Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In human Y-79 retinoblastoma cells corticotropin-releasing hormone (CRH) produces a marked and rapid increase of adenylate cyclase activity. The concentration of the peptide producing half-maximal stimulation is 60 nM. The effect of CRH is significantly antagonized by the specific CRH receptor antagonist alpha-helical CHR 9-41 and is mimicked by sauvagine and urotensin I, two peptides displaying sequence homology with CRH. These results demonstrate the presence of functional CRH receptors in human Y-79 retinoblastoma cells and suggest that this cell line may be a suitable model in which to study the action of CRH on human retinal cell function.
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PMID:Human Y-79 retinoblastoma cells express functional corticotropin-releasing hormone receptors. 133 48

Retinoblastoma protein (RB) is a tumor suppressor gene product involved in embryogenesis and cell cycle progression. One of the major mechanisms leading to RB dysfunction is complex formation with viral oncoproteins using the common RB binding motif Leu X Cys X Glu (LXCXE) which has also been identified in cellular ligands, e.g., RBP-1 and RBP-2. p107, a cellular protein with RB sequence homology, has been shown to bind to the same viral oncoproteins associating with RB and is therefore thought to contribute to cell cycle regulation. It has recently been suggested that insulin stimulates gene transcription through direct association with an, as yet, unidentified intracellular transcription factor. Due to the central roles of RB and p107 in coupling external growth signals with the progression of the cell cycle clock, we have hypothesized that these two proteins might be candidates for mediating the effects of insulin on DNA. We report here the identification of a region in the B-chain of human insulin that has the sequence LXCXE. Based on this finding we predict that the insulin B-chain may interact with RB and/or p107. Since we have also identified sequences hydropathically related to LXCXE in insulin-like growth factor I (IGF-I) and II (IGF-II), but not in relaxin, nerve growth factor, epidermal growth factor, glucagon or beta-endorphin, we further propose that both IGF-I and -II may assemble with RB and/or p107, too. Moreover, binding sites on RB and p107 identical with those suggested for viral oncoproteins and cellular ligands are predicted for insulin/IGF-I/IGF-II by using the hydropathic complementarity approach.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Proposed interaction between insulin and retinoblastoma protein. 133 81

Two human retinoblastoma cell lines (Y79 and McA) were evaluated for the presence of binding sites for human beta-endorphin (beta h-EP). Using tritiated beta h-EP (3H-beta h-EP) and synthetic beta-EP analogues, it was possible to demonstrate binding sites for 3H-beta h-EP with an ED50 of 3.5 nM in Y79 cells and 8 nM in McA cells respectively. The non-opioid segment [beta h-EP-(6-31)] retained about 20% relative potency in Y79 and 40% in McA in displacing the tritiated hormone when compared with beta h-EP. Camel beta-EP had a relative potency of less than 1% and beta h-EP-(1-27) was inactive in both cells in doses as high as 4 microM. Taken together with previous reports on similar binding sites in human neuroblastoma and glioblastoma cell lines, it appears that cell lines of neural origin have binding sites for the COOH-terminal of human beta-EP.
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PMID:Human retinoblastomas have binding sites for the COOH-terminal segment of human beta-endorphin. 300 97

In human Y-79 retinoblastoma cells, corticotropin-releasing hormone (CRH) stimulates adenylyl cyclase activity and increases cyclic AMP accumulation. Different CRH analogues mimic the CRH stimulation of adenylyl cyclase and show similar sensitivity to the CRH receptor antagonist alpha-helical CRH9-41. Vasoactive intestinal peptide (VIP) also increases the enzyme activity but less potently than CRH, and its effect is counteracted by the VIP receptor antagonist [D-p-Cl-Phe6,Leu17]VIP. The VIP antagonist does not affect the response to CRH. The CRH-stimulated adenylyl cyclase activity is amplified by Mg2+, is inhibited by submicromolar concentrations of Ca2+, and requires GTP. Moreover, the CRH stimulation is reduced by pretreatment of cells with cholera toxin and by incubation of membranes with the RM/1 antibody, which recognizes the C-terminus of the alpha subunit of Gs. In immunoblots, the RM/1 antibody identifies a doublet of 45 and 52 kDa. Two proteins of similar molecular weights are ADP-ribosylated by cholera toxin. These data demonstrate that in human Y-79 retinoblastoma cells, specific CRH receptors stimulate cyclic AMP formation by interacting with Gs and by affecting a Ca(2+)-inhibitable form of adenylyl cyclase.
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PMID:Coupling of corticotropin-releasing hormone receptors to adenylyl cyclase in human Y-79 retinoblastoma cells. 779 37

