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)

Primary tumors originating from cells of the glial lineage usually affect predominantly the white matter of the brain. Only rarely do gliomas destroy the surrounding bone by invasion of the extracellular matrix, especially without prior surgery. This paper describes the unusual case of a 66-year-old female patient with a left-sided intra- and extracranial tumor involving the temporal lobe, destroying the underlying skull base, and growing into the paranasal sinuses, orbit, and temporal bone. Biopsy revealed glioblastoma multiforme with strong GFAP positivity. Molecular biologic investigations of the p53, EGFR, and mdm2 genes showed functional inactivation of the p53 gene but no overexpression of oncogenes. Because the tumor was considered inoperable, palliative irradiation was carried out. The patient died 7 months after diagnosis. The causes of this phenomenon are discussed and the literature reviewed.
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PMID:Local invasivity of glioblastoma multiforme with destruction of skull bone. Case report and review of the literature. 887 8

Cell proliferation control is ensured by a group of proteins named cyclin-dependent kinases (CDKs), the activation of which is dependent on phosphorylation and cyclin association. In parallel, these CDKs are negatively controlled by two distinct groups of inhibitory proteins, the cyclin-dependent kinase inhibitors (CKIs). The first group, including p16Ink4a, p15Ink4b, p18Ink4c and p19Ink4d, is specific for the G1 CDKs, CDK4 and CDK6, inhibiting the kinase activity of cyclin D/CDK4-CDK6 complexes on pRb. p16Ink4a, down-regulated by pRb, inhibits G1 CDKs by competition with cyclin D; p15Ink4b, the synthesis of which is induced by TGF beta, seems to be a mediator of TGF beta-mediated cell cycle arrest. Furthermore, p18Ink4c inhibits CDK6 phosphorylation and activation by CAK. The second CKIs family is constituted by p21Waf1, p27Kip1 and p57Kip2. Their inhibitory action concerns a large range of cyclin/CDK complexes involved in G1 and S phase. p21Waf1, induced in part by p53, is up-regulated by senescence, DNA damage and cellular differentiation. p21Waf1 forms quaternary complexes with CDKs, cyclins and PCNA. Its inhibitory action, preventing CDK from phosphorylation, depends on the stoichiometry of the components. As p15Ink4b, p27Kip1 causes late G1 cell cycle arrest after TGF beta treatment and contact inhibition. The implications of CKIs in hematological malignancies are function of deletions or mutations of their genes. p16Ink4a and p15Ink4b genes, localized on 9p21, present frequent homozygous deletions in ALL T, ATL and lymphoblastic acutisation of CML. The other CKIs present very rare homozygous deletions or mutations, particularly p21Waf1 and p27Kip2. However, reduction of inhibitory activity due to hemizygous deletions might favour leukemogenesis.
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PMID:Cyclin-dependent kinase inhibitors (CKIs) and hematological malignancies. 889 23

Various molecular genetic abnormalities have been reported in esophageal carcinoma. These include amplification of the chromosome 11q13 region containing cyclin D1, EXP1 and EMS1 genes, and the oncogenes, the epidermal growth factor receptor gene, EGFR/c-ERBB1, and c-myc. Loss of heterozygosity (LOH) at several chromosome loci and point mutation of the p53 and p16/CDKN2 tumor suppressor genes have also been described. Mutations of p53 gene and LOH at 3p and 9q loci were investigated in esophageal epithelial dysplasia. In contrast, amplification of cyclin D1, EGFR, c-myc and other genes was accumulated in advanced tumors with invasion. Cyclin D1 amplification is found more in metastatic lesions than in primary tumors.
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PMID:[Genetic events during development of esophageal squamous cell carcinoma]. 892 Jun 74

