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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The opposing effects on proliferation mediated by G-protein-coupled receptor isoforms differing in their COOH termini could be correlated with the abilities of the receptors to differentially activate p38, implicated in apoptotic events, or phosphatidylinositol 3-kinase (PI 3-K), which provides a source of survival signals. These contrasting growth responses of the somatostatin sst(2) receptor isoforms, which couple to identical Galpha subunit pools (Galpha(i3) > Galpha(i2) >> Galpha(0)), were both inhibited following betagamma sequestration. The sst(2(a)) receptor-mediated ATF-2 activation and inhibition of proliferation induced by basic fibroblast growth factor (bFGF) were dependent on prolonged phosphorylation of p38. In contrast, cell proliferation and the associated transient phosphorylation of Akt and p70(rsk) induced by sst(2(b)) receptors were blocked by the PI 3-K inhibitor LY 294002. Stimulation with bFGF alone had no effect on the activity of either p38 or Akt but markedly enhanced p38 phosphorylation mediated by sst(2(a)) receptors, suggesting that a complex interplay exists between the transduction cascades activated by these distinct receptor types. In addition, although all receptors mediated a sustained activation of extracellular signal-regulated kinases (ERK1 and ERK2), induction of the tumor suppressor p21(cip1) was detected only following amplification of ERK and p38 phosphorylation by concomitant bFGF and sst(2(a)) receptor activation. Expression of constitutively active Akt in the presence of a p38 inhibitor enabled a proliferative response to be detected in sst(2(a)) receptor-expressing cells. These findings demonstrate that the duration of activation and a critical balance between the mitogen-activated protein kinase and PI 3-K pathways are important for controlling cell proliferation and that the COOH termini of the sst(2) receptor isoforms may determine the selection of appropriate betagamma-pairings necessary for interaction with distinct kinase cascades.
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PMID:Receptor isoforms mediate opposing proliferative effects through gbetagamma-activated p38 or Akt pathways. 1091 80

A large body of data from a number of different laboratories worldwide has demonstrated a general tendency for reduced adrenocortical responsiveness in CFS. It is still not clear if this is secondary to CNS abnormalities leading to decreased activity of CRH- or AVP-producing hypothalamic neurons. Primary hypofunction of the CRH neurons has been described on the basis of genetic and environmental influences. Other pathways could secondarily influence HPA axis activity, however. For example, serotonergic and noradrenergic input acts to stimulate HPA axis activity. Deficient serotonergic activity in CFS has been suggested by some of the studies as reviewed here. In addition, hypofunction of sympathetic nervous system function has been described and could contribute to abnormalities of central components of the HPA axis. One could interpret the clinical trial of glucocorticoid replacement in patients with CFS as confirmation of adrenal insufficiency if one were convinced of a positive therapeutic effect. If patient symptoms were related to impaired activation of central components of the axis, replacing glucocorticoids would merely exacerbate symptoms caused by enhanced negative feedback. Further study of specific components of the HPA axis should ultimately clarify the reproducible abnormalities associated with a clinical picture of CFS. In contrast to CFS, the results of the different hormonal axes in FMS support the assumption that the distortion of the hormonal pattern observed can be attributed to hyperactivity of CRH neurons. This hyperactivity may be driven and sustained by stress exerted by chronic pain originating in the musculoskeletal system or by an alteration of the CNS mechanism of nociception. The elevated activity of CRH neurons also seems to cause alteration of the set point of other hormonal axes. In addition to its control of the adrenal hormones, CRH stimulates somatostatin secretion at the hypothalamic level, which, in turn, causes inhibition of growth hormone and thyroid-stimulating hormone at the pituitary level. The suppression of gonadal function may also be attributed to elevated CRH because of its ability to inhibit hypothalamic luteinizing hormone-releasing hormone release; however, a remote effect on the ovary by the inhibition of follicle-stimulating hormone-stimulated estrogen production must also be considered. Serotonin (5-HT) precursors such as tryptophan (5-HTP), drugs that release 5-HT, or drugs that act directly on 5-HT receptors stimulate the HPA axis, indicating a stimulatory effect of serotonergic input on HPA axis function. Hyperfunction of the HPA axis could also reflect an elevated serotonergic tonus in the CNS of FMS patients. The authors conclude that the observed pattern of hormonal deviations in patients with FMS is a CNS adjustment to chronic pain and stress, constitutes a specific entity of FMS, and is primarily evoked by activated CRH neurons.
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PMID:Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome. 1108 55

Somatostatin is a peptide with a multitude of functions in the central nervous system and the periphery. It mediates its actions by binding to high-affinity G-protein coupled receptors, genes for five of which (sst1-sst5) have recently been cloned. The somatostatin sst2 receptor exists as two splice variants, sst2(a) and sst2(b) receptors, which differ in length and composition of their intracellular carboxy-termini. In this review, we describe the localisation of the two receptor isoforms in the central nervous system, the periphery and also in tumour tissue. Furthermore, we summarise and discuss the data on the functional properties of the recombinant splice variants that have been generated so far, which include activation of extracellular acidification rates, inhibition of adenylate cyclase and activation of MAP-kinases as well as the transcription factor Elk-1.
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PMID:Characterisation of somatostatin sst2 receptor splice variants. 1108

