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)

Skin tumour development was studied in groups of mice painted once with 125 mug of 3-methylcholanthrene (MCA) either at 12:00 or at 24:00 MET. Eight animals were kept in each box. The animals were observed weekly for 20 months and all tumours were registered. There was no difference between the two groups of mice as regards tumour induction time or number of papilloma-bearing mice. In the groups of mice treated at 24:00 the number of skin tumours to develop was 9 per cent higher than in groups of mice treated at 12:00. This difference in papilloma yields is not statistically significant. Among female mice painted at 24:00 carcinoma-bearing animals were significantly more numerous (50 per cent) than among those painted at 12:00, whereas there was no difference between the groups of male mice. Considering the groups collectively (males + females), the intergroup difference (17 per cent) in advantage of painting at 24:00 was barely significant (0.5 less than p less than 0.10). There was no difference between the groups as regards the total number of carcinomas to occur. When the tumour yields in individual boxes were found to vary greatly. The slight increase in tumour yield after night painting correlates with the circadian variation in proliferative activity of the epidermidis. Previous reports in the literature have shown similar differences. Further investigations and better methods seem necessary before a definite conclusion can be drawn concerning a possible diurnal variation in the susceptibility of mouse skin to chemical carcinogenesis. It is also emphasized that it is necessary to exercise great caution when the results of classical epidermal chemical carcinogenesis experiments are to be interpreted. It seems necessary to observe animals for at least 15 months before any conclusion can be drawn.
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PMID:Is there a diurnal variation in the susceptibility of mouse skin to the tumorigenic action of methylcholanthrene? A study of tumour yield with special reference to the variation between cages. 98 89

Most cervical carcinomas appear to arise from cervical intraepithelial neoplasia (CIN) lesions. In addition to infection with high-risk human papilloma viruses, which is indicative of an increased risk of progression, alterations of oncogenes and tumor suppressor genes play a role. Genetic studies of CIN lesions, primary cervical carcinoma, and metastases may shed light on the relative importance of various genetic alterations involved in the progression of CIN to invasive carcinoma. We examined tumor material from 10 patients with squamous cell carcinoma of the uterine cervix and synchronous CIN lesions and lymph node metastases. The CIN component, invasive carcinoma, and lymph node metastases were analyzed separately for loss of heterozygosity (LOH) on the following loci: VHL (3p21), HLA region (6p22-23), PGL (11q 22-24), E6 associated protein (15q11-13), TP53 (17p13), DCC (18q21.1), and chromosomes 1, 2, 4, 9, 20, and X. Using immunohistochemistry, the expression of the EGF receptor, ERBB2, and TP53 was determined. In CIN lesions, frequent LOH was found at chromosome arms 3p, 6p, and 11q. Primary invasive carcinoma showed additional LOH at chromosome arms 6q, 17p, and 18q. In lymph node metastases, an additional locus on the X chromosome displayed LOH. All carcinomas and synchronous lesions but one showed high expression levels of the EGF receptor. TP53 staining, when present, was found in all synchronous lesions. Focal staining of ERBB2 was found in one CIN lesion, two invasive carcinomas, and four metastases. The molecular alterations accumulated in a fashion that paralleled the progression of the tumors. These results indicate that cervical tumorigenesis occurs in a stepwise fashion, including infection and integration of oncogenic HPV and several specific genetic alterations. Genes Chromosomes Cancer 26:346-354, 1999.
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PMID:Genetic alterations during the progression of squamous cell carcinomas of the uterine cervix. 1053 70