The effect of the CSF-1 receptor, cFMS, on the phosphorylation of the retinoblastoma (RB) tumor suppressor protein and on the cell cycle and cell differentiation was analyzed in a cultured promyelocytic leukemia cell capable of induced myelomonocytic differentiation. A series of cFMS-transfected HL-60 sublines with progressively higher cell surface FMS expression was derived by flow cytometric cell sorting. Overexpression of FMS increased the duration of the cell cycle, prolonging all cell cycle phases especially S phase, which doubled. The increased cell cycle generation times occurred without any detectable changes in RB expression level or phosphorylation. For retinoic acid (RA)-induced myeloid differentiation, progressive overexpression of FMS caused a greater fraction of cells to differentiate and G1/0 arrest compared to wild-type cells after the same number of cell cycle generation times. FMS overexpression also progressively increased the relative amount of dephosphorylated RB protein induced, while reducing the total amount of RB protein. The inducer-originated and FMS-driven changes in RB hypophosphorylation were not effected through changes in p21/WAF1/CIP1 in this p53-negative cell. Similar effects on differentiation and G0 arrest occurred with 1,25-dihydroxy vitamin D3 (D3)-induced monocytic differentiation. FMS did not significantly affect myeloid differentiation induced by DMSO, which does not target steroid-thyroid hormone receptors like RA and D3. While differentiation is typically associated with hypophosphorylated RB in all these cases, the kinetics indicate that the FMS-induced changes in cell cycle and cell differentiation do not depend in a direct causal fashion on the interconversion between hyperphosphorylated and hypophosphorylated RB.
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PMID:FMS (CSF-1 receptor) prolongs cell cycle and promotes retinoic acid-induced hypophosphorylation of retinoblastoma protein, G1 arrest, and cell differentiation. 894 Feb 55

Cyclic phosphorylation/dephosphorylation of the retinoblastoma gene product (pRB) has been found to play a central role in the progression of the normal cell cycle, through modulation of the activity of the E2F family of transcription factors. Mutations of the retinoblastoma gene have been described in a wide variety of human malignancies including carcinomas of the breast. The present investigation reports the production and application of a new monoclonal antibody in an immunohistochemical study of pRB expression in 233 primary breast carcinomas, allowing an assessment of the contribution made by this tumour suppressor gene to tumour development and progression. Overall, there was loss of pRB expression in 21 per cent of breast tumours. Although high-grade tumours were found to lack detectable pRB more frequently than low-grade tumours, the difference did not prove statistically significant. In addition, pRB immunostaining was not related significantly to relapse or survival. No significant correlations were observed between apparent loss of pRB and tumour size, parity, patient lymph-node status, p53, c-erbB-2, c-jun, EGFR or steroid hormone receptor expression. Preliminary findings, however, did suggest a relationship between pRB expression and response to endocrine therapy.
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PMID:Retinoblastoma protein in human breast carcinoma: immunohistochemical study using a new monoclonal antibody effective on routinely processed tissues. 894 17

Genomic alterations and expression of the p53 tumor suppressor gene and the epidermal factor receptor gene (EGFR) were investigated in 22 patients with primary World Health Organization (WHO) grade II gliomas that on recurrence had progressed to malignant gliomas of WHO grades III or IV. Mutations of the p53 gene (exons 5 to 8) were found in 12 of 22 primary tumors (10 of 13 astrocytomas, 1 of 7 oligodendrogliomas, 1 of 2 oligoastrocytomas). In each of these cases identical p53 mutations were present in the respective malignant recurrences. In all instances in which the p53 mutation was associated with p53 protein accumulation (10 of 12 cases) the percentage of p53 immunopositive tumor cells had increased from the primary to the recurrent tumor. None of the primary low-grade and none of the recurrent high-grade tumors (7 anaplastic astrocytomas, 10 anaplastic oligodendrogliomas, 4 anaplastic oligoastrocytomas, and 5 glioblastomas) showed evidence of EGFR gene amplification. Our results thus demonstrate p53 is mutated in a high fraction of low-grade astrocytomas with progression to anaplastic astrocytomas and glioblastomas and that progression in such cases is frequently associated with an increase in the fraction of p53 immunopositive tumor cells. The general absence of EGFR amplification in our tumor series supports the hypothesis that the significance of p53 mutation and EGFR amplification may be different in glioblastomas that developed by progression from low-grade astrocytomas (secondary glioblastomas) compared to glioblastomas that developed rapidly in a de novo manner without a history of previous low-grade tumor (primary glioblastomas).
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PMID:Analysis of p53 mutation and epidermal growth factor receptor amplification in recurrent gliomas with malignant progression. 896 97

