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)

Liver resections are usually performed under occlusion of the hepatoduodenal ligament (Pringle manoeuvre) in order to limit operative blood loss. The maximal ischemic tolerance, although individually different, is generally accepted to be 60 min. Resections of centrally located tumors require precise preparation, sometimes combined with vascular reconstructions. In such cases a prolonged ischemic time is inevitable. A save prolongation of the ischemic tolerance could be useful for extensive liver resections. In an experimental study in pigs ischemic tolerance of the liver was studied under hypothermic protection with the HTK solution of Bretschneider during 2 and 3 h. Deterioration of liver function was compared with a warm ischemia during 2 h. Results showed significantly less serum transaminase activities and better hepatic blood flow (ICG test) after an ischemia under protection with the HTK solution compared to a warm ischemia during 2 h. A prolonged ischemia during 3 h under protection with the HTK solution was well tolerated. First clinical applications of hypothermic hepatic protection during resection were successful.
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PMID:[In situ protection of the liver with Bretschneider HTK solution]. 190 77

Most cancers appear to be sporadic. However, 5 to 10% of cancers occur in genetically predisposed individuals. This inherited genetic risk is observed in syndromes such as familial polyendocrinopathies or phacomatosis such as neurofibromatosis, but also in familial aggregations of frequent cancers such as breast or colon cancers. Thanks to studies on molecular genetics, it has been possible over the last ten years to localize and to identify a large number of predisposing genes. These discoveries have permitted to better understand the biological basis of the predisposition and to offer counselling by identifying at-risk individuals in those families. In the case of multiple endocrine neoplasia type 2 associated with an elevated risk for medullary thyroid cancer, the gene involved is a protooncogene named RET and located on chromosome 10. Point mutations affecting specific regions of this gene are the basis of the genetic predisposition. For familial breast cancer, a susceptibility gene named BRCA1 has been located on the long arm of chromosome 17. Mutation of this gene (yet to be identified) led to very elevated risk of breast cancer and also in some families of ovarian cancer.
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PMID:[Genetic predisposition to cancer: familial forms of medullary thyroid cancer and breast cancer]. 803 90

Genetic studies of families at high risk for developing malignant and benign renal neoplasms led to cloning of genes whose alteration results in tumor formation. These genes are either tumor suppressors (VHL, TSC) or oncogenes (MET). Their significance in understanding oncogenesis extends far beyond the familial syndromes. The identification of these genes and the elucidation of their biochemical functions are likely to facilitate (1) our understanding of the full clinical spectrum of the corresponding diseases, (2) genetic counseling, and (3) rational design of effective strategies to prevent and/or treat familial and sporadic forms of these neoplasms.
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PMID:Genetic and clinical aspects of familial renal neoplasms. 1076 93

Tumors often exhibit activation of specific tyrosine kinases, which may allow targeting of therapy through inhibition of tyrosine kinase signaling. This strategy has been used successfully in the development of STI571 (gleevec), an inhibitor of bcr-abl tyrosine kinase that has been used successfully in the treatment of chronic myelogenous leukemia. STI571 also shows activity against c-kit and platelet-derived growth factor receptor-beta (PDGFRbeta) tyrosine kinase signaling, thus potentially expanding the number of tumors that may respond to it. We describe a simple and rapid method to assess functional activity of tyrosine kinase signaling that is broadly applicable to tumor types. As proof of principle, we have applied it to cells that serve as models of the autosomal-dominant tumor syndrome tuberous sclerosis (TS). We found that TS model cells derived from tuberin heterozygous mice and from a human renal angiomyolipoma are highly sensitive to PDGFR antagonists and that these cells express PDGFRbeta. Given that PDGFRbeta signaling is inhibited by STI571, we found that SV7tert human angiomyolipoma cells are sensitive to STI571. Thus, we describe a novel but simple method of determining the functional tyrosine kinase profile of a neoplastic cell and our results suggest that STI571 might be useful in the treatment of neoplasms commonly seen in patients with TS.
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PMID:Functional tyrosine kinase inhibitor profiling: a generally applicable method points to a novel role of platelet-derived growth factor receptor-beta in tuberous sclerosis. 1221 5

