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)

The heptapeptide TT-232 is structurally related to the hypothalamic hormone somatostatin and shows promise as an anticancer drug because of its tumor-specific cytotoxic effects. Apart from the ability to induce apoptosis, the synthetic peptide can trigger an alternative pathway that leads to cell cycle arrest in certain tumor cell systems. We found that pulse treatment with TT-232 blocks the cell cycle G(1)/S transition irreversibly in A431 cells. Investigation of the TT-232 signaling pathway yielded results similar to those reported for somatostatin although its affinity to the somatostatin receptor 1 is significantly reduced. We show that functional protein kinase C (PKC) delta as well as c-Src are necessary mediators of the TT-232 cytostatic effect and we propose a signaling pathway that leads to cell cycle arrest.
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PMID:The antitumor somatostatin analogue TT-232 induces cell cycle arrest through PKCdelta and c-Src. 1144 68

Somatostatin receptors and glutamate N-methyl-D-aspartate (NMDA) receptors coexist on hippocampal noradrenergic axon terminals. Activation of somatostatin receptors was previously found to positively influence the function of NMDA receptors regulating norepinephrine release. The somatostatin receptors involved were pharmacologically characterized as sst5 type in experiments in Mg2+-free solutions. Here, we first confirm the pharmacology of these receptors using selective sst5 ligands in Mg2+-containing solutions. Moreover, we show by Western blot that the sst5 protein exists on purified hippocampal synaptosomal membranes. We then investigated the pathways connecting the two receptors using as a functional response the release of norepinephrine from rat hippocampal synaptosomes in superfusion. The release of norepinephrine evoked by somatostatin-14 plus NMDA/glycine was partly prevented by the protein kinase C inhibitor GF109203X [dihydrochloride3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione] and by the nonreceptor tyrosine kinase (Src) inhibitors PP2 [3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-D]pyrimidin-4-amine] and lavendustin A; it was largely and almost totally abolished by the phospholipase C inhibitor U73122 [1-(6-[([17beta]-3-methoxyextra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione] and by the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93 [N-(2-[N-[4-chlorocinnamyl]-N-methyl-amino-methyl]phenyl)-N-(2-hydroxyethyl)-4-methoxy-benzene-sulfonamide-phosphate salt], respectively; and it was unaffected by the protein kinase A inhibitor H89 [N-(2-[p-bromocinnamylamino]ethyl)5-isoquinolinesulfonamide hydrochloride]. The norepinephrine release evoked by somatostatin-14/NMDA/glycine was inhibited when anti-phosphotyrosine antibodies had been entrapped into synaptosomes. Entrapping the recombinant activated tyrosine kinase pp60(c-Src) strongly potentiated the release of norepinephrine elicited by NMDA/glycine in Mg2+-free medium but failed to permit NMDA receptor activation in presence of external Mg2+ ions. The results suggest the involvement of CaMKII in the sst5 receptor-mediated activation of NMDA receptors in presence of Mg2+ and of the PLC/PKC/Src pathway in the up-regulation of the ongoing NMDA receptor activity.
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PMID:Somatostatin-induced activation and up-regulation of N-methyl-D-aspartate receptor function: mediation through calmodulin-dependent protein kinase II, phospholipase C, protein kinase C, and tyrosine kinase in hippocampal noradrenergic nerve endings. 1560 72

Medications targeting the somatostatin type 2 receptor (SSTR2) have been employed for pancreatic inflammations and cancers, possibly via the regulation of the transcription factor nuclear factor kappaB (NFkappaB). Here we demonstrate that in tumoral pancreatic acinar AR42J cells, activation of SSTR2 leads to stimulation of the inhibitor kappaB kinase (IKK)/NFkappaB signaling cascade via pertussis toxin-insensitive G proteins in a time- and dose-dependent manner. The inability of G(q/11) and G(12/13) proteins to activate IKK/NFkappaB by SSTR2 in transfected human embryonic kidney 293 cells and the lack of Galpha(16) in AR42J cells suggested a possible role of Galpha(14) in mediating SSTR2-induced responses. This regulatory role of Galpha(14) was further confirmed by the activation of IKK and NFkappaB in human embryonic kidney 293 cells expressing SSTR2 and Galpha(14) upon induction. The stimulatory effect of Gbeta(1)gamma(2) and the abrogation by overexpressing transducin confirmed the participation of Gbetagamma in SSTR2-mediated IKK/NFkappaB activation. By the application of specific inhibitors and dominant negative mutants, phospholipase Cbeta, protein kinase C, and calmodulin-dependent kinase II were shown to be involved in SSTR2-induced responses. Inhibition of c-Src and numerous intermediates, including Ras, Raf-1 kinase, MEK1/2, along with the extracellular signal-regulated kinase cascade attenuated somatostatin-mediated IKK/NFkappaB activation. Although c-Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK) were also stimulated by SSTR2, suppression of these two MAPKs was ineffective in altering the somatostatin-mediated responses. Similar results were also obtained using AR42J cells. These data suggest that activation of the IKK/NFkappaB signaling cascade by SSTR2 requires a complicated network consisting of Galpha(14) and multiple intermediates.
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PMID:Activation of nuclear factor {kappa}B by somatostatin type 2 receptor in pancreatic acinar AR42J cells involves G{alpha}14 and multiple signaling components: a mechanism requiring protein kinase C, calmodulin-dependent kinase II, ERK, and c-Src. 1611 92