The mitogen activated protein (MAP) kinase cascade represents one of the major regulator of cell growth by hormones and growth factors. However, although the activation of this intracellular pathway has been often regarded as mediator of cell proliferation, in many cell types the increase in MAP kinase (also called extra-cellular signal regulated kinase: ERK) activity may result in cell growth arrest, depending on the length or the intensity of the stimulation. In this review we examine recent data concerning the effects of somatostatin on the MAP kinase cascade through one of its major receptor subtype, the somatostatin receptor 1 (SSTR1), stably expressed in CHO-K1 cells. Somatostatin inhibits the proliferative effects of basic FGF (bFGF) in CHO-SSTR1 cell line. However, in these cells, somatostatin robustly activates the MAP kinase and augments bFGF-induced stimulation of ERK. We show that the activation of ERK via SSTR1 is mediated by the betagamma subunit of a pertussis toxin-sensitive G-protein and requires both the small G protein Ras and the serine/threonine kinase Raf-1. Moreover the phosphatidyl inositol-3kinase and the cytosolic tyrosine kinase c-src participate in the signal transduction regulated by SSTRI to activate ERK, as well as it is involved the protein tyrosine phosphatase (PTP) SHP-2. Previous studies have suggested that somatostatin-stimulated PTP activity mediates the growth inhibitory actions of somatostatin, in CHO-SSTR1 cells. Thus, the activation of SHP-2 by SSTR1 may mediate the antiproliferative activity of somatostatin. SHP-2 may. in turn, regulate the activity of kinases upstream of ERK that require tyrosine dephosphorylation to be activated, such as c-src. Finally, the synergism between somatostatin and bFGF in the activation of ERK results in an increased expression of the cyclin-dependent kinase inhibitor p21cip/WAF1 as molecular effector of the antiproliferative activity of somatostatin.
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PMID:Somatostatin receptor 1 (SSTR1)-mediated inhibition of cell proliferation correlates with the activation of the MAP kinase cascade: role of the phosphotyrosine phosphatase SHP-2. 1108 1

The somatostatin receptor subtype sst2A is highly expressed, non-mutated and functionally active in gliomas. After stimulation of cultivated human U343 glioma cells with somatostatin, octreotide (sst2-, sst3- and sst5-selective peptide agonist) or the sst2-selective non-peptide agonist L-054,522 multiple signal transduction pathways are induced: elevated cAMP levels are reduced, protein tyrosine phosphatases (especially SHP2) are activated and mitogen-activated protein kinases are inhibited. Stimulation of the phosphatases resulted in dephosphorylation of activated receptors for EGF and PDGF (epidermal and platelet-derived growth factor), and as a consequence the mitogen-activated protein kinases ERK 1 and 2 (p42/p44) were de-phosphorylated in co-stimulation experiments. Furthermore, somatostatin or sst2-selective agonists reduced EGF-stimulated expression of the AP-1 complex (c-jun/c-jun) on the transcriptional and translational level. These experiments show that the interaction of stimulatory and inhibitory receptors are important mechanisms for the regulation of signal cascades and gene expression.
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PMID:Influence of the somatostatin receptor sst2 on growth factor signal cascades in human glioma cells. 1122 55

TT-232 is a somatostatin analogue containing a five-residue ring structure. The present report describes TT-232-induced signalling events in A431 cells, where a 4-h preincubation with the peptide irreversibly induced a cell death program, which involves DNA-laddering and the appearance of shrunken nuclei, but is unrelated to somatostatin signalling. Early intracellular signals of TT-232 include a transient two-fold activation of the extracellular signal-regulated kinase (ERK2) and a strong and sustained activation of the stress-activated protein kinases c-Jun NH(2)-terminal kinase (JNK)/SAPK and p38MAPK. Blocking the signalling to ERK or p38MAPK activation had no effect on the TT-232-induced cell killing. At the commitment time for inducing cell death, TT-232 decreased EGFR-tyrosine phosphorylation and prevented epidermial growth factor (EGF)-induced events like cRaf-1 and ERK2 activation. Signalling to ERK activation by FCS, phorbol 12-myristate 13-acetate (PMA) and platelet-derived growth factor (PDGF) was similarly blocked. Our data suggest that TT-232 triggers an apoptotic type of cell death, concomitant with a strong activation of JNK and a blockade of cellular ERK2 activation pathways.
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PMID:The somatostatin analogue TT-232 induces apoptosis in A431 cells: sustained activation of stress-activated kinases and inhibition of signalling to extracellular signal-regulated kinases. 1160 82

This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.
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PMID:Guidelines for diagnosis and therapy of MEN type 1 and type 2. 1205 Feb 90