In this study we have identified specific binding sites for corticotropin-releasing hormone (CRH) in human Y-79 retinoblastoma cell membranes by using 125I-Tyr-ovine CRH (125I-oCRH) as radioligand. Binding at 19 degrees C was rapid with steady state being reached within 20 min, reversible and linear with membrane protein concentration. The 125I-oCRH binding was enhanced by Mg2+ and inhibited by the GTP analogue guanosine 5'-O-(3'-thiotriphosphate). Y-79 cell membranes exhibited two populations of binding sites, a high-affinity site with an apparent dissociation constant (KD) of 1 nM and a low-affinity site with an apparent KD of 500 nM. 125I-oCRH binding was completely antagonized by human/rat CRH, [Met(O)21]oCRH, alpha-helical CRH9-41, urotensin I, and sauvagine with a rank order of potency similar to that displayed by CRH receptors of other tissues. These data describe for the first time the presence of specific CRH-binding sites in retinal cells. The Y-79 cell line may therefore constitute a valuable model in which to study CRH action on retinal cells.
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PMID:Human Y-79 retinoblastoma cells exhibit specific corticotropin-releasing hormone binding sites. 779 38

The endogenous opioid beta-endorphin, a derivative of proopiomelanocortin, stimulates the growth of cloned human small cell lung carcinoma. The present hypothesis states that mutations of the retinoblastoma gene (a tumor suppressor gene) associated to the malignant transformation of bronchial cells would trigger a cascade of biomolecular events leading to 'de novo' proopiomelanocortin expression in small cell lung carcinoma.
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PMID:A novel hypothesis: specific oncogenes and tumor suppression genes are involved in the expression of the proopiomelanocortin gene by small cell lung cancer. 793 88

Humans with a germline mutation of the RB gene are predisposed to retinoblastoma with a 90% penetrance and are at higher risk for other rare tumors. We have established a mouse strain carrying a germ-line mutation of the Rb-1 gene. Here we describe a nearly 100% incidence of spontaneous pituitary tumors which arise in Rb-1 heterozygous mice from ages 2 to 11 months. Histological and immunological analysis indicate that these tumors originate from the intermediate lobe of the pituitary gland, which is a vestigial structure in adult humans. Progression of the tumors can be followed by the elevated level of a specific proteolytic product of pro-opiomelanocortin prohormone, alpha-melanocyte stimulating hormone, in the circulating blood of the tumor-bearing animals. Multiple foci are frequently seen in the tiny intermediate lobe of the pituitary gland which contains approximately 1.5 x 10(5) cells. The tumor tissues invariably lose expression of full-length Rb protein due to loss of the single wild-type Rb-1 allele. The Rb knock out mouse strain provides a unique model for addressing tissue-specific tumor predisposition by inactivation of a ubiquitously expressed tumor suppressor gene.
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PMID:Heterozygous Rb-1 delta 20/+mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. 813 5

