enzyme genes is the recruitment by nuclear receptors of coregulators (coactivators and corepressors) which interact with and effect transactivation ( McKenna et al. 1999 a ). It has been suggested that cofactors serve as a bridging apparatus between the
Sinead N Kelly, T Joseph McKenna, and Leonie S Young
C Marc Luetjens, Aditya Didolkar, Sabine Kliesch, Werner Paulus, Astrid Jeibmann, Werner Böcker, Eberhard Nieschlag, and Manuela Simoni
Introduction In males, the expression of the genomic progesterone receptor (PR) and the physiological function of progesterone at the molecular level are not well understood ( Oettel & Mukhopadhyay 2004 ). Recently a non-genomic PR
M. G. Parker
Hormone receptors which function in the cell nucleus to regulate the expression of specific genes appear to be members of a discrete family of proteins. The best characterized of these are the steroid receptors which, not too surprisingly, share similar structural and functional properties with one another (King, 1987) but it is now emerging from molecular cloning studies that the receptors for thyroid hormone and retinoic acid and a number of novel receptors are also members of this same family of proteins (Table 1). The justification for assigning all these nuclear-acting receptors to a single family of proteins is the subject of this commentary.
table 1. Members of the nuclear receptor family. Receptors which have been cloned are listed together with the chromosomal location of the human genes if known
Androgens (X) Thyroid hormone α (17)
Glucocorticoids (5) Thyroid hormone β (3)
Oestrogens (6) Retinoic acid α (17)
J M P Pabona, M C Velarde, Z Zeng, F A Simmen, and R C M Simmen
Introduction Estrogen (E) control of cell proliferation is a complex process that is subject to regulation at many levels. The nuclear receptor/transcription factor estrogen receptor-α (ESR1) is the key regulatory participant, transducing E action
Z Yu, CH Lee, C Chinpaisal, and LN Wei
The orphan nuclear receptor TR2 and its truncated isoform deleted in the ligand binding domain (LBD) were localized exclusively in the nuclei as revealed by two methods of detection. An anti-hemagglutinin (HA) antibody detected specific nuclear localization of HA-tagged receptors and the green fluorescent protein (GFP)-tagged receptors were found to be distributed in the nuclei of living cells. By deletion analyses, the sequence responsible for targeting this receptor into the nucleus was defined. A stretch of 20 amino acid residues (KDCVINKHHRNRCQYCRLQR) within the second zinc-finger of this receptor is required for its nuclear localization and this signal is constitutively active. No nuclear localization signal was found in the N-terminus or the LBD. The GFP-tagged receptor remained biologically active, as evidenced by its repressive activity on the reporter that carried a binding site for this receptor, a direct repeat-5 (DR5). An electrophoretic mobility shift assay was performed to characterize the binding property of TR2 and its truncated isoform. TR2 bound to the DR5 as dimers whereas its truncated isoform bound as monomers.
G. R. Williams and G. A. Brent
The retinoids, vitamin D3 and thyroid hormone exert diverse and complex tissue-specific actions by a common mechanism within the cell nucleus. These hormones, like the classical steroid hormones, glucocorticoid and oestrogen, bind to nuclear receptor proteins and modify transcriptional activity of target genes. The receptors are members of the steroid/thyroid hormone nuclear receptor superfamily of structurally homologous ligand-responsive transcription factors which activate or repress expression of hormone-responsive target genes (Evans, 1988; Green & Chambon, 1988; Moore, 1990; O'Malley, 1990; Moore & Brent, 1991).
