Abstract
The thyroid hormone receptor alpha (THRA or c-erbA-1) gene belongs to a family of genes which encode nuclear receptors for various hydrophobic ligands such as steroids, vitamin D, retinoic acid and thyroid hormones. These receptors are composed of several domains important for hormone-binding, DNA-binding, dimerization and activation of transcription. We show here that the human THRA gene is organized in 10 exons distributed along 27 kbp of genomic DNA on chromosome 17. The position of the introns in human THRA is highly conserved when compared to the chicken gene despite their differing lengths. The N-terminal A/B domain as well as the 5' untranslated region is encoded by two exons. Interestingly, each of the putative zinc fingers of the receptor DNA-binding domain is encoded by one exon and the hormone-binding domain is assembled from three exons. The two last exons of the gene are alternatively spliced to generate two different messenger RNAs. In addition, we confirm that another gene, belonging to the nuclear receptor superfamily, ear-1, overlaps with the 3' region of THRA in an opposite transcriptional orientation.
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- Beato M. Gene regulation by steroid hormones. Cell. 1989 Feb 10;56(3):335–344. doi: 10.1016/0092-8674(89)90237-7. [DOI] [PubMed] [Google Scholar]
- Benbrook D., Pfahl M. A novel thyroid hormone receptor encoded by a cDNA clone from a human testis library. Science. 1987 Nov 6;238(4828):788–791. doi: 10.1126/science.3672126. [DOI] [PubMed] [Google Scholar]
- Brand N. J., Petkovich M., Chambon P. Characterization of a functional promoter for the human retinoic acid receptor-alpha (hRAR-alpha). Nucleic Acids Res. 1990 Dec 11;18(23):6799–6806. doi: 10.1093/nar/18.23.6799. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brand N., Petkovich M., Krust A., Chambon P., de Thé H., Marchio A., Tiollais P., Dejean A. Identification of a second human retinoic acid receptor. Nature. 1988 Apr 28;332(6167):850–853. doi: 10.1038/332850a0. [DOI] [PubMed] [Google Scholar]
- Breathnach R., Chambon P. Organization and expression of eucaryotic split genes coding for proteins. Annu Rev Biochem. 1981;50:349–383. doi: 10.1146/annurev.bi.50.070181.002025. [DOI] [PubMed] [Google Scholar]
- Damm K., Thompson C. C., Evans R. M. Protein encoded by v-erbA functions as a thyroid-hormone receptor antagonist. Nature. 1989 Jun 22;339(6226):593–597. doi: 10.1038/339593a0. [DOI] [PubMed] [Google Scholar]
- Debuire B., Henry C., Bernissa M., Biserte G., Claverie J. M., Saule S., Martin P., Stehelin D. Sequencing the erbA gene of avian erythroblastosis virus reveals a new type of oncogene. Science. 1984 Jun 29;224(4656):1456–1459. doi: 10.1126/science.6328658. [DOI] [PubMed] [Google Scholar]
- Dejean A., Bougueleret L., Grzeschik K. H., Tiollais P. Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma. Nature. 1986 Jul 3;322(6074):70–72. doi: 10.1038/322070a0. [DOI] [PubMed] [Google Scholar]
- Evans R. M. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. doi: 10.1126/science.3283939. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Forrest D., Sjöberg M., Vennström B. Contrasting developmental and tissue-specific expression of alpha and beta thyroid hormone receptor genes. EMBO J. 1990 May;9(5):1519–1528. doi: 10.1002/j.1460-2075.1990.tb08270.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gandrillon O., Jurdic P., Benchaibi M., Xiao J. H., Ghysdael J., Samarut J. Expression of the v-erbA oncogene in chicken embryo fibroblasts stimulates their proliferation in vitro and enhances tumor growth in vivo. Cell. 1987 Jun 5;49(5):687–697. doi: 10.1016/0092-8674(87)90545-9. [DOI] [PubMed] [Google Scholar]
- Gandrillon O., Jurdic P., Pain B., Desbois C., Madjar J. J., Moscovici M. G., Moscovici C., Samarut J. Expression of the v-erbA product, an altered nuclear hormone receptor, is sufficient to transform erythrocytic cells in vitro. Cell. 1989 Jul 14;58(1):115–121. doi: 10.1016/0092-8674(89)90408-x. [DOI] [PubMed] [Google Scholar]
- Green S., Chambon P. Nuclear receptors enhance our understanding of transcription regulation. Trends Genet. 1988 Nov;4(11):309–314. doi: 10.1016/0168-9525(88)90108-4. [DOI] [PubMed] [Google Scholar]