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a new 2-aminothiazole derivative, shows nanomolar affinity for human cloned or native corticotrophin-releasing factor (CRF)(1) receptors (pK(i) values of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF(1) versus CRF(2 alpha) receptor and CRF binding protein. SSR125543A antagonizes CRF-induced stimulation of cAMP synthesis in human retinoblastoma Y 79 cells (IC(50) = 3.0 +/- 0.4 nM) and adrenocorticotropin hormone (ACTH) secretion in mouse pituitary tumor AtT-20 cells. SSR125543A is devoid of agonist activity in these models. Its brain penetration was demonstrated in rats by using an ex vivo [(125)I-Tyr(0)] ovine CRF binding assay. SSR125543A displaced radioligand binding to the CRF(1) receptor in the brain with an ID(50) of 6.5 mg/kg p.o. (duration of action >24 h). SSR125543A also inhibited the increase in plasma ACTH levels elicited in rats by i.v. CRF (4 microg/kg) injection (ID(50) = 1, 5, or 5 mg/kg i.v., i.p., and p.o., respectively); this effect lasted for more than 6 h when the drug was given orally at a dose of 30 mg/kg. SSR125543A (10 mg/kg p.o.) reduced by 73% the increase in plasma ACTH levels elicited by a 15-min restraint stress in rats. Moreover, SSR125543A (20 mg/kg i.p.) also antagonized the increase of hippocampal acetylcholine release induced by i.c.v. injection of 1 microg of CRF in rats. Finally, SSR125543A reduced forepaw treading induced by i.c.v. injection of 1 microg of CRF in gerbils (ID(50) = approximately 10 mg/kg p.o.). Altogether, these data indicate that SSR125543A is a potent, selective, and orally active CRF(1) receptor antagonist.
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PMID:4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A): a potent and selective corticotrophin-releasing factor(1) receptor antagonist. I. Biochemical and pharmacological characterization. 1190 90

The retinoblastoma protein (pRB), the product of the retinoblastoma gene, is a key regulator of the cell cycle, affecting apoptosis, proliferation and differentiation. Dysregulation of pRB is implicated in the pathogenesis of many cancers, including malignant melanoma. Recently we demonstrated that alpha-melanocyte-stimulating hormone (alpha-MSH)-induced activation of p38 mitogen-activated protein (MAP) kinase leads to differentiation of B16 murine melanoma cells. The current study assesses the ability of alpha-MSH to activate p38 MAP kinase in COLO 853 human melanoma cells and determines whether this is linked to modulation of pRB activity. Treatment of COLO 853 cells with alpha-MSH induced time- and concentration-dependent increases in the phosphorylation of p38 MAP kinase, which corresponded with its ability to induce melanogenesis and inhibit cell growth. SB 203580, a selective inhibitor of p38 MAP kinase, blocked both the alpha-MSH-induced melanogenic response and inhibition of cell growth. Cell cycle analysis using flow cytometry revealed that treatment of COLO 853 cells with alpha-MSH for 72 h led to an increase in the proportion of cells in the G(1) phase and a marked reduction in the amount of phosphorylated pRB. Both of these effects were reversed by pre-treatment of cells with SB 203580. In summary, we have demonstrated for the first time that the alpha-MSH-induced differentiation of COLO 853 human melanoma cells proceeds via a p38 MAP kinase-mediated pathway and is associated with decreased pRB phosphorylation and accumulation of cells in the G(1) phase.
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PMID:Differentiation of human melanoma cells through p38 MAP kinase is associated with decreased retinoblastoma protein phosphorylation and cell cycle arrest. 1214 Mar 74

Gene inactivation studies have suggested that the product of the retinoblastoma gene, Rb, is particularly limiting in pituitary pro-opiomelanocortin (POMC)-expressing cell lineages. Indeed, in Rb knock-out mice, these cells develop tumors with high frequency. To understand the implication of limiting Rb expression in these cells, we investigated the action of Rb and its related pocket proteins, p107 and p130, on POMC gene transcription. This led to the identification of the neurogenic basic helix-loop-helix transcription factor, NeuroD1, as a target of Rb action. Rb and to a lesser extent p107, but not p130, enhance NeuroD1-dependent transcription, and this activity appears to depend on direct protein interactions between the Rb pocket and the helix-loop-helix domain of NeuroD1. In vivo, NeuroD is found in a complex that includes Rb and also the orphan nuclear receptor NGFI-B, which mediates corticotropin-releasing hormone activation of POMC transcription. The formation of a similar complex in vitro requires the presence of Rb as a bridge between NeuroD and NGFI-B. In POMC-expressing AtT-20 cells, Rb and p107 are present on the POMC promoter and inhibition of their expression through small interfering RNA decreases POMC mRNA levels. The action of Rb and its related proteins on POMC transcription may contribute to the establishment and/or maintenance of the differentiation phenotype.
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PMID:Retinoblastoma and the related pocket protein p107 act as coactivators of NeuroD1 to enhance gene transcription. 1570 40


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