Carcinogenesis involves inactivation or subversion of the normal controls of proliferation, differentiation, and apoptosis. However, these controls are robust, redundant, and interlinked at the gene expression levels, regulation of mRNA lifetimes, transcription, and recycling of proteins. One of the central systems of control of proliferation, differentiation and apoptosis is retinoid signaling. The hRAR alpha nuclear receptor occupies a central position with respect to induction of gene transcription in that when bound to appropriate retinoid ligands, its homodimers and heterodimers with hRXR alpha regulate the transcription of a number of retinoid-responsive genes. These include genes in other signaling pathways, so that the whole forms a complex network. In this study we showed that simple, cause-effect interpretations in terms of hRAR alpha gene transcription being the central regulatory event would not describe the retinoid-responsive gene network. A set of cultured bladder-derived cells representing different stages of bladder tumorigenesis formed a model system. It consisted of 2 immortalized bladder cell lines (HUC-BC and HUC-PC), one squamous cell carcinoma cell line (SCaBER), one papilloma line (RT4), and 4 transitional cell carcinomas (TCC-Sup, 5637, T24, J82) of varying stages and grades. This set of cells were used to model the range of behaviors of bladder cancers. Relative gene expression before (constitutive) and after treatment with 10 microM all-trans-retinoic acid (aTRA) was measured for androgen and estrogen receptor; a set of genes involved with retinoid metabolism and action, hRAR alpha nd beta, hRXR alpha and beta CRBP, CRABP I and II; and for signaling genes that are known to be sensitive to retinoic acid, EGFR, cytokine MK, ICAM I and transglutaminase. The phenotype for inhibition of proliferation and for apoptotic response to both aTRA and the synthetic retinoid 4-HPR was determined. Transfection with a CAT-containing plasmid containing an aTRA-sensitive promoter was used to determine if the common retinoic acid responsive element (RARE)-dependent pathway for retinoid regulation of gene expression was active. Each of the genes selected is known from previous studies to react to aTRA in a certain way, either by up- or down-regulation of the message and protein. A complex data set not readily interpretable by simple cause and effect was observed. While all cell lines expressed high levels of the mRNAs for hRXR alpha and beta that were not altered by treatment with exogenous aTRA, constitutive and stimulated responses of the other genes varied widely among the cell lines. For example, CRABP I was not expressed by J82, T24, 5637 and RT4, but was expressed at low levels that did not change in SCaBER and at moderate levels that decreased, increased, or decreased sharply in HUC-BC, TCC-Sup and HUC-PC, respectively. The expression of hRAR alpha, which governs the expression of many retinoid-sensitive genes, was expressed at moderate to high levels in all cell lines, but in some it was sharply upregulated (TCC-Sup, HUC-PC and J82), remained constant (5637 and HUC-BC), or was down-regulated (SCaBER, T24 and RT4). The phenotypes for inhibition of proliferation showed no obvious relationship to the expression of any single gene, but cell lines that were inhibited by aTRA (HUC-BC and TCC-Sup) were not sensitive to 4-HPR, and vice versa. One line (RT4) was insensitive to either retinoid. Transfection showed very little retinoid-stimulated transfection of the CAT reporter gene with RT4 or HUC-PC. About 2-fold enhancement transactivation was observed with SCaBER, HUC-BC, J82 and T24 cells and 3-8 fold with 5637, TCC-Sup cells. In HUC-BC, a G to T point mutation was found at position 606 of the hRAR alpha gene. This mutation would substitute tyrosine for asparagine in a highly conserved domain. These data indicate that retinoid signaling is probably a frequent target of inactivation in bladder carcinogenesis. (ABSTRAC
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PMID:Complexity, retinoid-responsive gene networks, and bladder carcinogenesis. 1059 47

A 59-year-old woman who had parathyroid adenoma, parathyroid hyperplasia, thyroid follicular adenoma, thyroid papillary carcinoma, astrocytoma of the right temporal lobe, cerebellar meningioma, capillary hemangioma of the left external auditory meatus and papilloma of the left upper gingiva is reported. Dynamic magnetic resonance imaging, computed tomography with contrast-enhancement and gastrofiberscopy revealed no remarkable findings in the pituitary, pancreas, adrenals, stomach or duodenum. Similar lesions were not found in any family members. Defect of the causative genes of multiple endocrine neoplasia types I and IIa, MENIN and RET was not detected. Further follow-up of this patient and family members is needed.
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PMID:Undefined complications of parathyroid adenoma, parathyroid hyperplasia (primary hyperparathyroidism), thyroid follicular adenoma, thyroid papillary carcinoma, temporal astrocytoma, cerebellar meningioma, and hemangioma of external auditory meatus and oral papilloma. 1103 Feb 6

Activating point mutations in the FGFR3 gene occur frequently in low-grade and low-stage bladder carcinomas, whereas they are rare in high-grade carcinomas. This study investigates the incidence of FGFR3 mutations in 12 urothelial papillomas and 79 pTaG1 tumours which were regraded according to the 1998 WHO/ISUP classification system, resulting in 62 papillary urothelial neoplasms of low malignant potential (PUNs-LMP) and 17 low-grade papillary urothelial carcinomas (LG-PUCs). FGFR3 mutation analysis of 21 ovarian Brenner tumours was also performed. Seventy-seven cases were detected with a mutation in the FGFR3 gene. The mutations were exclusively found in bladder neoplasms. In urothelial papilloma, generally considered a benign lesion, 9/12 (75%) mutations were found. This report is the first to describe a genetic defect in urothelial papilloma. A comparable percentage of mutations was found in PUNs-LMP (85%) and LG-PUCs (88%). No mutations were found in matched normal DNA from bladder tumour patients. The mean follow-up was 5.78 years (range 0.21-17.60 years). Five patients developed high-grade papillary urothelial carcinoma from 2.5 to 12 years after first diagnosis. Two patients died of bladder cancer. The mean number of recurrences (recurrence rate) per year was 0.03, 0.21, and 0.46, respectively, for papilloma, PUN-LMP, and LG-PUC. Urothelial papilloma is a rare lesion with a benign natural behaviour compared with PUN-LMP and LG-PUC of the bladder, but from a molecular perspective, papillomas should be classified together with all well-differentiated urothelial neoplasms.
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PMID:Frequent FGFR3 mutations in urothelial papilloma. 1223 85

