-1111 · Cited by 424 · see citing works
Dohn, M. R., Zhang, S., & Chen, X. (2001) · Oncogene · doi:10.1038/sj.onc.1204427 · Cited by 294 · see citing works
Self-citationNelson, W. G., & Kastan, M. B. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.3.1815-1823.1994 · Cited by 205 · see citing works
cDNA sequence of adrenodoxin reductase
Hanukoglu, I., & Gutfinger, T. (1989) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1989.tb14671.x · Cited by 196 · see citing works
Chromatin remodeling and transcriptional activation: the cast (in order of appearance)
Urnov, F. D., & Wolffe, A. P. (2001) · Oncogene · doi:10.1038/sj.onc.1204323 · Cited by 195 · see citing works
Kinetics of p53 Binding to Promoter Sites In Vivo
Szak, S. T., Mays, D. J., & Pietenpol, J. A. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.10.3375-3386.2001 · Cited by 178 · see citing works
Müller, J. J., Ag, L., Bourenkov, G. P., Ruckpaul, K., & Heinemann, U. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008501200 · Cited by 167 · see citing works
Identification of a Novel p53 Functional Domain That Is Necessary for Mediating Apoptosis
Zhu, J., Zhou, W., Jiang, J., & Chen, X. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.21.13030 · Cited by 166 · see citing works
Self-citationReceptor tyrosine kinase EphA2 is regulated by p53-family proteins and induces apoptosis
Dohn, M. R., Jiang, J., & Chen, X. (2001) · Oncogene · doi:10.1038/sj.onc.1204816 · Cited by 146 · see citing works
Self-citationKaelin, W. G. (1999) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/91.7.594 · Cited by 142 · see citing works
Zhu, J., Jiang, J., Zhou, W., Zhu, K., & Chen, X. (1999) · Oncogene · doi:10.1038/sj.onc.1202533 · Cited by 117 · see citing works
Self-citationDefinition of the p53 Functional Domains Necessary for Inducing Apoptosis
Zhu, J., Zhang, S., Jiang, J., & Chen, X. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005676200 · Cited by 104 · see citing works
Self-citationZhu, J., & Chen, X. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.15.5602-5618.2000 · Cited by 98 · see citing works
Self-citationThe p53 family: same response, different signals?
Chen, X. (1999) · Molecular Medicine Today · doi:10.1016/s1357-4310(99)01545-2 · Cited by 67 · see citing works
Self-citationKramer, R. E., Bois, R. N. D., Simpson, E. R., Anderson, C. M., Kashiwagi, K., Lambeth, J. D., Jefcoate, C. R. E., & Waterman, M. R. (1982) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(82)90106-0 · Cited by 67 · see citing works
Akman, S. A., Doroshow, J. H., Burke, T. G., et al. (1992) · Biochemistry · doi:10.1021/bi00128a026 · Cited by 44 · see citing works
Disparate cell types use a shared complex of PDZ proteins for polarized protein localization
Rongo, C. (2001) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(01)00011-9 · Cited by 16 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Transcriptional control of human p53-regulated genes
Riley, T., Sontag, E., Chen, P., & Levine, A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2395 · Cited by 1,921 · see citing works
Census and evaluation of p53 target genes
Fischer, M. (2017) · Oncogene · doi:10.1038/onc.2016.502 · Cited by 971 · see citing works
Targeting p53 pathways: mechanisms, structures, and advances in therapy
Wang, H., Guo, M., Wei, H., & Chen, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01347-1 · Cited by 1,016 · see citing works
High-throughput RNAi screening in cultured cells: a user's guide
Echeverri, C. J., & Perrimon, N. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1836 · Cited by 380 · see citing works
Hanukoglu, I. (2006) · Drug Metabolism Reviews · doi:10.1080/03602530600570040 · Cited by 293 · see citing works
The transcription factor p53: Not a repressor, solely an activator.
Fischer, M., Steiner, L., & Engeland, K. (2014) · Cell Cycle · doi:10.4161/15384101.2014.949083 · Cited by 153 · see citing works
Liu, G., & Chen, X. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.4.1398-1413.2006 · Cited by 104 · see citing works
Self-citationA distinct p53 target gene set predicts for response to the selective p53–HDM2 inhibitor NVP-CGM097
Jeay, S., Gaulis, S., Ferretti, S., Bitter, H., Ito, M., Valat, T., Murakami, M., Ruetz, S., Guthy, D. A., Rynn, C., et al. (2015) · eLife · doi:10.7554/elife.06498 · Cited by 85 · see citing works
Trapasso, F., Pichiorri, F., Gaspari, M., Palumbo, T., Aqeilan, R. I., Gaudio, E., Okumura, H., Iuliano, R., Di Leva, G., Fabbri, M., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709062200 · Cited by 71 · see citing works
RetractedPeng, Y., Shinde, D. N., Valencia, C. A., Mo, J.-S., Rosenfeld, J., Truitt Cho, M., Chamberlin, A., Li, Z., Liu, J., Gui, B., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx377 · Cited by 60 · see citing works
Network Analysis Identifies Mitochondrial Regulation of Epidermal Differentiation by MPZL3 and FDXR
Bhaduri, A., Ungewickell, A., Boxer, L. D., Lopez-Pajares, V., Zarnegar, B. J., & Khavari, P. A. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.10.023 · Cited by 60 · see citing works
- Authors
- Liu, G., & Chen, X.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Chen, Xinbin
- Venue
- Oncogene
- Published
- 2002-10-09
- Volume
- 21
- Issue
- 47
- Pages
- 7195-7204
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2037509005
- Cited by
- 207
- References
- 39
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 6 · 2023: 13 · 2022: 12 · 2021: 11 · 2020: 4 · 2019: 8 · 2018: 4 · 2017: 7 · 2016: 7 · 2015: 8 · 2014: 4 · 2013: 8 · 2012: 7
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01 CA81237, CA76069, R01CA081237)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- ferredoxin reductase, p53 family, p63, p73, p53 response elements, transcriptional regulation, DNA damage response, histone acetylation, oxidative stress, apoptosis, reactive oxygen species, 5-fluorouracil, doxorubicin, hydrogen peroxide, tumor suppressor, feed-forward loop, gene overexpression
- MeSH terms
- Tumor Protein p73, Cell Cycle, DNA-Binding Proteins, Doxorubicin, Ferredoxin-NADP Reductase, Fluorouracil, Humans, Membrane Proteins, Nuclear Proteins, Phosphoproteins, Promoter Regions, Genetic, Protein Binding, Transcription Factors, Tumor Cells, Cultured, Trans-Activators, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Apoptosis, Oxidative Stress, Response Elements, Tumor Suppressor Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