The etiology of breast cancer involves a complex interplay of exogenous and endogenous factors, including genetic factors. The identification of oncogenes, tumor suppressor genes and human mismatch repair genes has helped to refine the characterization of breast carcinogenesis. The major types of genetic alterations in breast cancer are amplification of protooncogenes (ERBB2 and MYC) and DNA from chromosome band 11q13; mutation of p53; and loss of heterozygosity on 1p, 3p, 8p, 11p, 13q, 16q, 17p, 17q, 18q. The latter may imply inactivations of tumor suppressor genes. Recently, two distinct familial breast cancer susceptibility genes, BRCA1 and BRCA2, have been isolated. These findings enable to use these genes for genetic diagnosis in clinical oncology.
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PMID:[Cytogenetic abnormalities, genetic alterations, and applications for genetic diagnosis in breast cancer]. 897 25

More than 60 previously undetected SAM domain-containing proteins have been identified using profile searching methods. Among these are over 40 EPH-related receptor tyrosine kinases (RPTK), Drosophila bicaudal-C, a p53 from Loligo forbesi, and diacyglycerol-kinase isoform delta. This extended dataset suggests that SAM is an evolutionary conserved protein binding domain that is involved in the regulation of numerous developmental processes among diverse eukaryotes. A conserved tyrosine in the SAM sequences of the EPH related RPTKs is likely to mediate cell-cell initiated signal transduction via the binding of SH2 containing proteins to phosphotyrosine.
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PMID:SAM as a protein interaction domain involved in developmental regulation. 900 98

The carcinogenic and metastatic processes are thought to consist of a sequence of steps, and animal models featuring highly metastatic lesions are clearly necessary to allow analysis of the whole process of transformation from preneoplastic changes to high grade metastatic tumors, and to access effectiveness of therapeutic treatments of advanced cancers in vivo. The purpose of the present study was to establish a model and to screen for reported genetic alterations in induced lesions. In the present study, it was confirmed that lung metastasis of hepatocellular carcinomas (HCCs) induced in male F344 rats by N-nitrosomorpholine (NNM), given in the drinking water at a dose of 120 ppm for 24 weeks, was significantly enhanced by additional carcinogenic pretreatments and that a single i.p. injection of 100 mg/kg body weight N-diethylnitrosamine (DEN) alone was sufficient for that purpose. Molecular biological analyses of the induced lesions revealed point mutations in the p53 gene in 60.9% of HCCs, and elevated expression of mRNAs for p53, c-myc, c-fos, TGF-alpha, TGF-beta1, alpha-fetoprotein, GST-P, and GGT, and decreased mRNA expression of EGF and EGFR in HCCs when compared to controls. No obvious association of gene alterations with metastatic potential of primary tumors was found except for an increase in the incidence of p53 mutations. Since the process of metastasis is thought to be sequential and selective, further comparative analysis of metastatic and primary lesions should clarify the mechanisms involved in the multi-step process of metastasis.
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PMID:Highly metastatic hepatocellular carcinomas induced in male F344 rats treated with N-nitrosomorpholine in combination with other hepatocarcinogens show a high incidence of p53 gene mutations along with altered mRNA expression of tumor-related genes. 902 67

The three known mechanisms of cellular transformation and oncogenesis include mutations in proto-oncogenes, inactivation of both copies of a tumor suppressor gene, and defects in DNA mismatch repair genes. Examples of each are included to substantiate the importance of understanding these mechanisms. RET is a proto-oncogene that is fundamental to the pathogenesis, and in the current era, molecular diagnosis of MEN 2 syndromes. TP53 is a tumor suppressor gene that is mutated in individuals with Li-Fraumeni syndrome. CDKN2 is a tumor suppressor gene that is mutated in pancreatic cancers and is associated with a poorer prognosis and the development of melanoma. MSH2 is a mismatch repair gene that is important in the pathogenesis of HNPCC and Muir-Torre syndrome. Altered gene function such as loss of DCC in colon cancers may affect cell adhesion properties and promote metastases. As we begin to better define and understand the mechanisms of neoplasia, we will be able to improve current diagnosis and treatment.
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PMID:Advances in molecular genetics. 904 82


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