Recent Progress In Hormone Research[JOURNAL]

The molecular characterization of GHRH and the GHRH receptor provides a framework for understanding the hypothalamic regulation of pituitary somatotroph function. The signaling events discerned from our investigation of... The molecular characterization of GHRH and the GHRH receptor provides a framework for understanding the hypothalamic regulation of pituitary somatotroph function. The signaling events discerned from our investigation of GHRH receptor structure and function form the basis of a model for GHRH action, which is shown in Fig. 20. GHRH interaction with its seven transmembrane domain Gs-coupled receptor on the somatotroph (step 1) leads to the release of growth hormone from secretory granules (step 2), which is likely to involve a G protein-mediated interaction with ion channels, and to a stimulation of intracellular cAMP accumulation (step 3) (Mayo, 1992; Lin et al., 1992; Gaylinn et al., 1993). In several cell types tested, elevated cAMP leads to the phosphorylation and activation of the transcription factor CREB by protein kinase A (Gonzalez and Montminy, 1989; Sheng et al., 1991), and one target gene for CREB action is the pituitary-specific transcription factor Pit-1 or GHF-1 (step 4) (Bodner et al., 1988; Ingraham et al., 1988; McCormick et al., 1990). Pit-1 is a prototypic POU domain protein that is required for the appropriate regulation of the growth hormone gene in somatotroph cells, thus providing a pathway by which a GHRH signal can lead to increased growth hormone synthesis in the pituitary (step 5). In addition, Pit-1 is likely to directly regulate the synthesis of the GHRH receptor (step 6), in that the receptor is not expressed in the pituitary of dw/dw mice that lack functional Pit-1 (Lin et al., 1992), and a cotransfected Pit-1 expression construct can activate the GHRH receptor promoter in transiently transfected CV1 cells (Lin et al., 1993). It remains to be determined whether additional direct regulation of the GHRH receptor gene in response to the cAMP signaling pathway occurs (step 7). The inhibitory peptide somatostatin presumably interacts with this same signaling pathway through G protein-mediated suppression of the cAMP pathway (Tallent and Reisine, 1992; Bell and Reisine, 1993). In agreement with the importance of this signaling system for normal growth, a transgene encoding a nonphosphorylatable mutant CREB protein, which blocks the function of the endogenous CREB protein, is able to cause somatotroph hypoplasia and dwarfism in mice when its expression is targeted to pituitary somatotrophs (Struthers et al., 1991). Several steps in the signaling pathway leading to growth hormone secretion are subject to disruption, resulting in growth hormone deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

Get PDF PubMed ↗

The endocrine role in mammalian sexual differentiation.

Wilson JD, George FW, Renfree MB

Recent Prog Horm Res · 1995 · PMID 7740166 · Publisher ↗

Abstract loading — click title to view on PubMed.

Get PDF PubMed ↗

An alternative ligand-independent pathway for activation of steroid receptors.

O'Malley BW, Schrader WT, Mani S … +4 more , Smith C, Weigel NL, Conneely OM, Clark JH

Recent Prog Horm Res · 1995 · PMID 7740165 · Publisher ↗

Abstract loading — click title to view on PubMed.

Get PDF PubMed ↗

The molecular and genetic dissection of the retinoid signaling pathway.

Chambon P

Recent Prog Horm Res · 1995 · PMID 7740164 · Publisher ↗

Abstract loading — click title to view on PubMed.

Get PDF PubMed ↗

Amphibian metamorphosis: a complex program of gene expression changes controlled by the thyroid hormone.

Brown DD, Wang Z, Kanamori A … +3 more , Eliceiri B, Furlow JD, Schwartzman R

Recent Prog Horm Res · 1995 · PMID 7740163 · Publisher ↗

Abstract loading — click title to view on PubMed.

Get PDF PubMed ↗

Role of the renin-angiotensin system in blood pressure regulation and in human hypertension: new insights from molecular genetics.

Corvol P, Jeunemaitre X, Charru A … +2 more , Kotelevtsev Y, Soubrier F

Recent Prog Horm Res · 1995 · PMID 7740162 · Publisher ↗

Abstract loading — click title to view on PubMed.

Get PDF PubMed ↗

Molecular genetic analysis of mammalian spermatid differentiation.

Braun RE, Lee K, Schumacher JM … +1 more , Fajardo MA

Recent Prog Horm Res · 1995 · PMID 7740161 · Publisher ↗

Abstract loading — click title to view on PubMed.

Get PDF PubMed ↗

Oxytocin and oxytocin receptor gene expression in the uterus.

Zingg HH, Rozen F, Chu K … +4 more , Larcher A, Arslan A, Richard S, Lefèbvre D

Recent Prog Horm Res · 1995 · PMID 7740160 · Publisher ↗

Abstract loading — click title to view on PubMed.

Get PDF PubMed ↗

Ovarian cell differentiation: a cascade of multiple hormones, cellular signals, and regulated genes.

Richards JS, Fitzpatrick SL, Clemens JW … +3 more , Morris JK, Alliston T, Sirois J

Recent Prog Horm Res · 1995 · PMID 7740159 · Publisher ↗

During the development of preovulatory follicles, tonic levels of FSH (and steroid) induce expression of aromatase, the LH receptor, and RII beta in a coordinate manner. Despite the similar temporal increase in steady-st... During the development of preovulatory follicles, tonic levels of FSH (and steroid) induce expression of aromatase, the LH receptor, and RII beta in a coordinate manner. Despite the similar temporal increase in steady-state levels of mRNA encoding these proteins, the cis-acting DNA elements and trans-acting factors regulating each gene are distinct (Richards, 1993). Whereas the aromatase gene has a TATA motif and a single transcriptional initiation site (Fitzpatrick and Richards, 1993), both the LH receptor (Wang et al., 1992; Tsai-Morris et al., 1993) and RII beta (Kurten et al., 1992; Luo et al., 1992) genes have promoters that are GC rich, lack TATA motifs, and initiate transcription at multiple sites. The aromatase promoter appears to be regulated, in part, by SF-1, a CRE-like region, and possibly another or overlapping region binding an Ad3BP-like factor. The RII beta promoter has a region that binds several nuclear proteins, whose identity is not yet known. Likewise, the LH receptor promoter elements have yet to be clearly defined (Figures 2, 4, and 25; Kurten et al., 1992). FSH can also induce the expression of at least three immediate-early genes that encode novel kinases or kinase-like proteins (Figure 25). One of these is called serum-inducible kinase (snk) (Simmons et al., 1992), another is serum and glucocorticoid regulated kinase (sgk) (Webster et al., 1993), and a third is called pole kinase (Clay et al., 1993). Steady-state levels of snk and sgk mRNA are induced rapidly (within a few hours) by FSH in granulosa cells prior to the appearance of transcripts for aromatase, LH receptor, and RII beta (T. Alliston and J. S. Richards, in preparation). The functional role of these kinases in the initial response of granulosa cells to tonic (not surge) levels of FSH remains to be elucidated. The cellular signaling pathways mediating the effects of the LH surge appear equally or more complex (Fig. 25). Based on data presented herein, as well as on analyses of the cloned and expressed LH receptor (Guderman et al., 1992), it is clear that low concentrations of LH stimulate adenylyl cyclase, cAMP production, and activation of protein kinase A. Higher (surge) concentrations of LH also increase IP3 and activation of protein kinase C. GnRH has been used in several studies to examine the ability of the protein kinase C pathway to mimic effects of high LH.(ABSTRACT TRUNCATED AT 250 WORDS)

Get PDF PubMed ↗