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 present study was undertaken to examine the factors that regulate rat serum (RS)- and nerve growth factor (NGF)-induced differentiation in a rat parotid acinar cell line. RS elicited extracellular signal-regulated kinase (ERK1/ERK2) activation within 5min, while cyclic AMP (cAMP) levels transiently rose after 6hr. RS also elicited a rise in amylase mRNA levels within 30min, which preceded the rise in amylase protein levels. A possible role for NGF was suggested by the findings that parotid cells express both TrkA and p75 receptors. The immunoreactivity of these NGF receptors was reduced during exposure to RS. Following prolonged incubation in RS when ERK activity subsided to near basal levels, NGF restored ERK1/ERK2 activity to the elevated level initially observed in RS. NGF was ineffective when cells were incubated in fetal bovine serum. NGF, when incubated in combination with the cAMP-generating neuropeptides, calcitonin gene-related peptide and vasoactive intestinal peptide, markedly enhanced the cellular amylase content produced by RS. We conclude that parotid cell differentiation arises from an activation of cell surface receptors by humoral factors in combination with NGF and cAMP-generating neuropeptides.
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PMID:Role of nerve growth factor in the regulation of parotid cell differentiation induced by rat serum. 1273 63

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are characterized by development of medullary thyroid carcinoma (MTC) and caused by germline RET mutations. Patients with MEN 2A also develop pheochromocytoma and/or hyperparathyroidism (HPT). However, MEN 2A-affected individuals could display the FMTC phenotype at first clinical manifestation. To establish the correct phenotype and improve clinical management of patients affected by hereditary MTC, clinical screening, RET mutational analysis, penetrance of MTC, and genotype-phenotype correlation were performed in a large, suspected FMTC kindred of 86 individuals. Germline C634Y RET mutation was confirmed in 22 individuals, 15 of whom were thyroidectomized when high serum calcitonin levels were detected. MTC was confirmed in 12 individuals and C-cell hyperplasia in 3. HPT was detected in two patients. High penetrance of MTC at young age (79% at 30 yr of age) was found. This family was considered to be affected by FMTC for several years because MTC was the sole clinical manifestation. However, our results allowed reclassifying the family as MEN 2A, thereby improving clinical management of family members. Our findings regarding penetrance and genotype-phenotype correlation suggest that patients considered to have FMTC may in fact have MEN 2A in some kindreds.
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PMID:Penetrance of inherited medullary thyroid carcinoma and genotype-phenotype correlation in a large multiple endocrine neoplasia type 2A family with C634Y RET mutation. 1274 65

In the present study, we investigated whether activation of protease-activated receptor type 2 (PAR-2) with SLIGRL (SL)NH2, a short mimetic agonistic peptide, directly stimulates pepsinogen secretion from gastric-isolated, pepsinogen-secreting (chief) cells. Immunostaining of gastric-dispersed chief cells with a specific anti-PAR-2 antibody demonstrated expression of PAR-2 receptors on membrane and cytoplasm. SL-NH2 and trypsin potently stimulated pepsinogen secretion (EC50 = 0.3 nM) and caused Ca2+ mobilization (EC50 = 0.6 nM). In contrast to SL-NH2, the scramble peptide LSIGRL-NH2 failed to stimulate pepsinogen release. Exposure to SL-NH2 also resulted in ERK1/2 phosphorylation and activation. Exposure of chief cells to phosphotyrosine kinase inhibitors and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one, a selective MEK inhibitor, significantly reduced secretion induced by SL-NH2. Pepsinogen secretion induced by SL-NH2 was desensitized by pretreating the cells with the mimetic peptide and trypsin, and exposure to SL-NH2 abrogates pepsinogen secretion induced by carbachol and CCK-8, but not secretion induced by secretin and vasointestinal peptide. Exposure to Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (substance P) but not to calcitonin gene-related peptide increased pepsinogen release. The neurokinin-1 receptor antagonist, N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzyl ester, inhibited substance P-stimulated pepsinogen secretion, whereas it did not affect secretion induced by SL-NH2. Collectively, these data indicate that PAR-2 is expressed on gastric chief cells and that its activation causes a Ca2+-ERK-dependent stimulation of pepsinogen secretion.
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PMID:PAR-2 modulates pepsinogen secretion from gastric-isolated chief cells. 1274 62

