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)

Corticotropin-releasing hormone (CRH) plays a major role in the coordination of the stress response. Its gene is expressed in multiple brain regions, the peripheral sympathetic system and the placenta, as well as in peripheral inflammatory sites where CRH acts as a pro-inflammatory cytokine. The human (h) CRH gene, in addition to its primary promoter (TATA box I), has a second distal promoter-like structure (TATA box II) and a functional cyclic adenosine monophosphate-responsive element, all of which are preserved in the rat and ovine genes. To examine the functionality of TATA II, we positioned a 881-bp-long segment of the 5' flanking region of the hCRH gene containing TATA II, but lacking TATA I, upstream from a chloramphenicol acetyltransferase (CAT) reporter gene cloned in a pUC vector. We transfected COS-7 cells with this construct and examined responsiveness of CAT activity to potential stimulants and inhibitors. Phorbol ester (TPA) and forskolin had mild but clear stimulatory effects on CAT expression (approximately 1.5- and approximately 1.3-fold, respectively), with a combined effect of approximately 1.9-fold. Dexamethasone (DEX) inhibited TPA-stimulated CAT activity by approximately 2.6-fold. In contrast, in the presence of a co-transfected glucocorticoid receptor cDNA expression plasmid, DEX augmented TPA-stimulated CAT expression by approximately 3.1-fold. The predicted secondary structures of the primary transcripts employing the distal and proximal promoters had significant differences, which could affect their stability and translatability.2
Mol Cell Endocrinol 1993 Jul
PMID:Regulated activity of the distal promoter-like element of the human corticotropin-releasing hormone gene and secondary structural features of its corresponding transcripts. 839 23

The hypothalamic hormone CRH is also expressed in the placentas of humans and higher primates and may play an important role in the regulation of labor. In choriocarcinoma cell lines, activation of cAMP-dependent pathways increases human (h)CRH reporter gene expression. A cAMP-responsive region distinct from the cAMP response element at -220 bp, has been identified between -200 and -99 bp, and a candidate transcription factor was identified in nuclear extracts of human, but not rodent, choriocarcinoma cell lines. This region, which does not contain a canonical cAMP response element (CRE), transfers protein kinase A responsiveness to a heterologous promoter. Electromobility shift assays and methylation and uracil interference studies localized factor binding to a 20-bp region from -128 to -109 bp of the hCRH promoter. This 20-bp fragment exhibited a similar shift in nuclear extracts from both human term placenta and from human JEG-3 cells. Base contacts, identified in interference studies, were confirmed as critical for binding, as a mutation of these bases abolished factor binding. Furthermore, a CRH promoter containing this mutation exhibited a diminished response to forskolin. UV cross-linking demonstrated the protein in nuclear extracts from human, but not rodent, choriocarcinoma cell lines and estimated its size as 58 kDa. Although this factor participates in cAMP-regulated gene expression, competition electrophoretic mobility assays demonstrated that the factor does not bind to a CRE. Furthermore, neither anti-CREB nor anti-ATF2 antibodies alter factor binding. These data identify this 58-kDa protein as the human-specific CRH activator previously identified as a candidate factor contributing to the species-specific expression of CRH in human placenta.
Mol Endocrinol 1998 Aug
PMID:Characterization of a human-specific regulator of placental corticotropin-releasing hormone. 971 48

Since AP-2alpha induces the expression of hPL, hCG and other syncytiotrophoblast-specific marker genes in cytotrophoblast cells during in vitro differentiation, we have examined whether AP-2alpha also induces hCRH gene expression during differentiation of cytotrophoblast cells. Infection of human cytotrophoblast cells in vitro with an adenovirus expressing AP-2alpha resulted in a twofold increase in hCRH mRNA levels, while infection with an adenovirus expressing a dominant/negative mutant of AP-2alpha inhibited basal hCRH mRNA levels by 40% and completely blocked the induction of hCRH mRNA by AP-2alpha. Transient transfection studies in AtT-20 and HepG2 cells indicated that the induction of hCRH mRNA levels was due, at least in part, to transcriptional activation of the hCRH gene. Gel mobility shift and immunoprecipitation assays strongly suggest that AP-2alpha induces hCRH gene expression by interacting with CREB and not by binding directly to the hCRH promoter.
Mol Cell Endocrinol 2002 Jun 14
PMID:AP-2alpha modulates human corticotropin-releasing hormone gene expression in the placenta by direct protein-protein interaction. 1206 96

