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)

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

Glioblastoma multiforme (GBM) can be divided into genetic subsets: approximately one-third of GBM, primarily in older adults, have EGFR amplification; another one-third, primarily in younger adults, have TP53 mutation. The majority of GBM also have homozygous deletions of the CDKN2 (p16/MTS1) gene, resulting in cell cycle deregulation and elevated proliferation indices. We evaluated the relationship between CDKN2 deletions and the GBM subsets as defined by EGFR amplification or TP53 mutation in 70 GBM. Twenty-eight cases (40%) had EGFR amplification, 21 (30%) had TP53 mutation, and 21 (30%) had neither change. CDKN2 deletions were present in 36 (51%) GBM. Of the 28 GBM with EGFR amplification, 20 (71%) had CDKN2 deletion (p = 0.0078). The remaining 16 cases with CDKN2 loss were divided between GBM with TP53 mutations (6 cases) and GBM with neither EGFR amplification nor TP53 mutation (10 cases). Thus, CDKN2 deletions occur twice as commonly in GBM with EGFR amplification (71%) than in GBM with TP53 mutation (29%). CDKN2 deletions occurred in GBM from patients somewhat older than those patients with GBM lacking CDKN2 deletion (mean age 53 vs. 48 years). Specifically among GBM with EGFR amplification, those with CDKN2 deletions also occurred in patients slightly older than those few GBM without CDKN2 deletions (mean age 55 vs. 51 years). The presence of CDKN2 deletions in most GBM with EGFR amplification and in generally older patients may provide one explanation for the potentially more aggressive nature of such tumors.
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PMID:Association of EGFR gene amplification and CDKN2 (p16/MTS1) gene deletion in glioblastoma multiforme. 921 72

Glioblastomas (GBMs) are a heterogeneous group of tumors. Recently, distinct molecular genetic alterations have been linked to subgroups of patients with GBM. Giant cell (gc)GBMs are a rare variant of GBM characterized by a marked preponderance of multinucleated giant cells. Several reports have associated this entity with a more favorable prognosis than the majority of GBMs. To evaluate whether gcGBM may also represent a genetically defined subgroup of GBM, we analyzed a series of 19 gcGBMs for mutations in the TP53 gene for amplification of the EGFR and CDK4 genes and for homozygous deletions in the CDKN2A (p16/MTS1) gene. Seventeen of nineteen gcGBMs carried TP53 mutations whereas EGFR and CDK4 gene amplification was seen in only one tumor each and homozygous deletion of CDKN2A was not observed at all. The strikingly high incidence of TP53 mutations and the relative absence of other genetic alterations groups gcGBM together with a previously recognized molecular genetic variant of GBM (type 1 GBM). It is tempting to speculate that the better prognosis of gcGBM patients may result from the low incidence of EGFR amplification and CDKN2A deletion, changes known for their growth-promoting potential.
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PMID:Molecular genetic analysis of giant cell glioblastomas. 928 34

The p16INK4a gene product acts as a negative regulator of the cell cycle by binding to cyclin-dependent kinases (CDKs) 4 and 6, thereby inhibiting the formation of an active CDK/cyclin D complex. Deletion of the p16 locus has been observed in tumor cell lines and, less frequently, in primary human neoplasms. We analyzed 31 glioblastomas and identified 6 cases with hemizygous and 6 with homozygous deletions of the p16 locus. Eight of these cases showed a concurrent amplification of the EGFR gene (epidermal growth factor receptor) while the overall frequency was 35%. This close correlation suggests that deletion of the p16 chromosomal region constitutes another genetic hallmark of the primary glioblastoma, which rapidly develops de novo, without a less malignant precursor lesion and for which EGFR amplification is a characteristic genetic change. The p16 protein was not detectable in 15 of 22 glioblastomas but only 4 of these showed homozygous deletion of the gene. The alternative transcript p16 beta, for which a growth-suppressing function has been suggested, was co-expressed with p16 alpha mRNA in most cases. Hypermethylation of CpG islands in the 5' region of the p16 gene was identified in only 1 case, suggesting that this alternative mechanism of gene silencing is rarely responsible for loss of p16 expression in glioblastomas. Likewise, only 1 glioblastoma carried a p16 mutation and in addition, unexpectedly, a homozygous deletion of p16 in approximately 80% of tumor cells. This mutation, Arg24Pro, has previously been identified in a melanoma kindred.
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PMID:Hemizygous or homozygous deletion of the chromosomal region containing the p16INK4a gene is associated with amplification of the EGF receptor gene in glioblastomas. 933 10

