The Basic Helix-loop-helix-PAS Protein ARNT Functions As a Potent Coactivator of Estrogen Receptor-dependent Transcription

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2003 May 20

PMID 12754377

Citations 56

Authors

Sara Brunnberg

Katarina Pettersson

Elin Rydin

Jason Matthews

Annika Hanberg

Ingemar Pongratz

Affiliations

Soon will be listed here.

Abstract

The biological effects of estrogens are mediated by the estrogen receptors ERalpha and ERbeta. These receptors regulate gene expression through binding to DNA enhancer elements and subsequently recruiting factors such as coactivators that modulate their transcriptional activity. Here we show that ARNT (aryl hydrocarbon receptor nuclear translocator), the obligatory heterodimerization partner for the aryl hydrocarbon receptor and hypoxia inducible factor 1alpha, functions as a potent coactivator of ERalpha- and ERbeta- dependent transcription. The coactivating effect of ARNT depends on physical interaction with the ERs and involves the C-terminal domain of ARNT and not the structurally conserved basic helix-loop-helix and PAS (Per-ARNT-Sim) motifs. Moreover, we show that ARNT/ER interaction requires the E2-activated ligand binding domain of ERalpha or ERbeta. These observations, together with the previous role of ARNT as an obligatory partner protein for conditionally regulated basic helix-loop-helix-PAS proteins like the aryl hydrocarbon receptor or hypoxia inducible factor 1alpha, expand the cellular functions of ARNT to include regulation of ERalpha and ERbeta transcriptional activity. ARNT was furthermore recruited to a natural ER target gene promoter in a estrogen-dependent manner, supporting a physiological role for ARNT as an ER coactivator.

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References

Gillesby B, Stanostefano M, Porter W, Safe S, Wu Z, Zacharewski T . Identification of a motif within the 5' regulatory region of pS2 which is responsible for AP-1 binding and TCDD-mediated suppression. Biochemistry. 1997; 36(20):6080-9. DOI: 10.1021/bi962131b. View

Ikeda M, Nomura M . cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage. Biochem Biophys Res Commun. 1997; 233(1):258-64. DOI: 10.1006/bbrc.1997.6371. View

Gekakis N, Staknis D, Nguyen H, Davis F, Wilsbacher L, King D . Role of the CLOCK protein in the mammalian circadian mechanism. Science. 1998; 280(5369):1564-9. DOI: 10.1126/science.280.5369.1564. View

Darlington T, Ceriani M, Staknis D, Gekakis N, Steeves T, Weitz C . Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. Science. 1998; 280(5369):1599-603. DOI: 10.1126/science.280.5369.1599. View

Pongratz I, Antonsson C, Whitelaw M, Poellinger L . Role of the PAS domain in regulation of dimerization and DNA binding specificity of the dioxin receptor. Mol Cell Biol. 1998; 18(7):4079-88. PMC: 108992. DOI: 10.1128/MCB.18.7.4079. View

Cowley S, Parker M . A comparison of transcriptional activation by ER alpha and ER beta. J Steroid Biochem Mol Biol. 1999; 69(1-6):165-75. DOI: 10.1016/s0960-0760(99)00055-2. View

Duan R, Porter W, Samudio I, Vyhlidal C, Kladde M, Safe S . Transcriptional activation of c-fos protooncogene by 17beta-estradiol: mechanism of aryl hydrocarbon receptor-mediated inhibition. Mol Endocrinol. 1999; 13(9):1511-21. DOI: 10.1210/mend.13.9.0338. View

Klinge C . Estrogen receptor interaction with co-activators and co-repressors. Steroids. 2000; 65(5):227-51. DOI: 10.1016/s0039-128x(99)00107-5. View

Gu Y, Hogenesch J, Bradfield C . The PAS superfamily: sensors of environmental and developmental signals. Annu Rev Pharmacol Toxicol. 2000; 40:519-61. DOI: 10.1146/annurev.pharmtox.40.1.519. View

10.

Delaunay F, Pettersson K, Tujague M, Gustafsson J . Functional differences between the amino-terminal domains of estrogen receptors alpha and beta. Mol Pharmacol. 2000; 58(3):584-90. DOI: 10.1124/mol.58.3.584. View

11.

Pettersson K, Delaunay F, Gustafsson J . Estrogen receptor beta acts as a dominant regulator of estrogen signaling. Oncogene. 2000; 19(43):4970-8. DOI: 10.1038/sj.onc.1203828. View

12.

Shang Y, Hu X, DiRenzo J, Lazar M, Brown M . Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell. 2001; 103(6):843-52. DOI: 10.1016/s0092-8674(00)00188-4. View

13.

Pettersson K, Gustafsson J . Role of estrogen receptor beta in estrogen action. Annu Rev Physiol. 2001; 63:165-92. DOI: 10.1146/annurev.physiol.63.1.165. View

14.

Porter W, Wang F, Duan R, Qin C, Kim K, Safe S . Transcriptional activation of heat shock protein 27 gene expression by 17beta-estradiol and modulation by antiestrogens and aryl hydrocarbon receptor agonists. J Mol Endocrinol. 2001; 26(1):31-42. DOI: 10.1677/jme.0.0260031. View

15.

Urnov F, Wolffe A . Chromatin remodeling and transcriptional activation: the cast (in order of appearance). Oncogene. 2001; 20(24):2991-3006. DOI: 10.1038/sj.onc.1204323. View

16.

Aranda A, Pascual A . Nuclear hormone receptors and gene expression. Physiol Rev. 2001; 81(3):1269-304. DOI: 10.1152/physrev.2001.81.3.1269. View

17.

Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G . Mechanisms of estrogen action. Physiol Rev. 2001; 81(4):1535-65. DOI: 10.1152/physrev.2001.81.4.1535. View

18.

Berg P, Pongratz I . Differential usage of nuclear export sequences regulates intracellular localization of the dioxin (aryl hydrocarbon) receptor. J Biol Chem. 2001; 276(46):43231-8. DOI: 10.1074/jbc.M105261200. View

19.

Narlikar G, Fan H, Kingston R . Cooperation between complexes that regulate chromatin structure and transcription. Cell. 2002; 108(4):475-87. DOI: 10.1016/s0092-8674(02)00654-2. View

20.

Burakov D, Crofts L, Chang C, Freedman L . Reciprocal recruitment of DRIP/mediator and p160 coactivator complexes in vivo by estrogen receptor. J Biol Chem. 2002; 277(17):14359-62. DOI: 10.1074/jbc.C200099200. View