Cellular mechanism of hormone action
Hormone response elementKlug; Steroid hormone receptors: Steroid hormones SHs are lipophilic molecules derived from cholesterol and synthesized in the adrenal cortex glucocorticoids, mineralocorticoids, and adrenal androgensthe testes testicular androgens, oestrogenand the ovary and placenta oestrogens and progestagens or progestins. SHs reach their target cells via the blood, where they are bound to carrier proteins, and because of their lipophilic nature pass the cell membrane by simple diffusion. Within the target cells SHs bind testosteron mann frau hellen steroid hormone receptors SHRsthe key rfceptors of SH action, which steroid hormone receptors and their response elements complexed to chaperones, e. SHRs are intracellular transcription factors that can be activated, among other possibilities, by the specific and high affinity binding of ligand to exert positive or negative effects on the expression of target genes.
hormone response element
This results in promoter-localized histone hypoacetylation that contributes to the silencing of LHR transcriptional expression. Chromatin changes resulting from site-specific acetylation and methylation of histones regulate LHR gene expression.
The methylation status of the promoter provides another layer of modulation in a cell-specific manner. The luteinizing hormone receptor LHR is a G-protein coupled receptor that has an essential role in gonadal maturation and function. The LHR gene is expressed primarily in the gonads, where it mediates the luteinizing hormone LH signals that regulate cyclic ovarian changes and testicular function Dufau, ; Richards and Hedin, ; Richards et al.
The LHR is also found in non-gonadal, tumoral tissues and cancer cells Reshef et al. In the Leydig cells, LH action supports steroidogenic enzymes and other functions to regulate androgen production which is essential for the completion of spermatogenesis Dufau, ; Dufau and Tsai-Morris, More recently, Akt and Erk pathways have been shown to mediate the actions of FSH and IGF on granulosa cells and of LH on theca cells in vitro , and to participate in follicle growth and estradiol secretion in vivo Ryan et al.
However, their intrinsic molecular regulatory mechanisms in LHR transcription have not been elucidated. The receptor is a sialoglycoprotein that contains two functional units: The LHR is encoded by a single copy gene whose structure is highly conserved between species. It contains 11 exons and 10 introns - exons 1—10 encode most of the extracellular domain EC and exon 11 for the rest, including 43 aa of the EC.
The structure of the LHR gene was elucidated in the rat, human and mouse, and is highly conserved between species Tsai-Morris et al. Subsequently, significant advances in the control of LHR transcription have been derived from studies of the human gene hLHR in cancer cells in culture Zhang and Dufau, ; Zhang et al.
These studies have revealed that transcription of the LHR gene is subject to repression and derepression through various modalities of complex modulation at the epigenetic level, and the participation of phosphatases, signal transduction pathways, phosphorylation events and derecruitment of inhibitors.
The identification of the LHR gene promoter in different species and the various transcription factors that are involved in its basal transcription have facilitated the characterization of regulatory mechanisms that participate in LHR transcription.
Initiator-like elements encompass the transcriptional start sites, which are located within the promoter close to the translational initiation site ATG.
These sites that bind transcription factors Sp1 and Sp3 contribute similarly to LHR basal promoter activity and are of central importance in transcription of the LHR gene.
This type of modulation is independent of changes in histone acetylation status. In contrast, orphan receptor TR4, acts as an activator of human LHR transcription through the same DR responsive element, and is not operative in the rat due to a single base-pair mismatch in the DR Zhang and Dufau, ; Zhang and Dufau, ; Zhang and Dufau, These findings are relevant to the control of hLHR gene transcription by these orphan receptors during the ovarian cycle.
This type of control is independent of the pathway involving unliganded nuclear receptors see above. The co-requirement of TSA and 5-AzaC, but not 5AzaC alone, for demethylation of the promoter indicates the essential participation of chromatin structure in this process Zhang et al. These findings have indicated the requirement for coordinated changes in DNA methylation and histone modification of the LHR promoter. Expression is maximal in untreated PLC cells control and no changes were observed with treatment.
Changes of the histone code at the promoter are essential for derepression and combined histone hyperacetylation and DNA promoter demethylation are required for full derepression. TSA-induced histone hyperacetylation without changes in DNA methylation at the promoter, causes release of inhibitor p from Sp1 at the promoter and partial LHR derepression. These changes induce a more permissive chromatin state which ultimately favours the recruitment of TFII B and Pol II to the promoter and stimulates Sp1-driven transcription.
These negatively regulate the LHR gene transcription by promoting a key dephosphorylation of Sp1 that it is necessary for transcriptional activation. Derepression of LHR transcription induced by TSA is limited to changes in chromatin structure that are due to histone acetylation independent of the DNA methylation status.
These permit phosphatases to exert their regulatory effects on Sp1 phosphorylation levels that control silencing or activation of the LHR Fig. Phophorylation of Sp1 is not observed upon overexpression of the SA Sp1-mutant protein. Such dissociation is related to changes in chromatin structure caused by the histone code induced by TSA in presence of the fully demethylated promoter Zhang et al.
PMA caused significant enhancement of Sp1 phosphorylation at serine site Liao et al. Significant advances have been achieved in studies of LHR gene structure and regulation of transcription. These findings derived from studies on stable cultures of cancer cells have proven to be advantageous, since transient cultures of gonadal cells would permit only limited exploration of the basic aspects of transcription.
These approaches, which facilitated the identification of several layers of regulatory modalities participating in the basic control of LHR gene expression and regulation, are applicable to studies of their participation in LHR transcriptional regulation during development by hormones, growth factors and other activators of target gonadal systems. Deviations in these mechanisms could also provide insights into unexplained disease states related to LHR expression. This is a PDF file of an unedited manuscript that has been accepted for publication.
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See other articles in PMC that cite the published article. Luteinizing Hormone Receptor, transcription, epigenetic, repressor, co-repressor, histone deacetylase, histone acetylation, DNA methylation, Sp1, PKC phosphorylation, phosphatases. Open in a separate window. Conclusions Significant advances have been achieved in studies of LHR gene structure and regulation of transcription. J Clin Endocrinol Metab. Regulation of peptide hormone receptors and gonadal steroidogenesis.
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Hormone response element
Steroid hormone receptors are ligand-dependent transcription factors that control a GR-activation, the mechanism of their differential action is not understood. So far no mineralocorticoid-response element has been identified in promoters. Mai The luteinizing hormone receptor (LHR) transcription is subject to an epigenetic . Upstream of the Sp1 sites is present an inhibitory imperfect estrogen receptor response element direct repeat (DR) Orphan receptors are subject to regulation of their expression by LH/hCG, .. J Steroid Biochem Mol Biol. Nature – Smith DF, Toft DO () Steroid receptors and their Peterson DO () Functional elements of the steroid hormone-responsive.