The receptors for 3,5,3′-l-tri-iodothyronine (T3Rs), 1,25(OH)2-vitamin D3 (VDRs) and all-trans retinoic acid (RARs) form a subclass of homologous and functionally related proteins within the steroid superfamily. The receptors can bind to DNA in the absence of ligand (Brent, Dunn, Harney et al. 1989; Graupner, Wills, Tzukerman et al. 1989), they reside in the nucleus and their response elements possess
R.J. Sterling, J.M. Gasc, P.J. Sharp, P. Tuohimaa, and E.E. Baulieu
Using a double immunohistochemical technique, LH releasing hormone (LHRH) neurones and 110kDa nuclear progesterone receptor were localized in the hypothalamus of the laying hen. Nuclear progesterone receptor was widely distributed throughout the hypothalamus, occurring in the preoptic, septal, anterior and basal areas. The region where progesterone receptor was revealed in nuclei of neurones overlapped that containing LHRH neurones. However, LHRH cell bodies did not contain progesterone nuclear receptor. It is concluded that the positive feedback action of progesterone on LH release is not mediated by a genomic mechanism within the LHRH neurone.
C. R. Clark, N. J. MacLusky, and F. Naftolin
This study describes the presence of a population of oestrogen receptors in cell nuclei from the pituitary gland and brain of untreated and oestradiol-treated ovariectomized rats. The receptors behaved as if they were not occupied by oestradiol. These 'unfilled' oestrogen receptors could be distinguished from occupied nuclear receptor sites on the basis of their ability to bind [3H]oestradiol at low temperatures (0–4 °C). Occupied receptors bound labelled [3H]oestradiol only under exchange conditions at an increased temperature (25 °C). Unfilled and occupied nuclear receptors were physicochemically similar in terms of sedimentation coefficients in sucrose density gradients containing 0·4 m-KC1 (4–5S), equilibrium dissociation constants for reaction with [3H]oestradiol (0·2–0·6 nmol/l) and ligand specificity. In ovariectomized rats, unfilled receptors constituted more than 75 % of the total nuclear receptor population. One hour after i.v. treatment with oestradiol (3·6 μg/kg), both total and unfilled nuclear receptor concentrations increased and then subsequently declined over the next 12 h. The increase in unfilled sites was, however, proportionately less than that occurring in the filled component; at 1 h after oestradiol injection unfilled sites constituted less than 20% of the receptors present in brain and pituitary cell nuclei. The physiological significance of unfilled nuclear oestrogen receptors remains unknown. The observations that they exist in various oestrogen target tissues and that their levels are influenced by oestradiol treatment suggest a possible role for these receptors in the mechanism of oestrogen action.
S. Kyakumoto, R. Kurokawa, Y. Ohara-Nemoto, and M. Ota
Cytosol and nuclear androgen receptors in submandibular glands of male and female mice were measured by an exchange assay at 0 °C. The binding of [3H]methyltrienolone to cytosol receptors in females was mostly saturated within a short period of incubation (3 h), whereas the saturation was much slower in males; suggesting that almost all of the cytosol receptors were unoccupied in females and the receptors were partially occupied in males. Nuclear receptors were extracted with pyridoxal 5′-phosphate (5 mmol/l) from nuclear fractions with 93–95% efficiency. The exchange of the bound steroids occurred by 24–48 h at 0 °C, suggesting that most of the nuclear androgen receptor was occupied. The binding was low at higher temperatures, probably due to inactivation of the receptor. Scatchard analysis showed that the apparent dissociation constants of cytosol and nuclear receptors were similar (0·8 and 0·9 nmol/l respectively) in both sexes. On the other hand, the number of androgen-binding sites in the nucleus was much higher in males than in females (1052 fmol/mg DNA and 32 fmol/mg DNA respectively), while the number in the cytosol was higher in females than in males (512 fmol/mg DNA and 368 fmol/mg DNA respectively). These observations show that androgen receptors exist mainly (74%) in the nuclei of males, while they exist mostly (94%) in the cytosol of females.
J. Endocr. (1986) 108, 267–273
Jung-Min Koh, Young-Sun Lee, Chang-Hyun Byun, Eun-Ju Chang, Hyunsoo Kim, Yong Hee Kim, Hong-Hee Kim, and Ghi Su Kim
been addressed. We therefore tested the effects of α-LA on osteoblast-lineage cells and osteoclasts, and observed a dissociation of receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) expression and osteoclastogenesis. That is, α-LA markedly