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 diagnosis of gastrointestinal stromal tumor (GIST) is currently based on morphologic features and immunohistochemical demonstration of KIT (CD117). However, some tumors (in our estimation approximately 4%) have clinicopathologic features of GIST but do not express KIT. To determine if these lesions are truly GISTs, we evaluated 25 tumors with clinical and histologic features typical of GIST, but with negative KIT immunohistochemistry, for KIT and PDGFRA mutations using DNA extracted from paraffin-embedded tissue. Most tumors originated in the stomach (N = 14) or omentum/mesentery (N = 5). The neoplasms were composed of epithelioid cells (13 cases), admixed epithelioid and spindle cells (8 cases), or spindle cells (4 cases). Absence of KIT expression was confirmed by immunoblotting in 5 cases. Tumor karyotypes performed in 4 cases were noncomplex with monosomy 14 or 14q deletion, typical of GIST. Mutational analysis revealed PDGFRA and KIT mutations in 18 and 4 tumors, respectively, whereas 3 tumors did not have apparent KIT or PDGFRA mutations. The PDGFRA mutations primarily involved exon 18 (N = 15) and included 11 tumors with missense mutation in codon 842 (PDGFRA D842V or D842Y). In conclusion, a small subset of GISTs with otherwise typical clinicopathologic and cytogenetic features do not express detectable KIT protein. When compared with KIT-positive GISTs, these KIT-negative GISTs are more likely to have epithelioid cell morphology, contain PDGFRA oncogenic mutations, and arise in the omentum/peritoneal surface. Notably, some KIT-negative GISTs contain imatinib-sensitive KIT or PDGFRA mutations; therefore, patients with KIT-negative GISTs should not, a priori, be denied imatinib therapy.
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PMID:KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications. 1522 58

Stem cell factor (SCF) and endothelin-1 (ET-1) have been reported to be up-regulated at the protein and gene levels in human epidermis after ultraviolet B (UVB) irradiation and to play central roles in UVB-induced pigmentation. However, little is known about the time sequence of SCF and ET-1 expression in UVB-exposed human epidermis and the coordination of their roles during epidermal pigmentation. To clarify such parameters in UVB-exposed human skin, we measured the expression patterns of SCF and ET-1 (as well as of their corresponding receptors) at the gene level at various times during UVB-induced human pigmentation. When human forearm skin was exposed to UVB radiation at two minimal erythemal doses, the expression of SCF mRNA transcripts was significantly enhanced at 3 days after irradiation with an early decrease and subsequently constant expression of SCF receptor (c-KIT) mRNA transcripts. In contrast, up-regulation of ET-1 and endothelin B receptor (ET(B)R) mRNA expression was synchronized at 5 to 10 days after irradiation in concert with an increased expression of tyrosinase mRNA transcripts and the increase in pigmentation. In parallel the expression of tyrosinase and ET(B)R proteins as well as ET-1 was up-regulated at 7 to 10 days after irradiation, whereas KIT protein decreased at 3 days after irradiation and returned to the nonirradiated control level at 5 days after irradiation. When cultured human melanocytes were treated with human recombinant SCF, ET(B)R protein expression and the binding of (125)I-labeled ET-1 to the ET(B)R were significantly increased, further suggesting the preferential and coordinated role of early expression of SCF in UVB-induced melanogenesis. These findings suggest that SCF/KIT signaling is predominantly involved in the early phase of UVB-induced human pigmentation during which it stimulates the ET-1/ET(B)R linkage that is associated with the later phase of UVB-induced melanogenesis.
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PMID:Biphasic expression of two paracrine melanogenic cytokines, stem cell factor and endothelin-1, in ultraviolet B-induced human melanogenesis. 1557 52

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and are characterized by mutations in the proto-oncogene KIT (c-kit). To date, the detection of genomic alterations of the c-kit gene has been based mostly on direct sequencing. However, sequencing is an expensive and time-consuming approach. Since the technology of WAVE DNA Fragment Analysis System (Transgenomic, Inc., Worcester, MA) (dHPLC) is available in our laboratory, we decided to evaluate its use. Sixteen patients with small/large intestine, stomach tumors were included in the study. Immunohistochemical evaluation was performed on formalin-fixed, paraffin-embedded specimens with the polyclonal antibody CD117 for the KIT protein. After DNA extraction and isolation from paraffin-embedded sections, a nested PCR approach was applied to amplify sequences of exon 11 of the c-kit gene. dHPLC and the ABI Prism 310 Genetic Analyzer (Applied Biosystems, Bedford, MA) were used respectively for screening and identification of genomic alterations. Immunohistochemical analysis revealed strong and diffuse KIT expression in each of the 16 paraffin-embedded sections examined. dHPLC analysis in two temperatures showed the presence of genomic alterations in 8 out of 16 (50%) samples examined. Subsequently, sequence analysis of exon 11 in those samples revealed c-kit alterations in only 8 out of 16 (50%) samples. These were five deletions, one of which was an in-frame deletion one-point mutation and one insertion. Furthermore, the sensitivity of both methods was compared by using different mixtures of a wild-type and a sample with a deletion in exon 11. dHPLC was shown to be able to detect genomic alterations in all four different sample mixtures, whereas with sequence analysis genomic alterations were detected only in the 1:2 and 1:4 sample mixtures. In conclusion, we showed that dHPLC is an efficient and accurate, as well as a more sensitive, method for screening of genomic alterations in exon 11 of the c-kit gene, compared to sequence analysis.
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PMID:Molecular analysis of GISTs: evaluation of sequencing and dHPLC. 1558 36