Gain-of-function mutations in the RET proto-oncogene resulting in a constitutively active receptor tyrosine kinase have been identified as responsible for three subtypes of multiple endocrine neoplasia type 2 (MEN-2) and the development of sporadic medullary and papillary thyroid carcinoma. An important strategy in cancer gene therapy is the inhibition of oncogenic signal transduction by interfering with the molecular mechanisms of activation. In the present study, we tested the therapeutic capacity of an adenovirus expressing a dominant-negative (dn) RET mutant, RET(51).flag, under the control of a synthetic C cell-selective calcitonin promoter (TSE2.CP1) against human medullary thyroid cancer (MTC). Infection of human MTC-derived TT cells with Ad-TSE2.CP1-dn-RET(51).flag resulted in the accumulation of immature RET protein in the endoplasmic reticulum and a strong reduction of oncogenic RET receptor on the cell surface, indicating that RET(51).flag exhibits a dominant-negative effect over endogenous oncogenic protein. Analysis of potential downstream mechanisms associated with the inhibition of oncogenic RET signaling by overexpression of mutant RET(51).flag revealed a significant loss of cell viability in TT cells due to the induction of apoptosis. Finally, we examined the antitumor activity of the dominant-negative RET approach in vivo. Inoculation of Ad-TSE2.CP1- dn-RET(51).flag-expressing MTC cells into nude mice led to complete suppression of tumor growth. Moreover, a single intratumoral injection of Ad-TSE2.CP1-dn-RET(51).flag into established thyroid tumors resulted in prolonged survival of treated mice compared with the controls. Our data suggest that adenoviral delivery of dn-RET(51).flag may be a reliable strategy of effective molecular intervention for RET oncogene-related MTC.
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PMID:Antitumor capacity of a dominant-negative RET proto-oncogene mutant in a medullary thyroid carcinoma model. 1286 15

Routine calcitonin (CT) assay programs and genetic testing for RET proto-oncogene mutations have consistently modified the management and understanding of C-cell proliferative disorders. We report a series of 66 consecutive patients with C-cell hyperplasia (CCH) or medullary thyroid carcinoma (MTC) observed in our institution within an 8-year time period. All the patients had a preoperative basal CT assay and an RET proto-oncogene sequencing. Seventeen patients (F-M ratio: 8:9, mean age: 29.7 y) had a multiple endocrine neoplasia Type 2: 3 children <10 years of age had CCH only, and 14 patients had an MTC, with neoplastic CCH in 10/14 cases. Twenty-seven patients (F-M ratio: 18:9, mean age: 56.6 y) had a sporadic MTC, with physiological CCH in 8 and neoplastic CCH in 3 cases. Twenty-two men (mean age: 46.2 y) had CCH only (physiological CCH in 17 men and neoplastic CCH in 5). We conclude that (1) clinical and pathological characteristics (familial MTC, tumor multifocality, neoplastic CCH) usually associated with hereditary MTC may be misleading and that on the contrary, RET sequencing gives no false positive result; (2) sporadic neoplastic CCH accompanies (and probably precedes) a number of sporadic MTC; and (3) women presenting with a sporadic elevated basal CT have a 100% risk of having an MTC (15/15), but this risk is 3-fold less in men (31%), who will most often have CCH only (69%).
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PMID:C-cell hyperplasia and medullary thyroid carcinoma: clinicopathological and genetic correlations in 66 consecutive patients. 1292 Feb 19

Medullary thyroid cancer (MTC) arises from parafollicular C cells secreting calcitonin. MTC occurs both as sporadic tumors and as part of specific inherited autosomal dominant syndromes in which point mutations within a discrete set of RET codons were described. Total thyroidectomy and aggressive neck dissection represents the only chance for cure in the affected patients. Therefore, all patients with thyroid nodular disease should undergo measurement of calcitonin plasma levels to allow preclinical diagnosis of the disease and early appropriate surgery ("secondary prevention"). In case of proband patient for inherited disease, all the family members should be genetically screened to detect the disease gene carriers. Patients with germline mutation would benefit either from earlier surgery at the stage of C-cell hyperplasia or microcarcinoma or prophylactic surgery (total thyroidectomy without neck dissection) (primary prevention) before the onset of any C-cells pathology. The ideal age for performance of such prophylactic surgery is determined by the genotypic features of the disease.
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PMID:[Medullary thyroid cancer: how tumor markers and genetics determine preventive measures]. 1294 Jan 28

