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)

Here we investigated roles of the pituitary bone morphogenetic protein (BMP) system in modulating GH production regulated by a somatostatin analog, octreotide (OCT) and a dopamine agonist, bromocriptine (BRC) in rat pituitary somatolactotrope tumor GH3 cells. The GH3 cells were found to express BMP ligands, including BMP-4 and BMP-6; BMP type-1 and type-2 receptors (except the type-1 receptor, activin receptor-like kinase (ALK)-6); and Smad signaling molecules. Forskolin stimulated GH production in accordance with cAMP synthesis. BRC, but not OCT, suppressed forskolin-induced cAMP synthesis by GH3 cells. Individual treatment with OCT and BRC reduced forskolin-induced GH secretion. A low concentration (0.1 microM) of OCT in combination with BRC (1-100 microM) exhibited additive effects on reducing GH and cAMP production induced by forskolin. However, a high concentration (10 microM) of OCT in combination with BRC failed to suppress GH and cAMP production. BMP-4 specifically enhanced GH secretion and cAMP production induced by forskolin in GH3 cells. BRC, but not OCT, inhibited BMP-4-induced activation of Smad1,5,8 phosphorylation and Id-1 transcription and decreased ALK-3 expression. Of note, in the presence of a high concentration of OCT, the BRC effects suppressing BMP-4-Smad1,5,8 signaling were significantly impaired. In the presence of BMP-4, a high concentration of OCT also attenuated the BRC effects suppressing forskolin-induced GH and cAMP production. Collectively, a high concentration of OCT interferes with BRC effects by reducing cAMP production and suppressing BMP-4 signaling in GH3 cells. These findings may explain the mechanism of resistance of GH reduction to a combination therapy with OCT and BRC for GH-producing pituitary adenomas.
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PMID:Involvement of bone morphogenetic protein-4 in GH regulation by octreotide and bromocriptine in rat pituitary GH3 cells. 1837 42

Several different populations of interneurons in the murine cortex, including somatostatin (SST)- or parvalbumin (PV)-expressing cells, are born in the ventral ganglionic eminences during mid-gestation and then migrate tangentially to the cortex. SST is expressed by some interneuron progenitors in the cerebral cortex and in migrating populations in the ventrolateral cortex at birth. However, PV (also known as PVALB) is not expressed by interneurons until the second postnatal week after reaching the cortex, suggesting that molecular cues in the cerebral cortex might be involved in the differentiation process. BMP4 is expressed at high levels in the somatosensory cortex at the time when the PV(+) interneurons differentiate. Treatment of cortical cultures containing interneuron precursors is sufficient to generate PV(+) interneurons prematurely and inhibit SST differentiation. Furthermore, overexpression of BMP4 in vivo increases the number of interneurons expressing PV, with a reduction in the number of SST(+) interneurons. PV(+) interneurons in the cortex express BMP type I receptors and a subpopulation displays activated BMP signaling, assessed by downstream molecules including phosphorylated SMAD1/5/8. Conditional mutation of BMP type I receptors in interneuron precursors significantly reduces the number of cortical PV(+) interneurons in the adult brain. Thus, BMP4 signaling through type I receptors regulates the differentiation of two major medial ganglionic eminence-derived interneuron populations and defines their relative numbers in the cortex.
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PMID:Differential effects of BMP signaling on parvalbumin and somatostatin interneuron differentiation. 1959 76

The mechanism by which somatostatin analogs suppress ACTH production by corticotropinomas has yet to be fully elucidated. We here studied the effects of somatostatin analogs on ACTH secretion using mouse corticotrope AtT20 cells focusing on the biological activity of bone morphogenetic proteins (BMPs). BMP ligands, receptors and Smads, and somatostatin receptors (SSTRs)-2, -3, and -5 were expressed in AtT20 cells. BMP-2, -4, -6, and -7 decreased basal ACTH production with BMP-4 effects being the most prominent. BMP-4 also inhibited CRH-induced ACTH production and proopiomelanocortin (POMC) transcription. However, the decrease in CRH-induced cAMP accumulation caused by BMP-4 was not sufficient to completely account for BMP-4 actions, indicating that ACTH suppression by BMPs was not directly linked to cAMP inhibition. CRH-activated ERK1/ERK2, p38-MAPK, stress-activated protein kinase/c-Jun NH(2)-terminal kinase, protein kinase C, and Akt pathways and CRH-induced ACTH synthesis was significantly decreased in the presence of U0126 or SB203580. Because BMPs attenuated CRH-induced ERK and p38 phosphorylation, it was suggested that BMP-4 suppresses ACTH production by inhibiting CRH-induced ERK and p38 phosphorylation. Somatostatin analogs octreotide and pasireotide (SOM230) significantly suppressed CRH-induced ACTH and cAMP production in AtT20 cells and reduced ERK and p38 phosphorylation. Notably, CRH-induced ACTH production was enhanced in the presence of noggin, a BMP-binding protein. The inhibitory effects of octreotide and SOM230 on CRH-induced ACTH production were also attenuated by noggin, implying that the endogenous BMP system plays a key role in inhibiting CRH-induced ACTH production by AtT20 cells. The findings that OCT and SOM230 up-regulated BMP-Smad1/Smad5/Smad8 signaling and ALK-3 and BMPRII and down-regulated inhibitory Smad6/7 establish that the activation of endogenous BMP system is functionally involved in the mechanism by which somatostatin analogs suppress CRH-induced ACTH production.
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PMID:Effects of bone morphogenetic protein (BMP) on adrenocorticotropin production by pituitary corticotrope cells: involvement of up-regulation of BMP receptor signaling by somatostatin analogs. 2005 21

