Nuclear Receptors and Disease

Abstract

Nuclear receptors are ligand‐modulated transcription factors that act in the nucleus to regulate target gene transcription through interaction with cofactor proteins. Owing to their roles in many diverse cellular processes, nuclear receptors are important therapeutic targets and aberrant receptor action results in significant human disease.

Keywords: transcription factors; corepressor; ligand; coactivator; repression

Figure 1.

Model of a full‐length homodimeric estrogen receptor. The extreme C‐terminal domain is represented as a gold sphere. Helix 12 is shown in yellow. The ligand is shown as space‐filling pink spheres in the LBD. The flexible hinge domain is modeled as a pink ribbon. Zinc ions are represented as silver spheres. The extreme N‐terminal domain (A/B) is shown as a red sphere. The LBD structure is from Protein Data Bank (PDB) entry 1ERE; the DBD structure is from PDB entry 1HCQ.

Figure 2.

The action of ligand on a PPARγ ligand‐binding domain. In the absence of activating ligand (or with antagonist present, as shown here) helix 12 (yellow) is disordered and the corepressor (blue) binds to the surface of the receptor (left). In the presence of activating ligand (middle), helix 12 adopts an active conformation and coactivator (red) is recruited to the receptor (right). The corepressor structure is from PDB entry 1KKQ; the ligand and coactivator structures are from PDB entry 2PRG.

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References

Barroso I, Gurnell M, Crowley VE, et al. (1999) Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402: 880–883.

Bourguet W, Vivat V, Wurtz JM, et al. (2000) Crystal structure of a heterodimeric complex of RAR and RXR ligand‐binding domains. Molecular Cell 5: 289–298.

Glass CK and Rosenfeld MG (2000) The coregulator exchange in transcriptional functions of nuclear receptors. Genes & Development 14: 121–141.

Heery D, Kalkhoven E, Hoare S and Parker M (1997) A signature motif in transcriptional coactivators mediates binding to nuclear receptors. Nature 387: 733–736.

Kobayashi Y, Kitamoto T, Masuhiro Y, et al. (2000) p300 mediates functional synergism between AF‐1 and AF‐2 of estrogen receptor α and β by interacting directly with the N‐terminal A/B domains. Journal of Biological Chemistry 275: 15645–15651.

Kroll TG, Sarraf P, Pecciarini L, et al. (2000) PAX8–PPARγ1 fusion oncogene in human thyroid carcinoma [corrected]. Science 289(5484): 1474.

Lin RJ, Egan DA and Evans RM (1999) Molecular genetics of acute promyelocytic leukemia. Trends in Genetics 15: 179–184.

Nolte RT, Wisely GB, Westin S, et al. (1998) Ligand binding and co‐activator assembly of the peroxisome proliferator‐activated receptor‐γ. Nature 395: 137–143.

Rastinejad F, Wagner T, Zhao Q and Khorasanizadeh S (2000) Structure of the RXR‐RAR DNA‐binding complex on the retinoic acid response element DR1. The EMBO Journal 19: 1045–1054.

Wurtz JM, Bourguet W, Renaud JP, et al. (1996) A canonical structure for the ligand‐binding domain of nuclear receptors. Nature Structural Biology 3: 87–94.

Yoh SM, Chatterjee VK and Privalsky ML (1997) Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors. Molecular Endocrinology 11: 470–480.

Further Reading

Collingwood TN, Urnov FD and Wolffe AP (1999) Nuclear receptors: coactivators, corepressors and chromatin remodeling in the control of transcription. Journal of Molecular Endocrinology 23: 255–275.

Hu X and Lazar MA (2000) Transcriptional repression by nuclear hormone receptors. Trends in Endocrinology and Metabolism 11: 6–10.

Leo C and Chen JD (2000) The SRC family of nuclear receptor coactivators. Gene 245: 1–11.

Melnick A and Licht JD (1999) Deconstructing a disease: RARα, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93: 3167–3215.

Shang Y, Hu X, DiRenzo J, Lazar MA and Brown M (2000) Cofactor dynamics and sufficiency in estrogen receptor‐regulated transcription. Cell 103: 843–852.

Web Links

Nuclear receptor subfamily 4, group A, member 2 (NR4A2); LocusID: 4929. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=4929

Peroxisome proliferative activated receptor, gamma (PPARG); LocusID: 5468. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5468

Promyelocytic leukemia (PML); LocusID: 5371. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5371

Thyroid hormone receptor, beta (THRB); LocusID: 7068. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7068

Zinc‐finger protein 145 (ZNF145); LocusID: 7704. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7704

Nuclear receptor subfamily 4, group A, member 2 (NR4A2); MIM number: 601828. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?601828

Peroxisome proliferative activated receptor, gamma (PPARG); MIM number: 601487. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?601487

Promyelocytic leukemia (PML); MIM number: 102578. OMIM: http://www3.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?102578

Thyroid hormone receptor, beta (THRB); MIM number: 190160. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?190160

Zinc‐finger protein 145 (ZNF145); MIM number: 176797. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?176797

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How to Cite close
Love, James Daniel(Jan 2006) Nuclear Receptors and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0006024]