Disease relevance of UCN

• When used at 10(-8) M they increased the amount of live cells by 25% when added prior to hypoxia, and by 20% when UCN and SCP were added at the onset of reoxygenation [1].
• UCN mRNA and peptide expressions are decreased in endometrial adenocarcinoma [2].
• These data and the evidence that endometrial cancer expresses UCN receptors and UCN is involved in tumorigenesis of several tissues together suggest a role for UCN in endometrial tumoral cell growth and proliferation [2].
• Finally, UCN promoter activity was analyzed in the JEG3 human choriocarcinoma cell line [3].
• Urocortin (Ucn) is a new member of the corticotropin-releasing factor (CRF) neuropeptide family and has positive inotropic actions and protective effects against ischemia in the rat heart [4].

Psychiatry related information on UCN

• Urocortin peptide distribution at various stages of human development (n = 35, from 11 weeks of gestation to 6 years of age) was examined by immunohistochemistry using surgical and autopsy specimens [5].
• In home cage rats and rats exposed to the social interaction test, urocortin 1 treatment increased the number of c-Fos-immunoreactive serotonergic neurons within subdivisions of both the dorsal raphe nucleus and median raphe nucleus [6].
• Acute injection of urocortin 1 had anxiogenic effects in the social interaction test, reducing total interaction time without affecting locomotor activity or exploratory behavior [6].
• The urocortin 1 neurocircuit: ethanol-sensitivity and potential involvement in alcohol consumption [7].

High impact information on UCN

• UCN I was shown to directly alter the glucose sensitivity of VMH glucose-sensing neurons in whole-cell current clamp recordings in brain slices [8].
• In this issue of the JCI, McCrimmon and colleagues report that application of urocortin I (a corticotrophin-releasing factor receptor-2 agonist) to the ventromedial hypothalamus reduces the glucose counterregulatory response to hypoglycemia in rats (see the related article beginning on page 1723) [9].
• Thus, hypothalamic urocortin I release during antecedent hypoglycemia is, among other possibilities, a potential mechanism of HAAF [9].
• Those displaying vasoactivity all function as directly acting vasodilators and include adrenomedullin and the emerging urocortin transmitters [10].
• Corticotropin-releasing factor (CRF), its structurally related peptide urocortin (Ucn) and their receptors are also present in the skin and their levels are increased following stress [11].

Chemical compound and disease context of UCN

• The selective nonpeptide CRF-R1 antagonists antalarmin (20 mg/kg ip) and NBI-27914 (400 microgram/kg iv) did not influence intravenous CRF-, urocortin- or surgery-induced gastric stasis [12].
• UCN aerosol inhalation resulted in obvious pulmonary congestion and edema observed under light microscope by hematoxylin and eosin (HE) staining [13].
• Noraminophenazone blocked the development of urocortin 3-induced hyperthermia, or attenuated it when the hyperthermia was already present [14].
• High levels of intrauterine corticotrophin-releasing hormone, urocortin, tryptase, and interleukin-8 in spontaneous abortions [15].

Biological context of UCN

• In human embryonic kidney 293 cells overexpressing recombinant CRH-R1alpha, UCN I induced ERK1/2 and p38 MAPK activation was dependent on signaling molecules involved in agonist-induced CRH-R1alpha trafficking and endocytosis [16].
• UCN I effect on p38 MAPK phosphorylation was more transient, returned to basal within 40 min and was dependent on epidermoid growth factor receptor transactivation, but not PI3-K/Akt activation [16].
• Bisindolylmaleimide partially inhibited the UCN-mediated decrease in ERK phosphorylation in A7r5 cells, suggesting that the protein kinase C pathway is partially involved in CRF(2) receptor signal transduction [17].
• CRF-R1 activation inhibits cell growth and proliferation of a tumor cell line derived from the human endometrium, and the UCN signaling pathway has been implicated in tumorigenesis of several tissues [2].
• For this reason, immunohistochemistry was performed on tissue sections from paraffin-embedded human first trimester placentas and freshly isolated human invasive extravillous trophoblast cells (EVT) were analyzed for UCN expression using RT-PCR and immunofluorescence [3].