Tuberous sclerosis (TSC) is a familial tumor syndrome due to mutations in TSC1 or TSC2, in which progression to malignancy is rare. Primary Tsc2(-/-) murine embryo fibroblast cultures display early senescence with overexpression of p21CIP1/WAF1 that is rescued by loss of TP53. Tsc2(-/-)TP53(-/-) cells, as well as tumors from Tsc2(+/-) mice, display an mTOR-activation signature with constitutive activation of S6K, which is reverted by treatment with rapamycin. Rapamycin also reverts a growth advantage of Tsc2(-/-)TP53(-/-) cells. Tsc1/Tsc2 does not bind directly to mTOR, however, nor does it directly influence mTOR kinase activity or cellular phosphatase activity. There is a marked reduction in Akt activation in Tsc2(-/-)TP53(-/-) and Tsc1(-/-) cells in response to serum and PDGF, along with a reduction in cell ruffling. PDGFRalpha and PDGFRbeta expression is markedly reduced in both the cell lines and Tsc mouse renal cystadenomas, and ectopic expression of PDGFRbeta in Tsc2-null cells restores Akt phosphorylation in response to serum, PDGF, EGF, and insulin. This activation of mTOR along with downregulation of PDGFR PI3K-Akt signaling in cells lacking Tsc1 or Tsc2 may explain why these genes are rarely involved in human cancer. This is in contrast to PTEN, which is a negative upstream regulator of this pathway.
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PMID:Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR. 1456 7

The tuberous sclerosis-2 (Tsc-2) gene is a suppressor of renal tumorigenesis and an early target of reactive oxygen species-induced renal cancer. Tuberin, the protein product of the Tsc-2 gene, participates in the regulation of cell proliferation, although the mechanism by which it suppresses proliferation is unknown. Quinol-thioether-transformed rat renal epithelial (QT-RRE) cell lines, derived from quinol-thioether-transformed primary renal epithelial cells from Eker rats, lack tuberin expression due to loss of heterozygosity of the Tsc-2 gene. These cell lines were used to examine the mechanism by which tuberin exerts its antiproliferative action. Loss of tuberin function correlates with high ERK activity (39), which could contribute to the formation of renal tumors. In this study, we sought to identify possible downstream effectors regulated by tuberin, using QT-RRE cells transfected with Tsc-2 cDNA to restore tuberin expression. Constitutively high ERK, B-Raf, and Raf-1 activities were observed in QT-RRE cells. However, restoration of tuberin expression in QT-RRE cells by transient transfection with Tsc-2 cDNA substantially decreased both ERK and B-Raf activity, with only modest changes in Raf-1 activity, suggesting tuberin functions as an upstream negative regulator of the ERK pathway. High ERK activity was not mediated through EGF receptor activation, but treatment with genistein demonstrated that protein kinases are involved in ERK cascade activation. The data indicate that loss of tuberin results in the upregulation of the ERK signaling pathway with subsequent increases in new DNA synthesis, and ultimately, tumor formation.
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PMID:Tuberous sclerosis-2 tumor suppressor modulates ERK and B-Raf activity in transformed renal epithelial cells. 1461 83

The hypertrophic Gq-protein-coupled receptor agonist PE (phenylephrine) activates protein synthesis. We showed previously that activation of protein synthesis by PE requires MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] and mTOR (mammalian target of rapamycin). However, it remained unclear whether ERK activation was required and which downstream components were involved in activating mTOR and protein synthesis. Using an adenovirus encoding the MKP3 (MAPK phosphatase 3) to inhibit ERK activity, we demonstrate that ERK is essential for the activation of protein synthesis by PE. Activation and phosphorylation of S6K1 (ribosomal protein S6 kinase 1) and phosphorylation of eIF4E (eukaryotic initiation factor 4E)-binding protein (both are mTOR targets) were also inhibited by MKP3, suggesting that ERK is also required for the activation of mTOR signalling. PE stimulation of cardiomyocytes induced the phosphorylation of TSC2 (tuberous sclerosis complex 2), a negative regulator of mTOR activity. TSC2 was phosphorylated only weakly at Thr1462, but phosphorylated at additional sites within the sequence RXRXX(S/T). This differs from the phosphorylation induced by insulin, indicating that MEK/ERK signalling targets distinct sites in TSC2. This phosphorylation may be mediated by p90RSK (90 kDa ribosomal protein S6K), which is activated by ERK, and appears to involve phosphorylation at Ser1798. Activation of protein synthesis by PE is partially insensitive to the mTOR inhibitor rapamycin. Inhibition of the MAPK-interacting kinases by CGP57380 decreases the phosphorylation of eIF4E and PE-induced protein synthesis. Moreover, CGP57380+rapamycin inhibited protein synthesis to the same extent as blocking ERK activation, suggesting that MAPK-interacting kinases and regulation of mTOR each contribute to the activation of protein synthesis by PE in cardiomyocytes.
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PMID:Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2). 1575 2