- Hodin R. A., Lazar M. A., Wintman B. I., Darling D. S., Koenig R. J., Larsen P. R., Moore D. D., Chin W. W. Identification of a thyroid hormone receptor that is pituitary-specific. Science. 1989 Apr 7;244(4900):76–79. doi: 10.1126/science.2539642. [DOI] [PubMed] [Google Scholar]
- Hollenberg S. M., Weinberger C., Ong E. S., Cerelli G., Oro A., Lebo R., Thompson E. B., Rosenfeld M. G., Evans R. M. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. 1985 Dec 19;318(6047):635–641. doi: 10.1038/318635a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huckaby C. S., Conneely O. M., Beattie W. G., Dobson A. D., Tsai M. J., O'Malley B. W. Structure of the chromosomal chicken progesterone receptor gene. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8380–8384. doi: 10.1073/pnas.84.23.8380. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Izumo S., Mahdavi V. Thyroid hormone receptor alpha isoforms generated by alternative splicing differentially activate myosin HC gene transcription. Nature. 1988 Aug 11;334(6182):539–542. doi: 10.1038/334539a0. [DOI] [PubMed] [Google Scholar]
- Jackson R. J., Standart N. Do the poly(A) tail and 3' untranslated region control mRNA translation? Cell. 1990 Jul 13;62(1):15–24. doi: 10.1016/0092-8674(90)90235-7. [DOI] [PubMed] [Google Scholar]
- Kahn P., Frykberg L., Brady C., Stanley I., Beug H., Vennström B., Graf T. v-erbA cooperates with sarcoma oncogenes in leukemic cell transformation. Cell. 1986 May 9;45(3):349–356. doi: 10.1016/0092-8674(86)90320-x. [DOI] [PubMed] [Google Scholar]
- Kastner P., Krust A., Mendelsohn C., Garnier J. M., Zelent A., Leroy P., Staub A., Chambon P. Murine isoforms of retinoic acid receptor gamma with specific patterns of expression. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2700–2704. doi: 10.1073/pnas.87.7.2700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koenig R. J., Lazar M. A., Hodin R. A., Brent G. A., Larsen P. R., Chin W. W., Moore D. D. Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing. Nature. 1989 Feb 16;337(6208):659–661. doi: 10.1038/337659a0. [DOI] [PubMed] [Google Scholar]
- Koenig R. J., Warne R. L., Brent G. A., Harney J. W., Larsen P. R., Moore D. D. Isolation of a cDNA clone encoding a biologically active thyroid hormone receptor. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5031–5035. doi: 10.1073/pnas.85.14.5031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Krust A., Kastner P., Petkovich M., Zelent A., Chambon P. A third human retinoic acid receptor, hRAR-gamma. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5310–5314. doi: 10.1073/pnas.86.14.5310. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kwok S., Higuchi R. Avoiding false positives with PCR. Nature. 1989 May 18;339(6221):237–238. doi: 10.1038/339237a0. [DOI] [PubMed] [Google Scholar]
- Lawn R. M., Fritsch E. F., Parker R. C., Blake G., Maniatis T. The isolation and characterization of linked delta- and beta-globin genes from a cloned library of human DNA. Cell. 1978 Dec;15(4):1157–1174. doi: 10.1016/0092-8674(78)90043-0. [DOI] [PubMed] [Google Scholar]
- 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]
- Lazar M. A., Jones K. E., Chin W. W. Isolation of a cDNA encoding human Rev-ErbA alpha: transcription from the noncoding DNA strand of a thyroid hormone receptor gene results in a related protein that does not bind thyroid hormone. DNA Cell Biol. 1990 Mar;9(2):77–83. doi: 10.1089/dna.1990.9.77. [DOI] [PubMed] [Google Scholar]
- Mathieu-Mahul D., Xu D. Q., Saule S., Lidereau R., Galibert F., Berger R., Mauchauffé M., Larsen C. J. An EcoRI restriction fragment length polymorphism (RFLP) in the human c-erb A locus. Hum Genet. 1985;71(1):41–44. doi: 10.1007/BF00295666. [DOI] [PubMed] [Google Scholar]
- Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
