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• W2407726897 abstract "Miguel Beato,’ Peter Herrlich,t and Giinther Schlitz* *Institut ftir Molekularbiologie und Tumorforschung Philipps-Universitat Marburg Emil-Mannkopff-Strasse 2 D-35037 Marburg Federal Republic of Germany tForschungszentrum Karlsruhe lnstitut fiir Genetik D-76021 Karlsruhe Federal Republic of Germany *Deutsches Krebsforschungszentrum Im Neuenheimer Feld 280 D-691 20 Heidelberg Federal Republic of Germany It tookalmost aquarterof acenturyfrom the earliest indica- tion that steroid hormones play a role in transcriptional control, triggered by the observation by Ulrich Clever of ecdysoneinduced giant chromosome puffs, and from the earliest detection of steroid hormone receptors (SHRs) to the cloning of their genes (reviewed by Evans, 1988). Although availability of the first SHR cDNA clones 10 years ago triggered the isolation of the now huge superfamily of nuclear receptors by homology screening with the DNA- binding domain (DBD) (Mangelsdorf and Evans, 1995 [this issue of Cell]; Thummel, 1995 [this issue of CeW]), the vertebrate SHRs have remained a distinct class that are different in several respects from all other nuclear re- ceptors. Prologue: The Main Actors SHRs exert their influence in embryonic development and adult homeostasis as hormone-activated transcriptional regulators. Their modular structure, consisting of a DBD, nuclear localization signals, a ligand-binding domain (LBD), and several transcriptional activation functions (AFs) (Figure l), is conserved with other members of the nuclear receptor family. Unique to the SHRs is their ability upon activation to bind to palindromic DNA sequences, called hormone response elements (HREs) (Figure l), ex- clusively as homodimers, at least in vivo. The receptors for glucocorticoids, mineralocorticoids, progesterone, and androgens recognize the same DNA sequence (AGAACA as half-site) that creates a specificity problem to be dis- cussed later, while the estrogen receptor recognizes AGG- TCA, identical with the half-site used by the nonsteroid nuclear receptors. Mutant data, nuclear magnetic reso- nance studies, and X-ray analyses of DBDlHRE cocrystals of glucocorticoid and estrogen receptors have shown that half-sites are distinguished by several amino acids (origi- nally named the P box by Umesono and Evans, 1989) of a recognition helix that is coordinated by a zinc-binding motif and makes base-specific contacts within the major groove. A second zinc atom organizes both an a helix, which is oriented alongside the axis of the DNA, and the D box, responsible, at least in part, for specific homodimer- ization (Figure 1; reviewed by Glass, 1994). After binding to DNA, the receptor is thought interact with compo- nents of the basal transcriptional machinery and with se- quence-specific transcription factors. Although a number of such interactions have been described, the actual mechanism steroid hormone action is still far from being understood. We know many actors, but we do not the plot. The only certainty is that there are many more actors than expected and that the plot they are involved in is neither simple nor unique. In reviewing the wealth of recent reports on SHRs, we will describe various levels of regulation, focusing on a few well-characterized exam- ples of hormonal induction and repression on the in- sights gained by targeted disruption of the genes for SHRs. The Curtain Rises: The Unliganded SHR Complex In contrast with other nuclear receptors, all unliganded SHRs are associated with a large multiprotein complex of chaperones, including Hsp90 and the immunophilin Hsp56, which maintains the receptors in an inactive but ligand-friendly conformation (reviewed by Pratt, 1993). SHRs introduced into yeast can be activated upon ligand addition. Data obtained in mutant yeast strains suggest that the chaperoning proteins play an active role in keeping SHRs functional. In yeast strains expressing the glucocor- ticoid receptor, disruption of the Hsp90 homologs does not lead to constitutive activation of the receptor but rather to a significant impairment of hormone induction (Bohen and Yamamoto, 1993). Chaperones in addition to Hsp90 are required for SHR function, as suggested by mutants of the yeast dnaJ homolog YDJl , which also associates with the unliganded SHR complex. In contrast mu- tants found in hsp90, one ydil allele generates constitu- tively active estrogen and glucocorticoid receptors (Cap- Ian et al., 1995; Kimura 1995). Other Members of the Cast: Basal Transcription Factors and Coactivators To regulate transcription, liganded SHRs must talk to the transcription initiation complex. It is currently debated whether transcription initiation complexes assemble at the TATA box in an ordered stepwise fashion (TFIID > TFIIB > RNA polymerase II + TFIIF TFIIE TFIIH) or are recruited as preformed complexes. Such preformed holo- enzyme complexes, containing RNA polymerase II and all relevant general transcription factors along with several additional polypeptides, exist in yeast (Kim et al., 1994; Koleske and Young, 1994) in higher eukaryotes (Ossi- pow et al., 1995). SHRs have been shown to interact in vitro directly with components of the transcription initiation complex (re- viewed by Tsai and O’Malley, 1994), but the physiological significance of these interactions remains unclear. There have also been indications for the existence of coactiva- tors that would act as bridging factors between SHRs and the transcription initiation complex. A number of such in- termediary factors that interact with AF2 at the C-terminus" @default.
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• W2407726897 date "1995-01-01" @default.
• W2407726897 modified "2023-09-27" @default.
• W2407726897 title "Steroid Hormone Receptors: Many Actors in Search of a Plot Review" @default.
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