Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycolytic gene expression in Saccharomyces cerevisiae is thought to be activated by the GCR and TUF proteins. We tested the hypothesis that GCR function is mediated by TUF/GRF/RAP binding sites (UASRPG elements). We found that UASRPG-dependent activation of a heterologous gene and transcription of ADH1, TEF1, TEF2, and RP59 were sensitive to GCR1 disruption. GCR is not required for TUF/GRF/RAP expression or in vitro DNA-binding activity.
Mol Cell Biol 1990 Feb
PMID:Efficient transcription of the glycolytic gene ADH1 and three translational component genes requires the GCR1 product, which can act through TUF/GRF/RAP binding sites. 240 58

The report that ANF inhibits basal and CRF-stimulated adenylate cyclase activity in anterior pituitary homogenates suggested that the atrial peptide could inhibit ACTH secretion. This possibility was investigated in the ACTH-secreting AtT-20 mouse pituitary tumor cell line as well as homogenates or primary cell cultures from rat anterior hypophysis. ANF (up to 5 X 10(-7) M) was found to be completely ineffective in stimulating basal, CRF- and/or forskolin-stimulated adenylate cyclase activity, cAMP accumulation and ACTH secretion. Similarly, ANF had no effect on spontaneous or GRF-induced GH release from cells in primary culture. ANF receptors, however, are present in AtT-20 cells and anterior pituitary cells as evidenced by the ability of the peptide to stimulate intracellular cGMP accumulation. The data, therefore, suggests that ANF does not have a negative modulatory action on the secretory function of anterior pituitary. The role of cGMP in any other action(s) of ANF remains unknown.
Mol Cell Endocrinol 1986 Feb
PMID:Atrial natriuretic factor does not affect basal, forskolin- and CRF-stimulated adenylate cyclase activity, cAMP formation or ACTH secretion, but does stimulate cGMP synthesis in anterior pituitary. 241 82

Rat GH gene expression is known to be stimulated by several factors, including thyroid hormone and GRF. This effect of GRF appears to be mediated by cAMP resulting from activation of adenylate cyclase by the peptide. The elements of the rat GH gene important for thyroid hormone stimulation and cell-specific expression have been previously mapped using gene transfection techniques. Cell-specific expression of the gene is mediated by two cell-specific elements located from -137 to -107 and from -95 to -65. Sequences mediating thyroid hormone stimulation are thought to be located between -208 and -160. In this study, using three different methods to elevate cAMP levels in cells [forskolin, a direct activator of the adenylate cyclase catalytic subunit; 8-(4-chlorophenylthio)cAMP, a nonmetabolizable cAMP analog; and isobutylmethylxanthine, a phosphodiesterase inhibitor], we show that 5'-flanking DNA of the rat GH gene can mediate stimulation by cAMP (10- to 20-fold). The cAMP-responsive region was mapped to sequences between -104 and +11, which contains the proximal cell-specific element (-95/-65) important for cell-specific expression. Either the -97/-65 or the -104/-47 region of the gene, cloned upstream of a heterologous promoter, conferred only minimal or no activation by cAMP. This suggests that these sequences are not the direct target of cAMP action or that they are insufficient alone to mediate the cAMP response. The cAMP regulatory element (TGACGTCA) is not found between - 104 and +11, and cAMP activation does not appear to act via putative AP-2 elements, since phorbol esters did not stimulate expression.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1989 May
PMID:Identification of an adenosine 3',5'-monophosphate (cAMP)-responsive region in the rat growth hormone gene: evidence for independent and synergistic effects of cAMP and thyroid hormone on gene expression. 247 28

Regulation of GH gene expression by GRF involves cAMP as a second messenger. We have demonstrated that a 500-basepair fragment of the human GH (hGH) gene 5' flanking region can confer cAMP inducibility upon the chloramphenicol acetyltransferase transcription unit in transient transfections of rat pituitary tumor cells treated with forskolin, an activator of adenyl cyclase. The same hGH construct is not induced by forskolin in nonpituitary-derived cells. Experiments with hGH deletion constructs reveal that binding sites for transcription factor AP-2 and the pituitary-specific factor GHF-1 are not required for forskolin stimulation, but that GHF-1 may potentiate the effect. RNA analyses reveal that forskolin also stimulates accumulation of transcripts initiated at the hGH promoter. Other agents that elevate cAMP levels also stimulate hGH expression. Since the hGH 5' flanking region contains no sequences homologous to the cAMP-responsive element of the somatostatin gene, and the AP-2 sites do not appear to be required for the forskolin response, these results suggest that a novel cAMP-responsive element exists within 82 basepairs upstream from the transcriptional start of the hGH gene and that hGH regulation by GRF may involve interaction between a tissue-specific element and a cAMP-inducible element.
Mol Endocrinol 1989 May
PMID:Induction of human growth hormone promoter activity by the adenosine 3',5'-monophosphate pathway involves a novel responsive element. 254 55