- Mitsuhashi T., Tennyson G. E., Nikodem V. M. Alternative splicing generates messages encoding rat c-erbA proteins that do not bind thyroid hormone. Proc Natl Acad Sci U S A. 1988 Aug;85(16):5804–5808. doi: 10.1073/pnas.85.16.5804. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Miyajima N., Kadowaki Y., Fukushige S., Shimizu S., Semba K., Yamanashi Y., Matsubara K., Toyoshima K., Yamamoto T. Identification of two novel members of erbA superfamily by molecular cloning: the gene products of the two are highly related to each other. Nucleic Acids Res. 1988 Dec 9;16(23):11057–11074. doi: 10.1093/nar/16.23.11057. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murray M. B., Zilz N. D., McCreary N. L., MacDonald M. J., Towle H. C. Isolation and characterization of rat cDNA clones for two distinct thyroid hormone receptors. J Biol Chem. 1988 Sep 5;263(25):12770–12777. [PubMed] [Google Scholar]
- Nakai A., Sakurai A., Bell G. I., DeGroot L. J. Characterization of a third human thyroid hormone receptor coexpressed with other thyroid hormone receptors in several tissues. Mol Endocrinol. 1988 Nov;2(11):1087–1092. doi: 10.1210/mend-2-11-1087. [DOI] [PubMed] [Google Scholar]
- Petkovich M., Brand N. J., Krust A., Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987 Dec 3;330(6147):444–450. doi: 10.1038/330444a0. [DOI] [PubMed] [Google Scholar]
- Ponglikitmongkol M., Green S., Chambon P. Genomic organization of the human oestrogen receptor gene. EMBO J. 1988 Nov;7(11):3385–3388. doi: 10.1002/j.1460-2075.1988.tb03211.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ryseck R. P., Macdonald-Bravo H., Mattéi M. G., Ruppert S., Bravo R. Structure, mapping and expression of a growth factor inducible gene encoding a putative nuclear hormonal binding receptor. EMBO J. 1989 Nov;8(11):3327–3335. doi: 10.1002/j.1460-2075.1989.tb08494.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sap J., Muñoz A., Damm K., Goldberg Y., Ghysdael J., Leutz A., Beug H., Vennström B. The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature. 1986 Dec 18;324(6098):635–640. doi: 10.1038/324635a0. [DOI] [PubMed] [Google Scholar]
- Saule S., Roussel M., Lagrou C., Stehelin D. Characterization of the oncogene (erb) of avian erythroblastosis virus and its cellular progenitor. J Virol. 1981 May;38(2):409–419. doi: 10.1128/jvi.38.2.409-419.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Spurr N. K., Solomon E., Jansson M., Sheer D., Goodfellow P. N., Bodmer W. F., Vennstrom B. Chromosomal localisation of the human homologues to the oncogenes erbA and B. EMBO J. 1984 Jan;3(1):159–163. doi: 10.1002/j.1460-2075.1984.tb01777.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thompson C. C., Weinberger C., Lebo R., Evans R. M. Identification of a novel thyroid hormone receptor expressed in the mammalian central nervous system. Science. 1987 Sep 25;237(4822):1610–1614. doi: 10.1126/science.3629259. [DOI] [PubMed] [Google Scholar]
- Tilley W. D., Marcelli M., McPhaul M. J. Expression of the human androgen receptor gene utilizes a common promoter in diverse human tissues and cell lines. J Biol Chem. 1990 Aug 15;265(23):13776–13781. [PubMed] [Google Scholar]
- Vennström B., Fanshier L., Moscovici C., Bishop J. M. Molecular cloning of the avian erythroblastosis virus genome and recovery of oncogenic virus by transfection of chicken cells. J Virol. 1980 Nov;36(2):575–585. doi: 10.1128/jvi.36.2.575-585.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang A. M., Doyle M. V., Mark D. F. Quantitation of mRNA by the polymerase chain reaction. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9717–9721. doi: 10.1073/pnas.86.24.9717. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weinberger C., Thompson C. C., Ong E. S., Lebo R., Gruol D. J., Evans R. M. The c-erb-A gene encodes a thyroid hormone receptor. Nature. 1986 Dec 18;324(6098):641–646. doi: 10.1038/324641a0. [DOI] [PubMed] [Google Scholar]
- Wickens M. How the messenger got its tail: addition of poly(A) in the nucleus. Trends Biochem Sci. 1990 Jul;15(7):277–281. doi: 10.1016/0968-0004(90)90054-f. [DOI] [PubMed] [Google Scholar]
- Zahraoui A., Cuny G. Nucleotide sequence of the chicken proto-oncogene c-erbA corresponding to domain 1 of v-erbA. Eur J Biochem. 1987 Jul 1;166(1):63–69. doi: 10.1111/j.1432-1033.1987.tb13484.x. [DOI] [PubMed] [Google Scholar]
- Zelent A., Krust A., Petkovich M., Kastner P., Chambon P. Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin. Nature. 1989 Jun 29;339(6227):714–717. doi: 10.1038/339714a0. [DOI] [PubMed] [Google Scholar]