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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Chang, Cheng Mercurio, Arthur M. Mak, Paul Pursell, Bryan |
| Description | Author Affiliation: Mak P ( Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.); |
| Abstract | Estrogen receptor ß (ERß) promotes the degradation of hypoxia inducible factor 1 (HIF-1 ), which contributes to the ability of this hormone receptor to sustain the differentiation of epithelial and carcinoma cells. Although the loss of ERß and consequent HIF-1 activation occur in prostate cancer with profound consequences, the mechanism by which ERß promotes the degradation of HIF-1 is unknown. We report that ERß regulates the ligand (3ß-adiol)-dependent transcription of prolyl hydroxylase 2 (PHD2) also known as Egl nine homolog 1 (EGLN1), a 2-oxoglutarate-dependent dioxygenase that hydroxylates HIF-1 and targets it for recognition by the von Hippel-Lindau tumor suppressor and consequent degradation. ERß promotes PHD2 transcription by interacting with a unique estrogen response element in the 5' UTR of the PHD2 gene that functions as an enhancer. PHD2 itself is critical for maintaining epithelial differentiation. Loss of PHD2 expression or inhibition of its function results in dedifferentiation with characteristics of an epithelial-mesenchymal transition, and exogenous PHD2 expression in dedifferentiated cells can restore an epithelial phenotype. Moreover, expression of HIF-1 in cells that express PHD2 does not induce dedifferentiation but expression of HIF-1 containing mutations in the proline residues that are hydroxylated by PHD2 induces dedifferentiation. These data describe a unique mechanism for the regulation of HIF-1 stability that involves ERß-mediated transcriptional regulation of PHD2 and they highlight an unexpected role for PHD2 in maintaining epithelial differentiation. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 12 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-03-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cell Differentiation Physiology Epithelial Cells Metabolism Estrogen Receptor Beta Gene Expression Regulation, Enzymologic Procollagen-Proline Dioxygenase Biosynthesis Response Elements Transcription, Genetic Cell Line, Tumor Cytology Genetics Hydroxylation Hypoxia-Inducible Factor 1, Alpha Subunit Hypoxia-Inducible Factor-Proline Dioxygenases Mutation Protein Stability Proteolysis Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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