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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1996 Apr 16;93(8):3553–3558. doi: 10.1073/pnas.93.8.3553

A functional Rev-erb alpha responsive element located in the human Rev-erb alpha promoter mediates a repressing activity.

G Adelmant 1, A Bègue 1, D Stéhelin 1, V Laudet 1
PMCID: PMC39648  PMID: 8622974

Abstract

Rev-erb alpha belongs to the nuclear receptor superfamily, which contains receptors for steroids, thyroid hormones, retinoic acid, and vitamin D, as well as "orphan" receptors. No ligand has been found for Rev-erb alpha to date, making it one of these orphan receptors. Similar to some other orphan receptors, Rev-erb alpha has been shown to bind DNA as a monomer on a specific sequence called a Rev-erb alpah responsive element (RevRE), but its transcriptional activity remains unclear. In this paper, we characterize a functional RevRE located in the human Rev-erb alpha promoter itself. We also present evidence that (i) Rev-erb alpha mediates transcriptional repression of its own promoter in vitro, (ii) this repressing effect strictly depends on the binding of Rev-erb alpha to its responsive element and is transferable to a heterologous promoter; and (iii) Rev-erb alpha binds to this responsive sequence as a homodimer.

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Selected References

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  1. Barettino D., Vivanco Ruiz M. M., Stunnenberg H. G. Characterization of the ligand-dependent transactivation domain of thyroid hormone receptor. EMBO J. 1994 Jul 1;13(13):3039–3049. doi: 10.1002/j.1460-2075.1994.tb06603.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bonnelye E., Vanacker J. M., Desbiens X., Begue A., Stehelin D., Laudet V. Rev-erb beta, a new member of the nuclear receptor superfamily, is expressed in the nervous system during chicken development. Cell Growth Differ. 1994 Dec;5(12):1357–1365. [PubMed] [Google Scholar]
  3. Carlberg C., Hooft van Huijsduijnen R., Staple J. K., DeLamarter J. F., Becker-André M. RZRs, a new family of retinoid-related orphan receptors that function as both monomers and homodimers. Mol Endocrinol. 1994 Jun;8(6):757–770. doi: 10.1210/mend.8.6.7935491. [DOI] [PubMed] [Google Scholar]
  4. Chawla A., Lazar M. A. Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation. J Biol Chem. 1993 Aug 5;268(22):16265–16269. [PubMed] [Google Scholar]
  5. Danielian P. S., White R., Lees J. A., Parker M. G. Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. EMBO J. 1992 Mar;11(3):1025–1033. doi: 10.1002/j.1460-2075.1992.tb05141.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dumas B., Harding H. P., Choi H. S., Lehmann K. A., Chung M., Lazar M. A., Moore D. D. A new orphan member of the nuclear hormone receptor superfamily closely related to Rev-Erb. Mol Endocrinol. 1994 Aug;8(8):996–1005. doi: 10.1210/mend.8.8.7997240. [DOI] [PubMed] [Google Scholar]
  7. Durand B., Saunders M., Gaudon C., Roy B., Losson R., Chambon P. Activation function 2 (AF-2) of retinoic acid receptor and 9-cis retinoic acid receptor: presence of a conserved autonomous constitutive activating domain and influence of the nature of the response element on AF-2 activity. EMBO J. 1994 Nov 15;13(22):5370–5382. doi: 10.1002/j.1460-2075.1994.tb06872.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Ellinger-Ziegelbauer H., Hihi A. K., Laudet V., Keller H., Wahli W., Dreyer C. FTZ-F1-related orphan receptors in Xenopus laevis: transcriptional regulators differentially expressed during early embryogenesis. Mol Cell Biol. 1994 Apr;14(4):2786–2797. doi: 10.1128/mcb.14.4.2786. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Forman B. M., Chen J., Blumberg B., Kliewer S. A., Henshaw R., Ong E. S., Evans R. M. Cross-talk among ROR alpha 1 and the Rev-erb family of orphan nuclear receptors. Mol Endocrinol. 1994 Sep;8(9):1253–1261. doi: 10.1210/mend.8.9.7838158. [DOI] [PubMed] [Google Scholar]
  10. Giguère V., Tini M., Flock G., Ong E., Evans R. M., Otulakowski G. Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev. 1994 Mar 1;8(5):538–553. doi: 10.1101/gad.8.5.538. [DOI] [PubMed] [Google Scholar]
