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Molecular Identification and Characterization of a and B Forms of the Glucocorticoid Receptor

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Molecular Identification and Characterization of a and B Forms of the Glucocorticoid Receptor Molecular Identification and Characterization of A and B Forms of the Glucocorticoid Receptor Matthew R. Yudt and John A. Cidlowski Laboratory of Signal Transduction National Institute of Environmental Health Sciences Downloaded from https://academic.oup.com/mend/article/15/7/1093/2748001 by guest on 27 September 2021 National Institutes of Health Research Triangle Park, North Carolina 27709 The human glucocorticoid receptor (hGR␣)isa responsive promoters reveal the shorter hGR-B to ligand-activated transcription factor that mediates be nearly twice as effective as the longer hGR-A the physiological effects of corticosteroid hor- species in gene transactivation, but not in transre- mones and is essential for life. Originally cloned in pression. (Molecular Endocrinology 15: 1093–1103, 1986, the transcriptionally active hGR␣ was re- 2001) ported to be a single protein species of 777 amino kDa). Biochemical 94 ؍ acids (molecular mass data, obtained using various mammalian tissues INTRODUCTION and cell lines, however, have consistently revealed an additional, slightly smaller, second hGR protein The glucocorticoid receptor (GR) mediates the physi- kDa) that is not recognized ological effects of corticosteroid hormones in species 91 ؍ molecular mass) by antibodies specific for the transcriptionally in- from fish to mammals. GR is a member of the nuclear active and dominant negative, non-hormone-bind- hormone receptor superfamily of ligand-activated ing hGR␤ isoform. We report here that when a transcription factors (1) and is essential for life (2). The single GR cDNA is transfected in COS-1 cells, or activity of the GR, as well as the progesterone (PR), transcribed and translated in vitro, two forms of androgen (AR), and mineralocorticoid receptors (MR) the receptor are observed, similar to those seen in is partially mediated through a palindromic response cells that contain endogenous GR. These data sug- element termed the glucocorticoid response element gest that two forms of the hGR␣ are produced by (GRE) located in the promoter regions of target genes alternative translation of the same gene and are (3). Unlike most members of the steroid receptor su- henceforth termed GR-A and GR-B. To test this perfamily, the GR is primarily cytosolic in the absence hypothesis, we have investigated the role of an of ligand. Activation and nuclear translocation of the internal ATG codon corresponding to methionine GR after ligand binding proceeds through a complex 27 (M27) as a potential alternative translation initi- mechanism involving a loss of energy-dependent pro- ation site for the GR. Mutagenesis of this ATG tein interactions with hsp90, hsp70, and several other codon to ACG in human, rat, and mouse GR cDNA proteins (4). Although the classical view of steroid results in generation of a single 94-kDa protein action involves an increase in gene transcription in species, GR-A. Moreover, mutagenesis of the ini- response to receptor activation, in fact several glu- tial ATG codon to ACG (Met 1 to Thr) also resulted cocorticoid target genes undergo a hormone-depen- in production of single, shorter protein species (91 dent repression (5). Furthermore, in addition to GRE- kDa), GR-B. Mutagenesis of the Kozak translation dependent processes, a growing body of literature initiation sequence strongly indicates that a leaky indicates that many glucocorticoid responses involve ribosomal scanning mechanism is responsible for protein interactions with other transcription factors generating the GR-A and -B isoforms. Western blot and likely proceed through a mutual inhibitory antag- analysis using peptide-specific antibodies show onism involving direct protein-protein interactions with both the A and B receptor forms are present in other transcription factors including, for example, nu- ␬ ␬ human cell lines. Both receptors exhibit similar clear factor- B (NF- B) and AP1 (6). subcellular localization and nuclear translocation Our understanding of the complexity of nuclear re- after ligand activation. Functional analyses of ceptor signaling mechanisms has advanced signifi- -hGR؊A and hGR؊B under various glucocorticoid- cantly in recent years. The discovery and character ization of receptor coactivators and corepressors 0888-8809/01/$3.00/0 bridge the gap between the DNA-bound receptors and Molecular Endocrinology 15(7): 1093–1103 the general transcription machinery (7–9). Similarly, Copyright © 2001 by The Endocrine Society Printed in U.S.A. our knowledge regarding the role of chromatin struc- 1093 MOL ENDO · 2001 Vol. 15 No. 7 1094 ture in steroid receptor signaling has been enhanced in protein, independent of the alternatively