The human corticotropin-releasing factor receptor type 1 (hCRF-R1) functional transcript is mainly expressed in the anterior pituitary corticotrophs, a tissue usually not available for clinical investigation. Splice variants translated into defective isoforms of the receptor have been described in few peripheral tissues. The aim of this work was to determine whether peripheral white blood cells from healthy individuals, an accessible tissue for clinical investigation, were suitable for the analysis of the hCRF-R1 transcript and gene. We report that: (i) specific amplification of the hCRF-R1 transcript from peripheral white blood cells mRNAs is feasible; (ii) this transcript is similar to the functional transcript; (iii) the draft sequence of chromosome 17 and unrelated sequences allow direct sequencing of all 14 exons of the gene, adjacent splice sites and related branch points. In conclusion, these approaches would be suitable for studies in patients having isolated secondary glucocorticoids deficiency to implicate the hCRH-R1 in the etiology of the disease.
Mol Cell Endocrinol 2003 Jan 31
PMID:Human corticotropin-releasing factor type 1 receptor analysis with white blood cells mRNAs and DNA. 1258 90

The physiologic response to stress is highly dependent on the activation of corticotropin-releasing hormone (CRH) neurons by various neurotransmitters. A particularly rich innervation of hypophysiotropic CRH neurons has been detected by nerve fibers containing the neuropeptide PACAP, a potent activator of the cAMP-protein kinase A (PKA) system. Intracerebroventricular (icv) injections of PACAP also elevate steady-state CRH mRNA levels in the paraventricular nucleus (PVN), but it is not known whether PACAP effects can be associated with acute stress responses. Likewise, in cell culture studies, pharmacologic activation of the PKA system has stimulated CRH gene promoter activity through an identified cAMP response element (CRE); however, a direct link between PACAP and CRH promoter activity has not been established. In our present study, icv injection of 150 or 300 pmol PACAP resulted in robust phosphorylation of the transcription factor CREB in the majority of PVN CRH neurons at 15 to 30 min post-injection and induced nuclear Fos labeling at 90 min. Simultaneously, plasma corticosterone concentrations were elevated in PACAP-injected animals, and significant increases were observed in face washing, body grooming, rearing and wet-dog shakes behaviors. We investigated the effect of PACAP on human CRH promoter activity in alphaT3-1 cells, a PACAP-receptor expressing cell line. Cells were transiently transfected with a chloramphenicol acetyltransferase (CAT) reporter vector containing region - 663/+124 of the human CRH gene promoter then treated for with PACAP (100 nM) or with the adenylate cyclase activating agent, forskolin (2.5 muM). Both PACAP and forskolin significantly increased wild-type hCRH promoter activity relative to vehicle controls. The PACAP response was abolished in the CRE-mutant construct. Pretreatment of transfected cells with the PKA blocker, H-89, completely prevented both PACAP- and forskolin-induced increases in CRH promoter activity. Furthermore, CREB overexpression strongly enhanced PACAP-mediated stimulation of hCRH promoter activity, an effect which was also lost with mutation of the CRE. Thus, we demonstrate that icv PACAP administration to rats under non-stressed handling conditions leads to cellular, hormonal and behavioral responses recapitulating manifestations of the acute stress response. Both in vivo and in vitro data point to the importance of PACAP-mediated activation of the cAMP/PKA signaling pathway for stimulation of CRH gene transcription, likely via the CRE.
Brain Res Mol Brain Res 2005 Jul 29
PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) mimics neuroendocrine and behavioral manifestations of stress: Evidence for PKA-mediated expression of the corticotropin-releasing hormone (CRH) gene. 1588 14

Corticorelin is a synthetic analog of the naturally occurring human peptide corticotropin-releasing factor (CRF). Several studies have indicated the ability of CRF to reduce the brain edema caused by brain tumors. Peritumoral brain edema (PBE), caused by an intracerebral tumor, manifests several features of vasogenic edema, which is a type of edema characterized by disruption of the blood-brain barrier. Traditionally, PBE has been treated using corticosteroids, primarily dexamethasone. Introduced more than four decades ago, dexamethasone revolutionized the treatment of PBE, but the side effects and withdrawal symptoms associated with corticosteroids propelled the investigation of other drugs. Clinical trials with the synthetic human CRF (hCRF) corticorelin (Xerecept, NEU-3002; Celtic Pharmaceutical Holdings) have indicated that this drug has a distinct advantage over classical corticosteroids in the treatment of PBE. Fewer and/or milder side effects have been reported for corticorelin compared with dexamethasone, although at higher doses of corticorelin several side effects, including hypotension and transient flushing, have been reported. Nevertheless, corticorelin was reasonably well tolerated in patients and healthy volunteers, and may be a good candidate for reducing PBE and associated neural damage, as well as improving neurological symptoms.
Curr Opin Mol Ther 2010 Dec
PMID:Corticorelin, a synthetic human corticotropin-releasing factor analog, for the treatment of peritumoral brain edema. 2115 69