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Hypoxia down-regulates CCAAT/enhancer binding protein-alpha expression in breast cancer cells.
Cancer Res. 2008 Apr 01; 68(7):2158-65.CR

Abstract

The transcription factor CCAAT/enhancer binding protein-alpha (C/EBP alpha) is involved in the control of cell differentiation and proliferation, and has been suggested to act as a tumor suppressor in several cancers. By using microarray analysis, we have previously shown that hypoxia and estrogen down-regulate C/EBP alpha mRNA in T-47D breast cancer cells. Here, we have examined the mechanism by which the down-regulation by hypoxia takes place. Using the specific RNA polymerase II inhibitor 5,6-dichlorobenzimidazole-1-beta-D-ribofuranoside, the mRNA stability was analyzed under normoxia or hypoxia by quantitative reverse transcription-PCR. Hypoxia reduced the half-life of C/EBP alpha mRNA by approximately 30%. C/EBP alpha gene promoter studies indicated that hypoxia also repressed the transcription of the gene and identified a hypoxia-responsive element (-522; -527 bp), which binds to hypoxia-inducible factor (HIF)-1 alpha, as essential for down-regulation of C/EBP alpha transcription in hypoxia. Immunocytochemical analysis showed that C/EBP alpha was localized in the nucleus at 21% O(2), but was mostly cytoplasmic under 1% O(2). Knockdown of HIF-1 alpha by RNAi restored C/EBP alpha to normal levels under hypoxic conditions. Immunohistochemical studies of 10 tumor samples did not show any colocalization of C/EBP alpha and glucose transporter 1 (used as a marker for hypoxia). Taken together, these results show that hypoxia down-regulates C/EBP alpha expression in breast cancer cells by several mechanisms, including transcriptional and posttranscriptional effects. The down-regulation of C/EBP alpha in hypoxia is mediated by HIF-1.

Authors+Show Affiliations

INSERM U612, Institut Curie, Orsay, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18381421

Citation

Seifeddine, Ramzi, et al. "Hypoxia Down-regulates CCAAT/enhancer Binding Protein-alpha Expression in Breast Cancer Cells." Cancer Research, vol. 68, no. 7, 2008, pp. 2158-65.
Seifeddine R, Dreiem A, Blanc E, et al. Hypoxia down-regulates CCAAT/enhancer binding protein-alpha expression in breast cancer cells. Cancer Res. 2008;68(7):2158-65.
Seifeddine, R., Dreiem, A., Blanc, E., Fulchignoni-Lataud, M. C., Le Frère Belda, M. A., Lecuru, F., Mayi, T. H., Mazure, N., Favaudon, V., Massaad, C., Barouki, R., & Massaad-Massade, L. (2008). Hypoxia down-regulates CCAAT/enhancer binding protein-alpha expression in breast cancer cells. Cancer Research, 68(7), 2158-65. https://doi.org/10.1158/0008-5472.CAN-07-1190
Seifeddine R, et al. Hypoxia Down-regulates CCAAT/enhancer Binding Protein-alpha Expression in Breast Cancer Cells. Cancer Res. 2008 Apr 1;68(7):2158-65. PubMed PMID: 18381421.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypoxia down-regulates CCAAT/enhancer binding protein-alpha expression in breast cancer cells. AU - Seifeddine,Ramzi, AU - Dreiem,Anne, AU - Blanc,Etienne, AU - Fulchignoni-Lataud,Marie-Claude, AU - Le Frère Belda,Marie-Aude, AU - Lecuru,Fabrice, AU - Mayi,Thérèse Hervèe, AU - Mazure,Nathalie, AU - Favaudon,Vincent, AU - Massaad,Charbel, AU - Barouki,Robert, AU - Massaad-Massade,Liliane, PY - 2008/4/3/pubmed PY - 2008/4/26/medline PY - 2008/4/3/entrez SP - 2158 EP - 65 JF - Cancer research JO - Cancer Res VL - 68 IS - 7 N2 - The transcription factor CCAAT/enhancer binding protein-alpha (C/EBP alpha) is involved in the control of cell differentiation and proliferation, and has been suggested to act as a tumor suppressor in several cancers. By using microarray analysis, we have previously shown that hypoxia and estrogen down-regulate C/EBP alpha mRNA in T-47D breast cancer cells. Here, we have examined the mechanism by which the down-regulation by hypoxia takes place. Using the specific RNA polymerase II inhibitor 5,6-dichlorobenzimidazole-1-beta-D-ribofuranoside, the mRNA stability was analyzed under normoxia or hypoxia by quantitative reverse transcription-PCR. Hypoxia reduced the half-life of C/EBP alpha mRNA by approximately 30%. C/EBP alpha gene promoter studies indicated that hypoxia also repressed the transcription of the gene and identified a hypoxia-responsive element (-522; -527 bp), which binds to hypoxia-inducible factor (HIF)-1 alpha, as essential for down-regulation of C/EBP alpha transcription in hypoxia. Immunocytochemical analysis showed that C/EBP alpha was localized in the nucleus at 21% O(2), but was mostly cytoplasmic under 1% O(2). Knockdown of HIF-1 alpha by RNAi restored C/EBP alpha to normal levels under hypoxic conditions. Immunohistochemical studies of 10 tumor samples did not show any colocalization of C/EBP alpha and glucose transporter 1 (used as a marker for hypoxia). Taken together, these results show that hypoxia down-regulates C/EBP alpha expression in breast cancer cells by several mechanisms, including transcriptional and posttranscriptional effects. The down-regulation of C/EBP alpha in hypoxia is mediated by HIF-1. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/18381421/Hypoxia_down_regulates_CCAAT/enhancer_binding_protein_alpha_expression_in_breast_cancer_cells_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=18381421 DB - PRIME DP - Unbound Medicine ER -