spliced GR␤ recent years (10, 11). The three-dimensional structure variant (21, 22). The human hGR␣ and -␤ variants differ of many nuclear receptor ligand binding domains has by only 35 amino acids in length at the extreme car- not only revealed a common protein fold and ligand boxy terminus. Although quantitative measurement of binding symmetry among superfamily members, but their coexpression in human tissues or cell lines re- exposed the subtle ligand interactions and associated mains difficult because of the relative abundance of conformational changes necessary for a mechanistic hGR␣ to ␤, the two isoforms can be discriminated understanding of steroid action (reviewed in Ref. 12). immunologically using specific antibodies (23, 24). In- Furthermore, examples of ligand-independent activa- terestingly, the recombinant hGR␣ when expressed tion mechanisms in nuclear receptor signaling con- alone, either in vitro with 35S methionine or in COS-1 tinue to multiply (13). cells, known to be void of detectable endogenous GR, Downloaded from https://academic.oup.com/mend/article/15/7/1093/2748001 by guest on 27 September 2021 An additional level of complexity of steroid hormone consistently appears as a doublet of approximately receptor action is the existence of multiple receptor equal intensities (Fig. 1A). subtypes and isoforms with unique biological roles There are several possible explanations for the ori- (14–16). For example, multiple genes encode different gin of the observed hGR␣ protein doublet. Although forms of the estrogen, retinoid, and thyroid hormone proteolysis could explain the appearance of such a receptors. Alternative splicing of progesterone, glu- cocorticoid, and retinoid receptor mRNA gives rise to multiple forms of these proteins. The progesterone receptor (PR) exists as a mixture of A and B forms, generated from the same gene by alternative transla- tion initiation. Although both PR isoforms can arise from a single mRNA (17), it appears that specific pro- moters may also regulate mRNA production specific for each PR isoform (18). Both forms of PRs are well known to display distinct biochemical and physiolog- ical properties (19). This extensive multiplicity within the nuclear receptor superfamily suggests that the diversity of receptor expression may be an important component mediating the various physiological ac- tions of steroid hormones. We report here that the GR␣ gene is subject to alternative translation initiation from a downstream, in-frame ATG codon. Our data suggest that a leaky ribosomal scanning mechanism (20) produces two GR protein products, with the second initiating at an ATG codon corresponding to methionine 27 in the hGR. We term the longer protein, initiated from the first ATG codon (Met 1) as hGR-A, and the shorter protein (751 amino acids) as hGR-B. We have constructed a GR- A-specific antibody that, when used in conjunction with an antibody that recognizes both protein species, permits the discrimination of endogenous expression of the two hGR␣ isoforms. Interestingly, the shorter hGR-B is twice as effective as the longer hGR-A iso- Fig. 1. In Vitro and in Vivo Expression of Recombinant hGR␣ form in activating transcription from a GRE but has a A, The wild-type hGR␣ was prepared either by in vitro ␬ similar efficacy in repression of NF- B/p65 transacti- translation using 35S methionine and reticulocyte lysates (left vation. This discovery of an alternative initiation site panel) or by transient transfection of COS-1 cells (right panel). within the GR gene, and the functional divergence Approximately 25 ␮g of protein were electrophoresed on an observed, provides a new potential mechanism to ex- 8% polyacrylamide gel. The 35S-labeled receptor was de- plain the diversity of glucocorticoid responses in dif- tected by autoradiography of the dried gel, while the COS- ferent tissues. 1-expressed proteins were transferred to nitrocellulose and detected by Western blotting. The positions of the molecular mass markers in kilodaltons are indicated. Electrophoresis was carried out for an extended period to resolve the protein RESULTS doublet of approximately 94 and 91 kDa. B, Wild-type hGR (1–777) and two carboxy-terminal truncation mutants, Expression of Recombinant hGR hGR(1–742) and hGR(1–706), were expressed in vitro using reticulocyte lysates. Electrophoresis was carried out as in The cloning of the hGR␣ into mammalian and in vitro panel A to resolve the hGR protein doublet. Data shown are expression vectors has allowed a direct study of this representative of at least three different experiments. GR A and B 1095 doublet, inclusion of several protease inhibitors did not block production of the lower mol wt (Mr) product, arguing against degradation as the source of the dou- blet. Moreover, in vitro transcription and translation of two carboxy-terminal truncation mutants, hGR(1–742) and hGR(1–706),
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