Endocrine cells containing gastrin/cholecystokinin (CCK)-like immunoreactivity were localized to the islet tissue in the pancreas of the spiny dogfish. Most of these cells were located in the 'intestinal' lobe of the pancreas; only occasional cells were observed in the 'splenic' lobe. The gastrin/CCK-like immunoreactive cells were often co-localized with the 'classical' pancreas hormones (insulin, glucagon and somatostatin). Radioimmunoassay of water extracts with a C-terminally directed antiserum revealed high levels of immunoreactive material in the intestinal part (48.6 +/- 19.9 pmol/g) and lower levels (4.5 +/- 0.6 pmol/g) in the splenic part. Acetic acid extracts of the intestinal lobe contained low levels (6.8 +/- 3.3 pmol/g) of gastrin/CCK-like immunoreactivity, whereas corresponding extracts of the splenic part showed no immunoreactivity. When the extracts were subjected to DEAE ion-exchange chromatography the gastrin/CCK-like peptides eluted as a major peak. After Sephadex gel filtration, pooled immunoreactive material from the main DEAE chromatographic peak eluted at a position close to that of CCK4. Further characterization by ion-exchange and reversed-phase HPLC showed that, in general, the immunoreactive material behaved like the shorter forms of the gastrin/CCK family (CCK4/G5 and CCK8/Cae 3-10).
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PMID:Endocrine cells with gastrin/cholecystokinin-like immunoreactivity in the pancreas of the spiny dogfish, Squalus acanthias. 1250 16

The molecular basis of testicular germ cell tumourigenesis are not well elucidated. Growth factors regulate cell growth, differentiation and apoptosis. Major families of growth factors are present in the male gonad from early fetal development to adult life. They are involved in germ cell proliferation and differentiation. Growth signalling pathways suffer deregulation in many human malignancies. Given the importance of growth signals in normal testicular development and their acquired deregulation in most human cancers, growth factors and signalling molecules that have been implicated in the genesis of testicular germ cell tumours, are reviewed. We detected a somatic mutation of SMAD4 gene, responsible for loss of protein function in seminomas. This mutational inactivation may affect the activity of several members of TGFbeta superfamily (TGFbeta, activin, inhibin, BMP). VEGF expression has been shown to predict metastasis in seminomas. A significant association of HST-1 expression, a member of fibroblast growth factors, with the nonseminomatous phenotype and with tumour stage has been described. In contrast, C-KIT is expressed by seminomas only, from the preinvasive stage. Despite intense expression in almost all seminomas, activating mutation of C-KIT gene is seldom reported. Recently, the first animal model of classical testicular seminoma has been identified in transgenic mouse overexpressing GDNF. RET (GDNF receptor) expression is demonstrated in human seminomas, and not in nonseminomatous tumours. However, the exact molecular alterations of GDNF/RET/GFRalpha1 complex in germ cell tumours are not known. Finally, beside growth factors, other signalling molecules such as peptide hormones may be involved in testicular carcinogenesis. We have demonstrated a specific pattern of somatostatin receptors expression in each type of testicular germ cell tumours, with a loss of sst3 and sst4 in seminomas and loss of sst4 and expression of sst1 in nonseminomas only. These data suggest an antiproliferative action of somatostatin in testicular cancers. In summary, many growth factors and signalling molecules seem to represent specific markers for different histological types of germ cell tumours (seminomas versus nonseminomas) and may play a role in the differentiation of germ cell tumours. Despite a complex signalling pathway involved in the physiological functions of male gonad, little is known about the implication of this signalling network in testicular malignancies. From a practical stand-point, further studies on the role of growth factors in human germ cell tumours may offer a new therapeutical perspective with the development of specific pharmacological signalling modulators that could be used as therapeutic agents.
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PMID:Growth regulatory factors and signalling proteins in testicular germ cell tumours. 1275 64

Neuroendocrine tumors are rare neoplasms originating from cells belonging to a diffuse or confined neuroendocrine system and characterized by a significant histopatologic and biologic heterogeneity. Timely diagnosis is delayed because they are often clinically silent for their low differentiation grade and the absence of any symptom due to abnormal hormone release. For these reasons, many neuroendocrine tumor patients are not treated medically for metastatic or inoperable disease. Medical treatments include biotherapy, with interferon-alpha and somatostatin analogues, and chemotherapy. Somastostatin analogues are widely used in patients with symptoms and with carcinoids of low differentiation grade. Interferon-alpha is used alone or in combination with somatostatin analogues. Chemotherapy is active in patients with poorly differentiated neuroendocrine tumors. The therapeutic regimen commonly used is the combination of cisplatinum and etoposide. In conclusion, no standard treatment for NET has yet been identified, and the response criteria suggested by ITMO remain a reference point. The clinical aspect of the disease and biologic features suggest the identification of neuroendocrine tumors patients suitable for the appropriate therapies. On these bases, it is recommended that diagnosis and treatment of neuroendocrine tumors be carried out at specialized oncological centers involved in clinical trials.
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PMID:Current treatments of neuroendocrine tumors role of biotherapy and chemotherapy. 1284 54


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