Medullary thyroid carcinoma (MTC) rarely causes ectopic ACTH syndrome. We describe a 38-yr-old man with renal stones who had a 5-cm MTC removed in 1992. He was RET-protooncogene positive (codon 618). Serum calcitonin was 1597 pg/ml postoperatively. In 1996 he had rib fractures, bruising, weakness, and three to four stools per day. Laboratory studies revealed an elevated 24-h urine-free cortisol (780 micro g/d), epinephrine (66 micro g/d), and calcium (558 mg/d). Baseline serum cortisol was 23.9 micro g/dl and decreased to 12.9 and 4.5 micro g/dl after 2 mg and 8 mg dexamethasone suppression, respectively. Plasma ACTH was 170 pg/ml and decreased to 75 and 24 pg/ml after dexamethasone. Bone density t-score was -4.3 (trochanter). Computed tomography scans showed multiple cervical nodes and 2-cm right adrenal nodule. Magnetic resonance imaging (MRI) scan showed a prominent, homogeneous pituitary; the adrenal MRI scan was not typical for a pheochromocytoma. Serum CRH was less than 6.6 pg/ml. Bilateral adrenalectomy revealed two adjacent right adrenal pheochromocytomas and corrected the elevated urine cortisol (30 micro g/d), epinephrine (0 micro g/d), and calcium (281 mg/d) but not plasma ACTH (125 pg/ml). Neck dissection reduced calcitonin by 96% (5300 to 120 pg/ml) and ACTH by 91% (125 to 11 pg/ml). Carcinoembryonic antigen was reduced from 32.0 to 2.3 ng/ml. Immunohistochemical stain was negative for ACTH in the MTC-positive lymph nodes and the pheochromocytoma. Proopiomelanocortin mRNA by in situ hybridization was positive in the MTC but not in the pheochromocytoma. A repeat pituitary MRI scan was normal. The differential diagnosis of ACTH-dependent Cushing's syndrome in this case included pituitary disease or ectopic ACTH, either from medullary thyroid carcinoma or pheochromocytoma. ACTH stains were unrevealing, but proopiomelanocortin mRNA in situ hybridization in MTC tissue and plasma ACTH response to neck dissection confirmed MTC as the source of ectopic ACTH.
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PMID:Cushing's syndrome due to medullary thyroid carcinoma: diagnosis by proopiomelanocortin messenger ribonucleic acid in situ hybridization. 1455 23

With the objective of discovering novel putative intervention sites for anticancer therapy, we compared transcriptional profiles of breast cancer, lung squamous cell cancer (LSCC), lung adenocarcinoma (LAC), and renal cell cancer (RCC). Each of these tumor types still needs improvement in medical treatment. Our intention was to search for genes not only highly expressed in the majority of patient samples but which also exhibit very low or even absence of expression in a comprehensive panel of 16 critical (vital) normal tissues. To achieve this goal, we combined two powerful technologies, PCR-based cDNA subtraction and cDNA microarrays. Seven subtractive libraries consisting of approximately 9250 clones were established and enriched for tumor-specific transcripts. These clones, together with approximately 1750 additional tumor-relevant genes, were used for cDNA microarray preparation. Hybridizations were performed using a pool of 16 critical normal tissues as a reference in all experiments. In total, we analyzed 20 samples of breast cancer, 11 of LSCC, 11 of LAC, and 8 of RCC. To select for genes with low or even no expression in normal tissues, expression profiles of 22 different normal tissues were additionally analyzed. Importantly, this tissue-wide expression profiling allowed us to eliminate genes, which exhibit also high expression in normal tissues. Similarly, expression signatures of genes, which are derived from infiltrating cells of the immune system, were eliminated as well. Cluster analysis resulted in the identification of 527 expressed sequence tags specifically up-regulated in these tumors. Gene-wise hierarchical clustering of these clones clearly separated the different tumor types with RCC exhibiting the most homogeneous and LAC the most diverse expression profile. In addition to already known tumor-associated genes, the majority of identified genes have not yet been brought into context with tumorigenesis such as genes involved in bone matrix mineralization (OSN, OPN, and OSF-2) in lung, breast, and kidney cancer or genes controlling Ca(2+) homeostasis (RCN1,CALCA, S100 protein family). EGLN3, which recently has been shown to be involved in regulation of hypoxia-inducible factor, was found to be highly up-regulated in all RCCs and in half of the LSCCs analyzed. Furthermore, 42 genes, the expression level of which correlated with the overall survival of breast cancer patients, were identified. The gene dendogram clearly separates two groups of genes, those up-regulated such as cyclin B1, TGF-beta 3, B-Myb, Erg2, VCAM-1, and CD44 and those down-regulated such as MIG-6, Esp15, and CAK in patients with short survival time.
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PMID:Tissue-wide expression profiling using cDNA subtraction and microarrays to identify tumor-specific genes. 1487 11