We have examined the effects of human GH-releasing factor (1-44) (GRF), cortisol and somatostatin-(1-14) on GH gene expression in solid tissue and dispersed cells from human pituitary adenomas using quantitative in-situ hybridization histochemistry. Sections cut from tissue obtained at hypophysectomy from three acromegalic patients were hybridized to probes directed against mature alpha-subunit, GH, prolactin, pro-opiomelanocortin, TSH beta-subunit and LH beta-subunit mRNA. Only one biopsy contained GH mRNA in isolation. A second was found to coexhibit GH, prolactin and alpha-subunit mRNA, and a third was found to contain prolactin, TSH beta-subunit, alpha-subunit and LH beta-subunit mRNA, with GH mRNA below the limit of specific detection, indicating that the sample was composed of normal rather than adenomatous pituitary tissue. GH mRNA in individual dispersed cells derived from the latter declined to barely detectable levels over 287 h, both in cultures containing GRF (10 ng/ml) or GRF (10 ng/ml) plus somatostatin (10 ng/ml) and in controls, but increased fourfold in cultures containing GRF (10 ng/ml) plus cortisol (0.5 mumol/l). GH mRNA remained unchanged in both adenoma samples over 138 and 450 h, irrespective of the addition of GRF or GRF plus hydrocortisone. In these samples, somatostatin plus GRF had no consistent effect. These studies confirm that quantitative in-situ hybridization histochemistry can be used to investigate hormone gene regulation in small samples of human tissue and should enable us to define more clearly the level at which abnormal gene regulation occurs.
J Mol Endocrinol 1988 Jul
PMID:Quantitative in-situ hybridization histochemistry studies on growth hormone (GH) gene expression in acromegalic somatotrophs: effects of somatostatin, GH-releasing factor and cortisol. 290 68

A transgenic animal model system was used to analyze the mitogenic effects of GRF on its target cell, the pituitary somatotroph. We have previously established a strain of mice that express a mouse metallothionein-I/human GRF (hGRF) fusion gene, and that grow to be abnormally large due to GH hypersecretion. We show here that chronic GRF production in these mice leads to the development of enormous pituitary glands. The increase in pituitary size appears to be largely the result of a selective proliferation (hyperplasia) of somatotrophs, the GH-producing cells. This observation provides direct evidence that a neuropeptide may act as a specific trophic factor for its target cell. In addition to this effect on pituitary development, we find that the pituitary is a major site of expression of mouse metallothionein-I/hGRF mRNA, and of hGRF peptide. This tissue specificity was unexpected in that neither component of the fusion gene is highly expressed in the normal pituitary. It suggests that pituitary somatotrophs might produce and respond to GRF in an essentially autocrine fashion in these transgenic animals.
Mol Endocrinol 1988 Jul
PMID:Dramatic pituitary hyperplasia in transgenic mice expressing a human growth hormone-releasing factor gene. 313 55

A homologous radioimmunoassay (RIA) system was developed for human GRF 1-40 and used to measure immunoreactive (IR) concentrations of the peptide in rats to determine some of its pharmacokinetic characteristics after intravenous (i.v.) and subcutaneous (s.c.) administration. A plot of the disappearance of IR-hGRF from plasma after a single intravenous injection was fitted by a biexponential curve, analysis of which gave a half-life of 3.2 +/- 0.2 min for the initial distribution phase and 57.3 +/- 1.5 min for the elimination phase. Comparison of areas under the plasma IR-hGRF/time curves after injection of identical doses of hGRF 1-40 showed that the amount detected in the circulation after it was injected s.c. was only 14-16% of the amount detected after i.v. administration. Such results may indicate degradation of a substantial proportion of the dose of the peptide at the site of injection or during its transfer to plasma; this should be borne in mind when undertaking s.c. administration for clinical purposes or in assessing the effect of GRF analogues.
Mol Cell Endocrinol 1985 Jun
PMID:Radioimmunoassay for human growth hormone-releasing factor (hGRF 1-40): comparison of plasma immunoreactive GRF after intravenous and subcutaneous administration to rats. 392 85