BMP-4 plays a crucial role not only in the formation of the anterior pituitary during embryo development but also in the pathogenesis of pituitary tumors in adults. In tumor cells, BMP-4 promotes prolactin secretion and lactotroph cell proliferation through a Smad-estrogen receptor crosstalk but it inhibits ACTH production and cell proliferation of corticotrophs. In addition, BMP-4 increases GH secretion in rat pituitary tumor somatolactotroph GH3 cells and FSHbeta subunit gene transcription in the murine gonadotroph cell line, LbetaT2. Therefore, BMP-4 has a differential role on different types of pituitary tumors: it promotes pituitary prolactinoma while it inhibits corticotroph pathogenesis in Cushing's disease. The modulation of BMP-4 also plays an important role in the therapeutic mechanism of action of bromocriptine, somatostatin analogs and retinoic acid.
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PMID:Pituitary tumors: cell type-specific roles for BMP-4. 2039 28

Involvement of the pituitary BMP system in the modulation of prolactin (PRL) secretion regulated by somatostatin analogs, including octreotide (OCT) and pasireotide (SOM230), and a dopamine agonist, bromocriptine (BRC), was examined in GH3 cells. GH3 cells are rat pituitary somato-lactotrope tumor cells that express somatostatin receptors (SSTRs) and BMP system molecules including BMP-4 and -6. Treatment with BMP-4 and -6 increased PRL and cAMP secretion by GH3 cells. The BMP-4 effects were neutralized by adding a BMP-binding protein Noggin. These findings suggest the activity of endogenous BMPs in augmenting PRL secretion by GH3 cells. BRC and SOM230 reduced PRL secretion, but OCT failed to reduce the PRL level. In GH3 cells activated by forskolin, BRC suppressed forskolin-induced PRL secretion with reduction in cAMP levels. OCT did not affect forskolin-induced PRL level, while SOM230 reduced PRL secretion and PRL mRNA expression induced by forskolin. BMP-4 treatment enhanced the reducing effect of SOM230 on forskolin-induced PRL level while BMP-4 did not affect the effects of OCT or BRC. Noggin treatment had no significant effect on the BRC actions reducing PRL levels by GH3 cells. However, in the presence of Noggin, OCT elicited an inhibitory effect on forskolin-induced PRL secretion and PRL mRNA expression, whereas the SOM230 effect on PRL reduction was in turn impaired. It was further found that BMP-4 and -6 suppressed SSTR-2 but increased SSTR-5 mRNA expression of GH3 cells. These findings indicate that Noggin rescues SSTR-2 but downregulates SSTR-5 by neutralizing endogenous BMP actions, leading to an increase in OCT sensitivity and a decrease in SOM230 sensitivity of GH3 cells. In addition, BMP signaling was facilitated in GH3 cells treated with forskolin. Collectively, these findings suggest that BMPs elicit differential actions in the regulation of PRL release dependent on cellular cAMP-PKA activity. BMPs may play a key role in the modulation of SSTR sensitivity of somato-lactotrope cells in an autocrine/paracrine manner.
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PMID:Activities of bone morphogenetic proteins in prolactin regulation by somatostatin analogs in rat pituitary GH3 cells. 2097 Apr 74