Thirty-one canine cutaneous masses, diagnosed as mast cell tumors (MCT) by histopathologic analysis, were used to evaluate the immunohistochemical pattern of expression of KIT protein (CD117), a type III tyrosine kinase protein involved in mast cell growth and differentiation. Lesions were graded as I (well differentiated), II (intermediate differentiation), or III (poorly differentiated) according to the following morphologic features: invasiveness, cellularity and cellular morphology, mitotic index, and stromal reaction. Immunohistochemical KIT expression was compared with histologic grade and some histomorphologic features (cell differentiation and nuclear grade) evaluated separately. A possible predictive role of biologic behavior in MCTs for KIT expression was also investigated. Immunohistochemical analysis revealed three different patterns of KIT expression: a cytoplasmic diffuse pattern, a membranous pattern with immunostaining located on the cell surface, and a cytoplasmic perinuclear pattern, where KIT expression was detected in the cytoplasm of the neoplastic mast cells, close to the nucleus. Statistical analysis showed a close relationship between different KIT immunohistochemical patterns and histologic grade (P < 0.00000), cell differentiation (P < 0.00000), and nuclear grade (P < 0.0024). According to Kaplan-Meier-estimated survival curves compared by survival analysis, KIT expression was significantly associated with survival time (P = 0.037) but not cancer-free interval (P = 0.50). Similar to other well-known histomorphological features, KIT expression is a useful parameter of malignancy in cutaneous MCTs. KIT expression also predicted the biological behavior of the tumors in this study.
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PMID:Expression of the KIT protein (CD117) in primary cutaneous mast cell tumors of the dog. 1558 71

Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their cognate receptor tyrosine kinases are strongly implicated in angiogenesis associated with solid tumors. SU11657 (SUGEN) is a selective multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity exerted by targeting PDGF receptors (PDGFR), VEGF receptors (VEGFR), stem cell factor receptor (c-KIT), and FMS-related tyrosine kinase 3. Oral administration of SU11657 at 40 mg x kg(-1) x d(-1) to athymic mice resulted in significant growth inhibition of a panel of s.c. human neuroblastoma xenografts, namely, fast-growing SK-N-AS, MYCN- amplified IMR-32, and SH-SY5Y, by 90, 93.8, and 88%, respectively, and was well tolerated. All of the cell lines expressed VEGFR-2, PDGFR-beta, and c-KIT protein in the tumor cell and endothelial cell compartment by immunohistochemistry, and the expression decreased during therapy. Plasma concentrations of VEGF-A, PDGF-BB, and stem cell factor increased per milliliter of tumor volume at days 10, 18, and 20 of therapy. Furthermore, SU11657 reduced tumor angiogenesis by 63-96%. Our experimental data suggest that the angiogenesis inhibitor SU11657 may be beneficial in the treatment of rapidly growing and highly vascularized solid tumors of childhood, such as neuroblastoma. In summary, the class III/V receptor tyrosine kinases and their ligands are implicated in angiogenesis, tumor cell proliferation, and cell survival, and it seems reasonable to determine whether interference with these pathways can suppress neuroblastoma growth or not.
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PMID:The selective class III/V receptor tyrosine kinase inhibitor SU11657 inhibits tumor growth and angiogenesis in experimental neuroblastomas grown in mice. 1571 57

The gastrointestinal stromal tumor cell line, GIST-T1, has a heterogenic 57-base pair deletion in exon 11 of the c-kit mutation, and the c-KIT protein in the GIST-T1 cells constitutively activated. We report that STI571 (Glivec; Novartis, Basel, Switzerland), a specific inhibitor of c-KIT, inhibits the clustering of c-KIT at the cell membrane of the GIST-T1 cells. Furthermore, STI571 prevents the interaction between c-KIT and the molecular chaperone, heat shock protein 90 (Hsp90). Geldanamycin, an inhibitor of Hsp90, also prevents interaction between c-KIT and Hsp90, and inhibits tyrosine phosphorylation of c-KIT. Our results indicate that c-KIT molecules are assembled on the cell surface of the GIST-T1 cells, and that the interaction between c-KIT and Hsp90 plays an important role in c-KIT activation.
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PMID:STI571 (Glivec) inhibits the interaction between c-KIT and heat shock protein 90 of the gastrointestinal stromal tumor cell line, GIST-T1. 1572 56