  11. Harding H. P., Lazar M. A. The orphan receptor Rev-ErbA alpha activates transcription via a novel response element. Mol Cell Biol. 1993 May;13(5):3113–3121. doi: 10.1128/mcb.13.5.3113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jiang G., Nepomuceno L., Hopkins K., Sladek F. M. Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors. Mol Cell Biol. 1995 Sep;15(9):5131–5143. doi: 10.1128/mcb.15.9.5131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Laudet V., Adelmant G. Nuclear receptors. Lonesome orphans. Curr Biol. 1995 Feb 1;5(2):124–127. doi: 10.1016/s0960-9822(95)00031-5. [DOI] [PubMed] [Google Scholar]
  14. Laudet V., Begue A., Henry-Duthoit C., Joubel A., Martin P., Stehelin D., Saule S. Genomic organization of the human thyroid hormone receptor alpha (c-erbA-1) gene. Nucleic Acids Res. 1991 Mar 11;19(5):1105–1112. doi: 10.1093/nar/19.5.1105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Laudet V., Hänni C., Coll J., Catzeflis F., Stéhelin D. Evolution of the nuclear receptor gene superfamily. EMBO J. 1992 Mar;11(3):1003–1013. doi: 10.1002/j.1460-2075.1992.tb05139.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Laudet V., Vanacker J. M., Adelmant G., Begue A., Stehelin D. Characterization of a functional promoter for the human thyroid hormone receptor alpha (c-erbA-1) gene. Oncogene. 1993 Apr;8(4):975–982. [PubMed] [Google Scholar]
  17. Lazar J., Desvergne B., Zimmerman E. C., Zimmer D. B., Magnuson M. A., Nikodem V. M. A role for intronic sequences on expression of thyroid hormone receptor alpha gene. J Biol Chem. 1994 Aug 12;269(32):20352–20359. [PubMed] [Google Scholar]
  18. Lazar M. A., Hodin R. A., Darling D. S., Chin W. W. A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA alpha transcriptional unit. Mol Cell Biol. 1989 Mar;9(3):1128–1136. doi: 10.1128/mcb.9.3.1128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Milbrandt J. Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron. 1988 May;1(3):183–188. doi: 10.1016/0896-6273(88)90138-9. [DOI] [PubMed] [Google Scholar]
  20. Miyajima N., Horiuchi R., Shibuya Y., Fukushige S., Matsubara K., Toyoshima K., Yamamoto T. Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus. Cell. 1989 Apr 7;57(1):31–39. doi: 10.1016/0092-8674(89)90169-4. [DOI] [PubMed] [Google Scholar]
  21. Retnakaran R., Flock G., Giguère V. Identification of RVR, a novel orphan nuclear receptor that acts as a negative transcriptional regulator. Mol Endocrinol. 1994 Sep;8(9):1234–1244. doi: 10.1210/mend.8.9.7838156. [DOI] [PubMed] [Google Scholar]
  22. Spanjaard R. A., Nguyen V. P., Chin W. W. Rat Rev-erbA alpha, an orphan receptor related to thyroid hormone receptor, binds to specific thyroid hormone response elements. Mol Endocrinol. 1994 Mar;8(3):286–295. doi: 10.1210/mend.8.3.8015547. [DOI] [PubMed] [Google Scholar]
  23. Wilson T. E., Fahrner T. J., Johnston M., Milbrandt J. Identification of the DNA binding site for NGFI-B by genetic selection in yeast. Science. 1991 May 31;252(5010):1296–1300. doi: 10.1126/science.1925541. [DOI] [PubMed] [Google Scholar]
  24. Wilson T. E., Padgett K. A., Johnston M., Milbrandt J. A genetic method for defining DNA-binding domains: application to the nuclear receptor NGFI-B. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9186–9190. doi: 10.1073/pnas.90.19.9186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Woronicz J. D., Calnan B., Ngo V., Winoto A. Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature. 1994 Jan 20;367(6460):277–281. doi: 10.1038/367277a0. [DOI] [PubMed] [Google Scholar]
  26. Zechel C., Shen X. Q., Chambon P., Gronemeyer H. Dimerization interfaces formed between the DNA binding domains determine the cooperative binding of RXR/RAR and RXR/TR heterodimers to DR5 and DR4 elements. EMBO J. 1994 Mar 15;13(6):1414–1424. doi: 10.1002/j.1460-2075.1994.tb06395.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Zechel C., Shen X. Q., Chen J. Y., Chen Z. P., Chambon P., Gronemeyer H. The dimerization interfaces formed between the DNA binding domains of RXR, RAR and TR determine the binding specificity and polarity of the full-length receptors to direct repeats. EMBO J. 1994 Mar 15;13(6):1425–1433. doi: 10.1002/j.1460-2075.1994.tb06396.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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