In order to identify novel candidate tumor suppressor genes (TSGs) implicated in renal cell carcinoma (RCC), we performed genome-wide methylation profiling of RCC using the HumanMethylation27 BeadChips to assess methylation at > 14,000 genes. Two hundred and twenty hypermethylated probes representing 205 loci/genes were identified in genomic CpG islands. A subset of TSGs investigated in detail exhibited frequent tumor methylation, promoter methylation associated transcriptional silencing and reactivation after demethylation in RCC cell lines and down-regulation of expression in tumor tissue (e.g., SLC34A2 specifically methylated in 63% of RCC, OVOL1 in 40%, DLEC1 in 20%, TMPRSS2 in 26%, SST in 31% and BMP4 in 35%). As OVOL1, a putative regulator of c-Myc transcription, and SST (somatostatin) had not previously been linked to cancer and RCC, respectively, we (1) investigated their potential relevance to tumor growth by RNAi knockdown and found significantly increased anchorage-independent growth and (2) demonstrated that OVOL1 knockdown increased c-Myc mRNA levels.
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PMID:Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma. 2243 Aug 4

This study aims at investigating miR-196a roles using in vitro models. miR-196a was detected in small intestinal neuroendocrine tumors (SI-NETs) and lung NETs. miR-196a target prediction analysis suggested HOXA9, HOXB7, LRP4 and RSPO2 genes for further investigation. The level of these four genes is detectable in SI-NET tissue specimens at different disease stages and serum samples of untreated and somatostatin analogs treated patients with liver metastases. A miR-196a inhibitor was used to silence its effects in NET cells. We show that the four target genes were significantly upregulated at transcriptional level in silenced NET cells. HOXA9, HOXB7, LRP4 and RSPO2 encoded proteins are also upregulated at translational level in miR-196a silenced NET cells. miR-196a downstream genes BMP4, ETS1, CTNNB1, FZD5, LRP5 and LRP6 were significantly upregulated at transcriptional level in miR-196a silenced CNDT2.5 and NCI-H727 cells. In addition, miR-196a clearly does not play a role in NET cell growth control.
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PMID:Roles of miR-196a on gene regulation of neuroendocrine tumor cells. 2605 33

Dental pulp stem cells (DPSCs) are multipotent stem cells with the potential to differentiate into various cell types. For this reason, they have been proposed as an alternative source for mesenchymal stem cells. Somatostatin is a peptide hormone with an inhibitory effect on several endogenous hormones. The aim of our study is to investigate whether somatostatin can promote or inhibit differentiation of DPSCs in osteoblasts and bone tissue. DPSCs were extracted from third molars of healthy subjects, and were treated with somatostatin at the concentration of 100 ng/ml for 24 and 48 h. Gene expression in treated DPSCs was compared with untreated cells (control) in order to check the effect of somatostatin on stem cell differentiation. After 24 h of treatment many genes investigated were down-regulated in treated DPSCs vs untreated DPSCs. Significantly up-regulated gene (Fold change > 2) was the Bone Morphogenetic Protein BMP4. On the contrary somatostatin induced the over-expression of bone related genes after 48 h of treatment (i.e. BMPR1B and BMPR2). TGFB family genes and their receptors were also significantly up-regulated after 48 h of treatment. Somatostatin demonstrated to promote the self-renewal of DPSCs: in our experiments somatostatin mainly acted on TGFB family genes. Further studies are needed to explore this new way of creating bone tissue.
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PMID:EFFECT OF SOMATOSTATIN ON DENTAL PULP STEM CELLS. 2651 Nov 70

Although effective treatment regimens (surgical resection, drug treatment with dopamine agonists or somatostatin analogues, radiotherapy) have been established for the therapy of most pituitary tumours, a considerable proportion of affected patients cannot completely cured due to incomplete resection or drug resistance. Moreover, even if hormone levels have been normalized, patients with hormone-secreting tumours still show persistent pathophysiological alterations in metabolic, cardiovascular or neuropsychiatric parameters and have an impaired quality of life. In this review reasons for the discrepancy between biochemical cure and incomplete recovery from tumour-associated comorbidities are discussed and the clinical management is delineated exemplarily for patients with acromegaly and Cushing's disease. In view of the development of additional treatment concepts for the treatment of pituitary adenomas we speculate about the relevance of RSUME as a potential target for the development of an anti-angiogenic therapy. Moreover, the role of BMP-4 which stimulates prolactinoma development through the Smad signalling cascade is described and its role as putative drug target for the treatment of prolactinomas is discussed. Regarding the well-known resistance of a part of somatotropinomas to somatostatin analogue treatment, recently identified mechanisms responsible for the drug resistance are summarized and ways to overcome them in future treatment concepts are presented. Concerning novel therapeutic options for patients with Cushing's disease the impact of retinoic acid, which is currently tested in clinical studies, is shown, and the action and putative therapeutic impact of silibinin to resolve glucocorticoid resistance in these patients is critically discussed.
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PMID:GEOFFREY HARRIS AWARD 2019: Translational research in pituitary tumours. 3170 92