Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A metalloendopeptidase (MEP) isolated from rabbit liver microsomes with substrate specificity for peptides containing Arg at the P1 and P4 positions has recently proved to be identical to soluble angiotensin-binding protein present in the cytosol. Here we describe the peptide-degrading specificity of MEP, determined using various bioactive peptides and novel fluorogenic substrates for the enzyme. MEP degraded oligopeptides, including bradykinin, alpha-neoendorphin, bovine adrenal medulla dodecapeptide, substance P, bombesin, neurotensin, and alpha-endorphin, but not polypeptides such as reduced lysozyme and histone H4, hence, MEP probably belongs to the family of endo-oligopeptidases. It cleaved most preferentially at the -Phe-Ser- bond of bradykinin (kcat/Km = 2.8 x 10(4) M-1.S-1) but did not cleave high molecular weight and low molecular weight kininogens, the precursors of bradykinin. MEP did not cleave angiotensin I, dynorphin A 1-13, somatostatin, and luteinizing hormone-releasing hormone, some of which are good substrates for metalloendopeptidase-24.15, metalloendopeptidase-24.16, N-arginine dibasic convertase, and yeast endopeptidase-24.15 related peptidase. An active site-directed inhibitor of metalloendopeptidase-24.15, N-[1-(R,S)-carboxyl-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate also had no effects on the amidolytic activity of MEP. Based on the cleavage sites of bioactive peptides and processing sites of vitamin K-dependent proproteins, intramolecularly quenched fluorogenic peptide substrates were newly synthesized. Among the thirteen substrates used, the most reactive was 2-aminobenzoyl-Ala-Arg-Val-Arg-Arg-Ala- Asn-Ser-2,4-dinitroanilinoethylamide (kcat/Km = 9.3 x 10(5) M-1.S-1). An angiotensin antagonist, [Sar1, Ala8]-angiotensin II, inhibited hydrolysis of the substrate by MEP in a competitive manner (Kl = 7.6 microM). MEP cleaved oligopeptides even on the carboxyl side of proline residue and these peptides are resistant to hydrolysis by the cytosol-derived proteasome, therefore MEP may participate in the catabolism of oligopeptides in the cytosol, together with other endo-oligopeptidases.
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PMID:Substrate specificity of rabbit liver metalloendopeptidase and its new fluorogenic peptide substrates. 857 4

The aim of this study was the characterization of the intracellular effectors of the antiproliferative activity of somatostatin in PC Cl3 thyroid cells. Somatostatin inhibited PC Cl3 cell proliferation through the activation of a membrane phosphotyrosine phosphatase. Conversely, PC Cl3 cells stably expressing the v-mos oncogene (PC mos) were completely insensitive to the somatostatin antiproliferative effects since somatostatin was unable to stimulate a phosphotyrosine phosphatase activity. In PC mos cells basal phosphotyrosine phosphatase activity was also reduced, suggesting that the expression of a specific phosphotyrosine phosphatase was impaired in these transformed cells. We suggested that this phosphotyrosine phosphatase could be r-PTP eta whose expression was abolished in the PC mos cells. To directly prove the involvement of r-PTP eta in somatostatin's effect, we stably transfected this phosphatase in PC mos cells. This new cell line (PC mos/PTP eta) recovered somatostatin's ability to inhibit cell proliferation, showing dose-dependence and time course similar to those observed in PC Cl3 cells. Conversely, the transfection of a catalytically inactive mutant of r-PTP eta did not restore the antiproliferative effects of somatostatin. PC mos/PTP eta cells showed a high basal phosphotyrosine phosphatase activity which, similarly to PC Cl3 cells, was further increased after somatostatin treatment. The specificity of the role of r-PTP eta in somatostatin receptor signal transduction was demonstrated by measuring its specific activity after somatostatin treatment in an immunocomplex assay. Somatostatin highly increased r-PTP eta activity in PCCl3 and PC mos/PTP eta (+300%, P < 0.01) but not in PCmos cells. Conversely, no differences in somatostatin-stimulated SHP-2 activity, (approximately +50%, P < 0.05), were observed among all the cell lines. The activation of r-PTP eta by somatostatin caused, acting downstream of MAPK kinase, an inhibition of insulin-induced ERK1/2 activation with the subsequent blockade of the phosphorylation, ubiquitination, and proteasome degradation of the cyclin-dependent kinase inhibitor p27(kip1). Ultimately, high levels of p27(kip1) lead to cell proliferation arrest. In conclusion, somatostatin inhibition of PC Cl3 cell proliferation requires the activation of r-PTP eta which, through the inhibition of MAPK activity, causes the stabilization of the cell cycle inhibitor p27(kip1).
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PMID:The activation of the phosphotyrosine phosphatase eta (r-PTP eta) is responsible for the somatostatin inhibition of PC Cl3 thyroid cell proliferation. 1157 15