ped/pea-15 is a cytosolic protein performing a broad antiapoptotic function. We show that, upon DMBA/TPA-induced skin carcinogenesis, transgenic mice overexpressing ped/pea-15 (Tg(ped/pea-15)) display early development of papillomas and a four-fold increase in papilloma number compared to the nontransgenic littermates (P<0.001). The malignant conversion frequency was 24% for the Tg(ped/pea-15) mice and only 5% in controls (P<0.01). The isolated application of TPA, but not that of DMBA, was sufficient to reversibly upregulate ped/pea-15 in both untransformed skin and cultured keratinocytes. ped/pea-15 protein levels were also increased in DMBA/TPA-induced papillomas of both Tg(ped/pea-15) and control mice. Isolated TPA applications induced Caspase-3 activation and apoptosis in nontransformed mouse epidermal tissues. The induction of both Caspase-3 and apoptosis by TPA were four-fold inhibited in the skin of the Tg(ped/pea-15) compared to the nontransgenic mice, accompanied by a similarly sized reduction in TPA-induced JNK and p38 stimulation and by constitutive induction of cytoplasmic ERK activity in the transgenics. ped/pea-15 expression was stably increased in cell lines from DMBA/TPA-induced skin papillomas and carcinomas, paralleled by protection from TPA apoptosis. In the A5 spindle carcinoma cell line, antisense inhibition of ped/pea-15 expression simultaneously rescued sensitivity to TPA-induced Caspase-3 function and apoptosis. The antisense also reduced A5 cell ability to grow in semisolid media by 65% (P<0.001) and increased by three-fold tumor latency time (P<0.01). Thus, the expression levels of ped/pea-15 control Caspase-3 function and epidermal cell apoptosis in vivo and determine susceptibility to skin tumor development.
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PMID:Raised expression of the antiapoptotic protein ped/pea-15 increases susceptibility to chemically induced skin tumor development. 1604 59

Germinal activating mutations of FGFR3 are responsible for several forms of dwarfism due to the inhibitory effect of FGFR3 on bone growth. Surprisingly, identical somatic activating mutations have been found at the somatic level in tumours: at high frequency in benign epithelial tumours (seborrheic keratosis, urothelial papilloma) and in low-grade, low-stage urothelial carcinomas, and at a lower frequency in other types of urothelial carcinoma, in cervix carcinoma, and in haematological cancer, multiple myeloma. FGFR3 exists as two isoforms, FGFR3b and FGFR3c, differs in ligand specificity and tissue expression. FGFR3b is the main form in epithelial cells and derived tumours, whereas FGFR3c is the main form in mesenchyme-derived cells and multiple myeloma. Several lines of evidence suggest that mutated FGFR3c has transforming properties. Although mutated FGFR3b is mostly found in benign epithelial tumours or carcinomas of low malignant potential, we present evidence here that mutated FGFR3b is oncogenic. All bladder tumours presenting FGFR3 mutations expressed this receptor more strongly than normal urothelium or non-mutated tumours. NIH-3T3 cells transfected with a mutated form of FGFR3b--FGFR3b-S249C, the most common mutation in bladder tumours--presented a spindle-cell morphology, grew in soft agar and gave rise to tumours when xenografted into nude mice. We identified one line of 17 bladder cell lines tested (MGH-U3) that expressed a mutated form of FGFR3b, FGFR3b-Y375C. We showed using siRNA and SU5402, an FGFR inhibitor, that the tumour properties of MGH-U3 depended on mutated receptor activity. Thus, in two different models, mutated FGFR3b presents oncogenic properties.
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PMID:Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b. 1633 52