The protein gene product 9.5 (PGP9.5) is a ubiquitin hydrolase that is widely expressed in neuronal tissues at all stages of neuronal differentiation and is a known neuroendocrine marker. Medullary thyroid carcinoma (MTC) arises from parafollicular cells and is reported to overexpress several mRNAs such as RET, calcitonin, and CEA. These markers are thought to be useful in determining a molecular-based diagnosis of MTC. We examined the expression levels of PGP9.5 mRNA in 80 thyroid tissues using real-time quantitative reverse transcription (RT-PCR) and found that PGP9.5 mRNA was overexpressed in all 11 MTCs examined, both hereditary and sporadic, but not in other histological tumour types. Furthermore, by RT-PCR, PGP9.5 mRNA was detected only in aspirates from three medullary carcinomas, and not in aspirates from other tumour types. These results demonstrate that, in addition to the expression of RET, calcitonin and CEA, PGP9.5 mRNA expression may contribute to the molecular-based diagnosis of MTCs.
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PMID:PGP9.5 mRNA could contribute to the molecular-based diagnosis of medullary thyroid carcinoma. 1496 31

Mammary small cell carcinoma (SmCC) is a very rare neoplasm with a poor prognosis compared with other invasive carcinomas. We studied the histological and immunohistochemical profiles of two cases of mammary SmCC, and compared them with those of five cases of carcinoma with endocrine features (CEF) and five cases of invasive ductal carcinoma (IDC), to elucidate the correct diagnosis of mammary SmCC. Immunohistochemical analysis was performed with antibodies against cytokeratins (CKAE1/AE3, CK34betaE12, CKCAM5.2, CK7, CK8, CK19, CK20), epithelial membrane antigen (EMA), vimentin, CD10, neural cell adhesion molecule (NCAM; CD56), neuron-specific enolase (NSE), chromogranin A, S-100 protein, carcino-embryonic antigen (CEA), E-cadherin, N-cadherin, thyroid transcription factor-1 (TTF-1), p53, estrogen (ER), progesterone (PR), HER2/neu, bcl-2, synaptophysin, calcitonin and Leu7. SmCCs were diffusely and strongly positive for NCAM in comparison with CEFs and IDCs. SmCCs were negative for vimentin, whereas CEFs and IDCs were positive. Neuro-endocrine carcinomas, including SmCCs and CEFs, were diffusely and strongly positive for NSE, compared with IDCs. Moreover, neuroendocrine carcinomas were negative for CK34betaE12, CK20 and CD10, whereas IDCs were positive. Our study suggests that NCAM and vimentin are useful markers for the diagnosis of mammary SmCC. CK34betaE12, NSE, CD10, CK20 and chromogranin A appear to be useful for differentiating neuroendocrine carcinoma from IDCs.
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PMID:Comparative study of primary mammary small cell carcinoma, carcinoma with endocrine features and invasive ductal carcinoma. 1501 Aug 80


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