Primary glioblastomas develop rapidly de novo through a genetic pathway characterized by amplification/overexpression of EGFR and of MDM2 genes. Secondary glioblastomas develop more slowly through progression from low grade or anaplastic astrocytoma and show a high incidence of a p53 mutation. In the present study, primary and secondary glioblastomas were analyzed for p16 deletions and CDK4 amplification by differential PCR and for loss of expression of the retinoblastoma (RB) gene by immunohistochemistry. Except for one case, alterations in the structure or expression of p16, CDK4 and RB were mutually exclusive. The overall incidence of aberrant expression of these genes coding for components of the cell-cycling-regulatory system was similar in primary (14/28; 50%) and secondary glioblastomas (9/23; 39%). However, p16 deletions were significantly more frequent in the former (10/28; 36%) than in the latter (1/23, 4%; P = 0.0075), suggesting that this alteration constitutes an additional genetic hallmark of the primary (de novo) glioblastoma.
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PMID:Alterations of cell cycle regulatory genes in primary (de novo) and secondary glioblastomas. 934 29

Previously we reported that a karyotypically silent t(4;14)(p16. 3;q32.3) translocation is present in about 25% of multiple myeloma (MM) tumors, and causes overexpression of FGFR3, which is 50 to 100 kb telomeric to the 4p16 breakpoints. Frequent FGFR3 kinase activating mutations in MM with t(4;14) translocations substantiate an oncogenic role for FGFR3. We now report that the 4p16 breakpoints occur telomeric to and within the 5' introns of a novel gene, MMSET (Multiple Myeloma SET domain). In normal tissues, MMSET has a complex pattern of expression with a short form (647 amino acids [aa]) containing an HMG box and hath region, and an alternatively spliced long form (1365 aa) containing the HMG box and hath region plus 4 PHD fingers and a SET domain. Although t(4;14) translocation results in IgH/MMSET hybrid transcripts, overexpression of MMSET also occurs from endogenous promoters on 4p16. Given the homology to HRX/MLL1/ALL1 at 11q23 that is dysregulated by translocations in acute leukemia, we hypothesize that dysregulation of MMSET contributes to neoplastic transformation in MM with t(4;14) translocation. This is the first example of an IgH translocation that simultaneously dysregulates two genes with oncogenic potential: FGFR3 on der(14) and MMSET on der(4).
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PMID:The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. 1151 Apr 69

The molecular changes associated with the transition of melanoma cells from radial growth phase to vertical growth phase (metastatic phenotype) are not well defined. Our recent studies have demonstrated that the two tumor suppressor genes, p53 and p16/CDKN2, do not play a major role in the acquisition of the metastatic phenotype in human melanoma. Mutations in p53 are infrequent and do not correlate with the metastatic potential of human melanoma cells while p16/CDKN2 abnormalities are frequent, but are not pre-requisite for the acquisition of the metastatic phenotype. On the other hand, the tyrosine-kinase receptor c-KIT and the cell adhesion molecule MCAM/MUC-18 play active roles in the progression of human melanoma. Metastatic melanoma cells overexpress MCAM and do not express the c-KIT receptor. Enforced c-KIT expression in metastatic cells significantly inhibited their growth and metastatic potential in nude mice. Furthermore, exposure of c-KIT-positive melanoma cells in vitro and in vivo to stem cell factor (SCF), the ligand for c-KIT, triggered apoptosis of these cells but not of normal melanocytes. Ectopic expression of MCAM into primary cutaneous melanoma cells enhanced their tumorigenicity and metastatic ability in vivo. We found that both genes, c-KIT and MCAM, are regulated by the transcription factor AP-2 and that metastatic melanoma cells do not express AP-2. We therefore propose that loss of AP-2 might be a crucial event in the progression of human melanoma.
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PMID:Molecular changes in human melanoma metastasis. 981 May 13