An experimental model, based on Pringle's scheme of acute warm hepatic ischemia in normothermia was employed in order to study the hepatoprotective properties of prolactin (PRL). In the proposed model one liver lobe was maintained in the portal circulation and the remaining lobes were perfused with HTK solution for 2 hours. The experiment was carried out on female rabbits of the Chinchilla race. In the control group (n= 10) the liver was perfused with HTK solution. In the examined group (n=10), 3 microg of PRL per g of liver per hour was added to HTK solution. Additionally, the animals in the PRL-treated group were intravenously administered a dose of 600 microg of PRL / kg body weight. 1 h before the surgical treatment. The activities of alanine aminotransferase (ALT), alkaline phosphatase (ALP). gamma-glutamyl transferase (GGT) and the lactate concentration were determined in the eluate obtained from the perfused part of the liver. It was found that administration of prolactin during 2 h of perfusion led to a significant decrease of ALT, ALP and lactate concentrations in the eluate. In addition, increase of calcium concentration in the liver was significantly lower with the prolactin group. The observed results let us to draw the conclusion that administration of PRL shows signs of protective effects on hepatocytes in normothermic acute ischemia.
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PMID:The influence of prolactin on the chosen biochemical parameters of the rabbit liver in ischemia. 1579 42

Major advances have been made in the understanding of the genetic mechanisms underlying endocrine tumorigenesis, through the study of several syndromes of genetic predisposition and the identification of the genes involved. The syndrome of type 1 multiple endocrine neoplasia (MEN-1) is one of the best known; this autosomal dominant hereditary syndrome predisposes to the development of endocrine tumors of the pituitary, the parathyroids, the foregut and the adrenals. The responsible gene, known as MEN-1, encodes an original protein, menin, involved in several major cellular functions, such as the control of cell proliferation and differentiation. Type 2 multiple endocrine neoplasia (MEN-2) is an autosomal dominant hereditary syndrome associated with the development of medullary carcinomas of the thyroid, pheochromocytomas and hyperparathyroidism; the corresponding gene, RET, encodes a transmembrane receptor with tyrosine kinase activity. Endocrine tumors are also associated with non Hippel-Lindau disease and with phacomatoses, such as type 1 neurofibromatosis and tuberous sclerosis. Finally, isolated familial syndromes of endocrine tumors have been described: isolated familial hyperparathyroidism type II (HRPT2), associated with alterations in a gene coding for an original protein, parafibromin, or isolated familial syndromes of pheochromocytomas and paragangliomas (PRG) associated with mutations in the genes SDHB, SDHC or SDHD, which encode succinate-dehydrogenase subunits. The understanding of the genetic mechanisms underlying these syndromes of predisposition is essential for the diagnosis and management of these patients and their family; it also gives insight on the molecular mechanisms of endocrine tumorigenesis.
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PMID:[Genetics of endocrine tumours]. 1673 73

A case of monotypic variant of epithelioid angiomyolipoma (AML) observed in a 62-year old woman is reported. The patient complained of abdominal fullness caused by a huge left renal mass without evidence of tuberous sclerosis complex. Imaging studies showed a left renal mass with an area showing hemorrhage and necrosis. The left renal mass, spleen and pancreatic tail were removed en bloc transabdominally. The resected tumor weighed 1200 g and showed focal necrosis and hemorrhage. Microscopically, the tumor was composed exclusively of atypical polygonal cells with copious eosinophilic cytoplasm, pleomorphic nuclei and prominent nucleoli. Tumor cells were considered to derive from perivascular epithelioid cells, and exhibited strong positive staining for HMB-45 and c-KIT, but were negative for epithelial, smooth muscle, and neural markers. As this tumor had none of the typical elements of classic AML, the final pathological diagnosis was monotypic epithelioid AML.
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PMID:Monotypic epithelioid angiomyolipoma of the kidney: a case report. 1698 61


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