Anatomical context of UCN

• Immunohistochemistry revealed expression of UCN in the cytotrophoblast, the EVT and decidual cells [3].
• UCN is expressed in human reproductive tissues including endometrium, ovary, and placenta [3].
• Immunoreactive UCN was found in luminal and glandular epithelial cells in healthy, but not in neoplastic samples [2].
• This study was designed to investigate the cellular localization of UCN at the implantation site of the human blastocyst, as well as the regulation of the UCN promoter by two major intracellular signaling pathways, the cAMP/PKA and diacylglycerol/PKC pathways, in cells of placental origin [3].
• In cultured human pregnant myometrial cells, urocortin but not CRH was able to induce MAPK phosphorylation and activation, suggesting that in the human myometrium these two peptides have distinct actions and biological roles [18].

Associations of UCN with chemical compounds

• Finally, a human UCN promoter luciferase reporter construct transfected into JEG3 cells was significantly inducible by phorbol ester plus ionomycin, but not by phorbol ester alone or by forskolin [3].
• CRF is a potent local regulator of myometrial contractility and of prostaglandin release, Recently, urocortin, a new member of the CRF family, has been localized in human placenta and membranes [19].
• Mast cells and histamine may be involved in this effect of UCN [13].
• We also found that rats receiving inhalation aerosol of UCN had a significant elevation of lung vascular permeability compared with rats receiving vehicle and ovalbumin (OVA) by the Evans blue (EB) technique [13].
• Enhanced pulmonary vascular permeability induced by UCN was markedly inhibited by pretreatment with the mast-cell stabilizer cromolyn and histamine-1 (H(1)) receptor antagonist azelastine respectively, but not by the leukotriene receptor antagonist montelukast [13].

Physical interactions of UCN

• In conclusion, it appears that a complex intraadrenal CRF-UCN/CRF-receptor system exists in both human and rat adrenals controlling catecholamine secretion and synthesis [20].
• Urocortin has been found to bind with high affinity to CRF receptors [21].

Enzymatic interactions of UCN

• No UCN-01-induced G1 accumulation in SBC-3 cells was observed in SBC-3/UCN cells and decreased expression of phosphorylated RB protein was found in SBC-3 cells [22].

Regulatory relationships of UCN

• The peptide antagonist alpha-helical CRF(9-41) exhibited a non-competitive antagonism of urocortin-stimulated luciferase expression with both hCRF2 receptor isoforms [23].
• Acting on the same CRF receptors, urocortin stimulates myometrial contractility and ACTH and prostaglandin release from cultured human placental cells [24].
• In summary, in the present study, we demonstrated for the first time that UCN is expressed in rat lung and contributes to an increase in lung vascular permeability through activation of CRH receptors [13].
• The nonselective peptide CRH receptor antagonist astressin markedly reduced lung vascular permeability triggered by UCN [13].
• In order to study the possible role of prostaglandins, the animals were treated with either a urocortin together with the pyrazolone derivative noraminophenazone to inhibit the action of cyclooxygenase in initiating hyperthermia, or with noraminophenazone 30 min following urocortin administration to act on existing hyperthermia [14].

Other interactions of UCN

• Studies on Gq protein activation using [alpha-32P]-GTP-gamma-azidoanilide and IP3 production in cells expressing the R1alpha or R2beta CRH receptors demonstrated that urocortin was 10 times more potent than CRH [18].
• Adipose tissue also expressed urocortin and stresscopin, the predominant ligands of peripheral CRH-R2 [25].
• The inhibitory effect of the CRF-binding protein on human urocortin can be blocked by biologically inactive CRF fragments, such as CRF(9-33) [26].
• Synthetic human urocortin binds with high affinity to CRF receptor types 1, 2 alpha, and 2 beta, stimulates cAMP accumulation from cells stably transfected with these receptors, and acts in vitro to release ACTH from dispersed rat anterior pituitary cells [26].
• Urocortin in the synovial tissue of patients with rheumatoid arthritis [27].

Analytical, diagnostic and therapeutic context of UCN

• Here we demonstrate the presence of UCN mRNA in both the rat spleen and human Jurkat T-lymphoma cells using 3'-RACE (rapid amplication of cDNA ends) PCR [28].
• Immunohistochemistry was used to evaluate cellular UCN localization, with the intensity of immunostaining scored on a subjective scale [2].
• We studied the concentration of urocortin in the synovial fluid using RIA, and the expression of urocortin in synovial tissue using immunohistochemistry, mRNA in situ hybridization and reverse transcriptase-PCR (RT-PCR) [27].
• Interestingly, the suppressive effect of UCN I-mediated CRFR2 activation persisted for at least 24 hours after in vivo VMH microinjection [8].
• Reverse phase high-performance liquid chromatography of the UCN-LI in the human brain extract showed two immunoreactive peaks; one peak eluting earlier and one in the position of synthetic human UCN [29].

References