The main aim of this study was to compare the prognostic impact of different histologic grading systems, the expression of the cell cycle-associated antigen DNA-topoisomerase-II-alpha (Ki-S1) and the expression of cell cycle regulators in malignant fibrous histiocytomas (MFH) using multivariate analyses. Paraffin-embedded tissue of 161 cases of MFH were studied immunohistochemically for the expression of the proliferation marker Ki-S1, cell cycle regulators (p53, MDM2, waf-1, pRb, p16) and the oncoprotein EGFR. The percentage of immunolabelled tumor cells (index) was assessed. The histologic grade was determined by the two-level grading systems of Costa, Tsujimoto and Pezzi, by the three-level grading systems of Coindre and Van Unnik and by the grading system presented here. Univariate analyses using the LOG rank test showed that all of the applied grading systems produce highly significant differences in survival between the grades of malignancy. Multivariate analyses with COX regression demonstrated that only the grading system presented here, based on the parameters necroses, mitoses and cellularity, had independent prognostic relevance. Moreover, the inclusion of the proposed grading system, the Ki-S1-index and a prognostic index primarily based on the expression of cell cycle regulators into the COX regression was suited for predicting survival in MFH. The grading system presented shows considerable advantages over the grading systems compared in this study for use in the routine pathology of MFH. The prognostic power of the proposed grading system can be enhanced by the combined study of cell cycle regulators and Ki-S1.
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PMID:Prognostic relevance of histologic grading, the cell cycle-associated antigen Ki-S1 and cell cycle regulators in malignant fibrous histiocytomas: a multivariate analysis. 1009 40

We investigated the frequency and mutual relationship of molecular alterations in 33 malignant astrocytomas (28 glioblastomas and 5 anaplastic astrocytomas). The genetic alterations analyzed were: deletion of CDKN2a/p16 gene, TP53 mutations, and amplification of EGFR, MDM2 and CDK4. The most common genetic alteration was EGFR amplification which was revealed in 15 cases (45%). TP53 mutation was identified in 9 cases (27%) and CDKN2/p16 deletion was detected in 13 cases (41%). Either MDM2 and CDK4 amplifications were less frequent, as they were identified in 4 (12%) and 1 (3%) case, respectively. Of the 15 cases showing the amplification of EGFR, 9 had CDKN2/p16 deletion (60%, p = 0.04). On the other hand, CDKN2/p16 deletion and EGFR amplification rarely occurred with TP53 mutations (2 of 14 cases with CDKN2/p16 deletion, 14%). These results confirm the existence of at least two different pathways leading to the formation of a glioblastoma.
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PMID:Mutations of TP53, amplification of EGFR, MDM2 and CDK4, and deletions of CDKN2A in malignant astrocytomas. 1032 80

Astrocytic tumors occasionally arise in the central nervous system following radiotherapy. It is not clear if these gliomas represent a unique molecular genetic subset. We identified nine cases in which an astrocytoma arose within ports of previous radiation therapy, with total doses ranging from 2400 to 5500 cGy. Irradiated primary lesions included craniopharyngioma, pituitary adenoma, Hodgkin's lymphoma, ependymoma, pineal neoplasm, rhabdomyosarcoma, and three cases of lymphoblastic malignancies. Patients ranged from 9 to 60 years of age and developed secondary tumors 5 to 23 years after radiotherapy. The 9 postradiation neoplasms presented as either anaplastic astrocytoma (3 cases) or glioblastoma multiforme (6 cases). Two of the latter contained malignant mesenchymal components. We performed DNA sequence analysis, differential polymerase chain reaction (PCR), and quantitative PCR on DNA from formalin-fixed, paraffin-embedded tumors to evaluate possible alterations of p53, PTEN, K-ras, EGFR, MTAP, and p16 (MTS1/CDKN2) genes. By quantitative PCR, we found EGFR gene amplification in 2 of 8 tumors. One of these demonstrated strong immunoreactivity for EGFR. Quantitative PCR showed chromosome 9p deletions including p16 tumor suppressor gene (2 of 7 tumors) and MTAP gene (3 of 7). Five of 9 tumors demonstrated diffuse nuclear immunoreactivity for p53 protein. Sequencing of the p53 gene in these 9 cases revealed a mutation in only one of these cases, a G-to-A substitution in codon 285 (exon 8). Somewhat unexpectedly, no mutations were identified in PTEN, a commonly altered tumor suppressor gene in de novo glioblastoma multiformes. Unlike some radiation-induced tumors, no activating point mutations of the K-ras proto-oncogene or base pair deletions of tumor suppressor genes were noted. These radiation-induced tumors are distinctive in their high histological grade at clinical presentation. The spectrum of molecular genetic alterations appears to be similar to that described in spontaneous high grade astrocytomas, especially those of the de novo type.
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PMID:Molecular genetic alterations in radiation-induced astrocytomas. 1032 96


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