Synthetic human pancreatic growth hormone-releasing factor (hpGRF(1-40)-NH2) causes a 100% stimulation of cyclic AMP cell content in rat adenohypophysial cells in culture as early as 1 min after its addition while a maximal 33-fold increase is measured at 40 min. Somatostatin (10 nM) causes a 40-60% inhibition of GRF-induced cyclic AMP accumulation while GH release is inhibited by 90-95% at all time intervals. The inhibitory effect of somatostatin is exerted on the maximal effect of GRF while the ED50 values of GRF action on cyclic AMP cell content (approximately 1 nM) and GH release (approximately 0.1 nM) are not affected by the tetradecapeptide. Prostaglandin E2 causes a 2.5-fold increase in cyclic AMP levels within 1 min after its addition with a maximal 25-fold stimulation measured at 30 min. Although not completely additive, the stimulatory effects of PGE2 and GRF together on cyclic AMP cell content and GH release are more potent than when either substance is present alone. The inhibitory effects of somatostatin on PGE2 action are analogous to those observed in the presence of GRF. The present data suggest that the hypothalamic control of GH secretion by GRF and somatostatin results, at least to a large extent, from the balance between the stimulatory action of GRF and the inhibition of somatostatin on the adenylate cyclase system.
Mol Cell Endocrinol 1983 Dec
PMID:Interactions between growth hormone-releasing factor, prostaglandin E2 and somatostatin on cyclic AMP accumulation in rat adenohypophysial cells in culture. 614 Jan 96

The effects of luteinizing hormone-releasing hormone (LHRH) and human pancreatic growth hormone-releasing factor (hpGRF(1-40)-NH2) on phospholipid metabolism were studied in rat anterior pituitary cells in primary culture. In a 4-fold enriched population of gonadotrophs, 30 nM LHRH increased 32Pi incorporation into phosphatidic acid (PA) as early as 1 min after its addition. Phosphatidylinositol (PI) labeling was increased 1 min later. The stimulatory action of LHRH was observed in both phospholipids up to 100 min, the last time interval studied. The decapeptide did not affect 32Pi labeling of phosphatidylcholine (PC), lysoPC, phosphatidylethanolamine or phosphatidylserine. Dose-response studies performed after 25 min of incubation showed an ED50 value of LHRH action at approximately 1 nM for PI labeling. In contrast, the addition of 0.1 microM GRF to anterior pituitary cells enhanced 32Pi incorporation only into PC after a 60 min incubation period. The present data suggest that stimulation of acidic phospholipid metabolism, particularly an increase in PA-PI turnover, may represent an early event in the mechanism of action of LHRH but not GRF in the anterior pituitary gland.
Mol Cell Endocrinol 1984 Jul
PMID:LHRH rapidly stimulates phosphatidylinositol metabolism in enriched gonadotrophs. 643 3

Vav and Dbl are members of a novel class of oncogene proteins that share significant sequence identity in a approximately 250-amino-acid domain, designated the Dbl homology domain. Although Dbl functions as a guanine nucleotide exchange factor (GEF) and activator of Rho family proteins, recent evidence has demonstrated that Vav functions as a GEF for Ras proteins. Thus, transformation by Vav and Dbl may be a consequence of constitutive activation of Ras and Rho proteins, respectively. To address this possibility, we have compared the transforming activities of Vav and Dbl with that of the Ras GEF, GRF/CDC25. As expected, GRF-transformed cells exhibited the same reduction in actin stress fibers and focal adhesions as Ras-transformed cells. In contrast, Vav- and Dbl-transformed cells showed the same well-developed stress fibers and focal adhesions observed in normal or RhoA(63L)-transformed NIH 3T3 cells. Furthermore, neither Vav- or Dbl-transformed cells exhibited the elevated levels of Ras-GTP (60%) observed with GRF-transformed cells. Finally, GRF, but not Vav or Dbl, induced transcriptional activation from Ras-responsive DNA elements (ets/AP-1, fos promoter, and kappa B). However, like Ras- and GRF-transformed cells, both Vav- and Dbl-transformed cells exhibited constitutively activated mitogen-activated protein kinases (MAPKs) (primarily p42MAPK/ERK2). Since kinase-deficient forms of p42MAPK/ERK2 and p44MAPK/ERK1 inhibited Dbl transformation, MAPK activation may be an important component of its transforming activity. Taken together, our observations indicate that Vav and Dbl transformation is not a consequence of Ras activation and instead may involve the constitutive activation of MAPKs.
Mol Cell Biol 1994 Oct
PMID:Dbl and Vav mediate transformation via mitogen-activated protein kinase pathways that are distinct from those activated by oncogenic Ras. 793 2


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