Regulation of SNARE proteins by glucose in pancreatic islets is complex and insufficiently clarified. We aimed to study effects of glucose per se separate from enhancing effects on exocytosis. A 24h culture of rat islets at elevated glucose (27 mmol/L) increased t-SNARES (SNAP-25, syntaxin) (Western blotting). Co-culture with diazoxide, which inhibits glucose-induced insulin secretion, reversed these effects. Effects on SNAP-25 were similar in human and rat islets. Effects of diazoxide were mimicked by blocking secretion with somatostatin (rat islets). Blocking secretion by cooling abolished both glucose and diazoxide effects on SNAP-25. Total SNAP-25 mRNA as well as isoforms alpha and beta were increased by 24-h elevated glucose. Diazoxide failed to reverse the glucose effects on mRNA. However, effects of diazoxide on SNAP-25 protein were nullified by proteasome inhibitors (ALLN, MG-132, and epoxomicin) but not by lysosomal inhibition (NH(4)Cl). Exocytosis per se modifies SNAREs by a process linked to proteasomal activation.
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PMID:Evidence that insulin secretion influences SNAP-25 through proteasomal activation. 1575 69

Patients with well-differentiated neuroendocrine tumours of the gastrointestinal tract often present with metastases and hormonal symptoms. These patients can be palliated by interventional tumour reduction and medical treatment with somatostatin analogues; no effective chemotherapy is available. Radionuclide therapy via somatostatin receptors is one new therapeutic alternative. The recognition that neuroendocrine tumours express specific receptors for growth factors and chemokines, which are of importance for tumour growth, vascularization, and spread, may open the way for new therapeutic approaches. The signalling pathways in carcinoid tumours are incompletely explored. This review summarizes potential new treatment strategies from clinical and experimental studies, e.g. inhibition of angiogenesis, targeting of growth factors or their receptors by tyrosine kinase inhibitors, interference with specific cellular pathways (mTOR, PI3K, RAS/RAF, Notch), and also inhibition of the proteasome and histone deacetylation. Combining targeted therapy with chemotherapy, or using drugs to sensitize for radionuclide therapy, may enhance the treatment outcome.
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PMID:New medical strategies for midgut carcinoids. 2040 94

Clinical application of proteasome inhibitors (PIs) is so far limited to peripheral blood cancers due to the pronounced cytotoxicity towards all cell types. Targeted delivery of PIs could permit the treatment of other cancers along with decreasing side effects. Herein we describe the first small-molecule proteasome inhibitor conjugate for targeted delivery, created by fusing PIs to a synthetic ligand of somatostatin receptors, which are highly expressed in a variety of tumors. X-ray crystallographic studies and in vitro IC50 measurements demonstrated that addition of the cyclopeptide octreotide as a targeting vehicle does not affect the PI's binding mode. The cytotoxicity of the conjugate against somatostatin-receptor-expressing cells was up to 11-fold higher than that of a non-targeting surrogate. We have therefore established PIs as a new payload for drug conjugates and have shown that targeted delivery thereof could be a promising approach for the broader application of this FDA-approved class of compounds.
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PMID:Targeted Delivery of Proteasome Inhibitors to Somatostatin-Receptor-Expressing Cancer Cells by Octreotide Conjugation. 2647 Nov 24