The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Regulation of p53 by Hypoxia: Dissociation of Transcriptional Repression and Apoptosis from p53-Dependent Transactivation
Open accessAbstract
Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-dependent apoptosis in oncogenically transformed cells. Unlike DNA damage, hypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially regulated by these two stresses. Here we report that hypoxia induces p53 protein accumulation, but in contrast to DNA damage, hypoxia fails to induce endogenous downstream p53 effector mRNAs and proteins. Hypoxia does not inhibit the induction of p53 target genes by ionizing radiation, indicating that p53-dependent transactivation requires a DNA damage-inducible signal that is lacking under hypoxic treatment alone. At the molecular level, DNA damage induces the interaction of p53 with the transcriptional activator p300 as well as with the transcriptional corepressor mSin3A. In contrast, hypoxia primarily induces an interaction of p53 with mSin3A, but not with p300. Pretreatment of cells with an inhibitor of histone deacetylases that relieves transcriptional repression resulted in a significant reduction of p53-dependent transrepression and hypoxia-induced apoptosis. These results led us to propose a model in which different cellular pools of p53 can modulate transcriptional activity through interactions with transcriptional coactivators or corepressors. Genotoxic stress induces both kinds of interactions, whereas stresses that lack a DNA damage component as exemplified by hypoxia primarily induce interaction with corepressors. However, inhibition of either type of interaction can result in diminished apoptotic activity.
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Citations
Cites
Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
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Mdm2 promotes the rapid degradation of p53
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Tumor suppressor p53 is a direct transcriptional activator of the human bax gene
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“This transcriptional target of p53 participates in an autoregulatory feedback loop that regulates p53 levels by binding to the N terminus of p53, inhibiting its transactivation properties, and promoting its proteolytic degradation (20, 25, 33).”
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“These effector genes have p53-responsive elements in their promoter regions and are induced in a p53-dependent manner following treatment with IR in a wide variety of cell lines and tissues (11, 23, 30, 31).”
BackgroundSelf-citationHypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours
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Self-citationDNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2
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Self-citationDNA damage activates p53 through a phosphorylation–acetylation cascade
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p53 Activates the CD95 (APO-1/Fas) Gene in Response to DNA Damage by Anticancer Drugs
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Cited by
Hypoxia — a key regulatory factor in tumour growth
Harris, A. L. (2002) · Nature Reviews Cancer · doi:10.1038/nrc704 · Cited by 5,177
Fridman, J. S., & Lowe, S. W. (2003) · Oncogene · doi:10.1038/sj.onc.1207116 · Cited by 1,401
Self-citationDNA damage responses to oxidative stress
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Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response
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HIF-1α induces cell cycle arrest by functionally counteracting Myc
Koshiji, M., Kageyama, Y., Pete, E. A., Horikawa, I., Barrett, J. C., & Huang, L. E. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600196 · Cited by 652
Metadata
- Authors
- Koumenis, C., Alarcon, R., Hammond, E., Sutphin, P., Hoffman, W., Murphy, M., Derr, J., Taya, Y., Lowe, S. W., Kastan, M., & Giaccia, A.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2001-02-01
- Volume
- 21
- Issue
- 4
- Pages
- 1297-1310
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2038291224
- Cited by
- 346
- References
- 11
- FWCI
- 10.72
- Type
- journal article
- Language
- en
- Open access
- green
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- Koumenis, C., Alarcon, R., Hammond, E., Sutphin, P., Hoffman, W., Murphy, M., Derr, J., Taya, Y., Lowe, S. W., Kastan, M., & Giaccia, A. (2001). Regulation of p53 by Hypoxia: Dissociation of Transcriptional Repression and Apoptosis from p53-Dependent Transactivation. Molecular and Cellular Biology. https://doi.org/10.1128/mcb.21.4.1297-1310.2001
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