Urothelial neoplasms in patients 19 years of age or younger are rare, and the data regarding clinical outcome are conflicting. Molecular data are not available. Urothelial tumours from 14 patients aged 4 to 19 years were analysed, including FGFR3 and TP53 mutation screening, comparative genomic hybridization (CGH), UroVysion FISH analysis, polymerase chain reaction for human papillomavirus (HPV), microsatellite analysis using the NIH consensus panel for detection of microsatellite instability (MSI) and six markers for loss of heterozygosity on chromosome arms 9p, 9q, and 17p and immunohistochemistry for TP53, Ki-67, CK20 and the mismatch repair proteins (MRPs) hMSH2, hMLH1, and hMSH6. Based on the 2004 WHO classification, one urothelial papilloma, seven papillary urothelial neoplasms of low malignant potential (PUNLMPs), five low-grade, and one high-grade papillary urothelial carcinoma were included. No multifocal tumours were found and recurrence was seen in only one patient with a urothelial papilloma. All patients were alive with no evidence of disease at a median follow-up of 3.0 years. We found no mutations in FGFR3, deletions of chromosome arms 9p, 9q or 17p, MSI or MRP loss, or HPV positivity in any of the patients. Three cases showed chromosome alterations in CGH analyses, urothelial dedifferentiation with CK20 overexpression, or aneuploidy, and one TP53 mutation with TP53 overexpression was found. Urothelial neoplasms in people younger than 20 years are predominantly low grade and are associated with a favourable clinical outcome. Genetic alterations frequently seen in older adults are extremely rare in young patients. Urothelial neoplasms in children and young adults appear to be biologically distinct and lack genetic instability in most cases.
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PMID:Genomic aberrations are rare in urothelial neoplasms of patients 19 years or younger. 1707 25

We have established 3 cell lines ORL-48, -115 and -136 from surgically resected specimens obtained from untreated primary human oral squamous cell carcinomas of the oral cavity. The in vitro growth characteristics, epithelial origin, in vitro anchorage independency, human papilloma-virus (HPV) infection, microsatellite instability status, karyotype and the status of various cell cycle regulators and gatekeepers of these cell lines were investigated. All 3 cell lines grew as monolayers with doubling times ranging between 26.4 and 40.8 h and were immortal. Karyotyping confirmed that these cell lines were of human origin with multiple random losses and gains of entire chromosomes and regions of chromosomes. Immunohistochemistry staining of cytokeratins confirmed the epithelial origin of these cell lines, and the low degree of anchorage independency expressed by these cell lines suggests non-transformed phenotypes. Genetic analysis identified mutations in the p53 gene in all cell lines and hypermethylation of p16INK4a in ORL-48 and -136. Analysis of MDM2 and EGFR expression indicated MDM2 overexpression in ORL-48 and EGFR overexpression in ORL-136 in comparison to the protein levels in normal oral keratinocytes. Analysis of the BAT-26 polyadenine repeat sequence and MLH-1 and MSH-2 repair enzymes demonstrated that all 3 cell lines were microsatellite stable. The role of HPV in driving carcinogenesis in these tumours was negated by the absence of HPV. Finally, analysis of the tissues from which these cell lines were derived indicated that the cell lines were genetically representative of the tumours, and, therefore, are useful tools in the understanding of the molecular changes associated with oral cancers.
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PMID:Establishment and characterization of Asian oral cancer cell lines as in vitro models to study a disease prevalent in Asia. 1727 94

We previously showed that rasH2 transgenic mice carrying the human c-Ha-ras protooncogene are highly susceptible to chemical skin carcinogenesis. In the dermis of rasH2 mice, mast cells are recruited constitutively, and the number of mast cells increases more than in wild-type mice in response to treatment with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. To determine whether enhanced skin tumor development in rasH2 mice is dependent on the recruitment of mast cells, we generated rasH2 KIT(W/Wv) mice by crossing rasH2 mice and W or W(v) KIT mutants, and examined the chemical skin carcinogenesis. In rasH2 KIT(W/Wv) mice, mast cells were not found in the dermis either before or after treatment with 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. Papilloma multiplicity was up to 4.6-fold higher in rasH2 KIT(+/+) mice compared with their rasH2 KIT(W/Wv) siblings. At 12 weeks after the experiment began, the volumes of tumors were significantly smaller in rasH2 KIT(W/Wv) relative to rasH2 KIT(+/+) mice (rasH2 KIT(W/Wv): 29.2 +/- 19.9 mm(3) versus rasH2 KIT(+/+): 179.6 +/- 726.6 mm(3); P = 0.0153). There was no difference in the latency or multiplicity of papillomas between mice without the rasH2 transgene, KIT(W/Wv) mice and their wild-type littermates. Western blot analysis showed that expression of H-RAS protein in the skin was equivalent in rasH2 KIT(W/Wv) and rasH2 KIT(+/+) mice. In conclusion, the inhibition of c-kit decreased H-ras-induced skin carcinogenesis. The suppression of c-kit may be a unique and effective target as a preclinical model of cancer treatment where the activation of H-ras has a significant role. Targeting mast cells could also be a potential strategy for treating malignancies.
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PMID:Decreased c-kit function inhibits enhanced skin carcinogenesis in c-Ha-ras protooncogene transgenic mice. 1768 12


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