Steroid hormone receptors: many actors in search of a plot

M Beato, P Herrlich, G Schütz - Cell, 1995 - Elsevier
M Beato, P Herrlich, G Schütz
Cell, 1995Elsevier
It tookalmost aquarterof acenturyfrom the earliest indication 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 …
It tookalmost aquarterof acenturyfrom the earliest indication 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 receptors.
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), exclusively 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 discussed later, while the estrogen receptor recognizes AGGTCA, identical with the half-site used by the nonsteroid nuclear receptors. Mutant data, nuclear magnetic resonance studies, and X-ray analyses of DBDlHRE cocrystals of glucocorticoid and estrogen receptors have shown that half-sites are distinguished by several amino acids (originally 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-
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