Mutations in the c-KIT gene have been identified in many sporadic and familial cases of gastrointestinal stromal tumor (GIST). We report a familial case of GIST with cutaneous hyperpigmentation associated with a novel germline mutation in the c-KIT gene. Screening for mutations in exon 11 of the c-KIT gene in genomic DNA from tumors and peripheral blood of the members of a family with GISTs was undertaken by direct genomic sequencing. Tumors from GIST patients were analyzed histologically and immunohistochemically. Clinical examination of GIST patients was also performed to detect other systemic diseases associated with c-KIT mutations. Histological study showed that the tumors were GISTs expressing CD34 and c-KIT protein. This GIST-hyperpigmentation disease was associated in the family with a germline mutation in the c-KIT gene. The mutation is a duplication of the sequence CAACTT located in exon 11 of the c-KIT gene, which introduces two extra glutamine and leucine residues in the encoding protein between positions 576 and 577. This Spanish family was affected with GISTs and cutaneous hyperpigmentation associated with a novel germline mutation Leu576_Pro577insGlnLeu in the juxtamembrane domain of the c-KIT receptor. These types of mutation in the c-KIT gene activate the tyrosine kinase activity of the c-KIT receptor and induce constitutive signaling leading to GISTs, in some cases associated with cutaneous hyperpigmentation.
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PMID:Novel c-KIT germline mutation in a family with gastrointestinal stromal tumors and cutaneous hyperpigmentation. 1574 74

In the last few years a body of knowledge has been generated on the molecular basis of gastrointestinal stromal tumors (GIST). These mesenchymal tumors are characterized by the expression of KIT protein and because they have an activating mutation in a class III receptor tyrosine kinase gene (KIT or PDGFRA). Several KIT-activating mutations, which are largely responsible for the development of this tumor, promote cell survival, proliferation, and migration through different pathways such as MAPK p42/44, AKT, S6K, STAT1, and STAT3. Likewise, gene-activating mutations in the gene PDGFRalpha which codes for the receptor tyrosine kinase, Platelet-derived growth factor receptor alpha have been identified in GIST lacking KIT mutations. This means that KIT and PDGFRalpha mutations appear to be alternative and mutually exclusive oncogenic pathways for GIST development. These tumors may occur anywhere along the gastrointestinal tract (GI). The most frequently involved sites are stomach and small intestine. They are typically chemo- and radioresistant. The discovery of a specific inhibitor of this tyrosine kinase, imatinib mesylate, has radically changed the prognosis of patients with unresectable disease. Only 4 yr after the first patient was successfully treated with imatinib, multiple phase II and III trials have been published and, currently, imatinib mesylate is the only effective systemic treatment available of these tumors. Response rates are approximately 70-90% with acceptable toxicity. GIST are the first model of a solid tumor efficiently treated with a molecular-targeted agent. This review summarizes the clinical and biological aspects of this unique neoplasm.
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PMID:A clinical and biological overview of gastrointestinal stromal tumors. 1575 Jan 90

C- kit encodes the membrane-bound tyrosine kinase KIT, whose expression has been identified in several types of human neoplasms. Recently, KIT has been reported to be a marker for chromophobe renal cell carcinoma (RCC) and renal angiomyolipoma. However, expression of this molecule has not been adequately studied in other renal tumors, particularly oncocytoma, which may morphologically resemble chromophobe RCC. In this study, we analyzed c- kit messenger RNA (mRNA) levels in 17 chromophobe RCCs and 20 renal oncocytomas obtained from complementary DNA (cDNA) microarrays. Furthermore, comprehensive immunohistochemical analysis of KIT protein using a monoclonal antibody was performed in 226 renal tumors including chromophobe RCC (n=40), oncocytoma (n=41), clear-cell RCC (n=40), renal angiomyolipoma (n=29), and papillary RCC (n=21) on tissue microarrays (TMAs) and was compared with immunostaining results from 25 chromophobe RCCs and 30 oncocytomas using standard sections. The staining intensity was semiquantitatively graded on a 3-tier scoring system. All chromophobe RCCs and oncocytomas showed significant overexpression of c- kit mRNA. The average increase of mRNA compared with normal kidney tissue was 7.4-fold for chromophobe RCCs and 7.4-fold for oncocytomas. Immunohistochemical expression of KIT was found in most chromophobe RCCs (95% in TMAs and 96% in conventional sections) and oncocytomas (88% in TMAs and 100% in conventional sections) but was infrequently observed in renal angiomyolipomas (17%), papillary RCCs (5%), and clear-cell RCCs (3%). Furthermore, the average KIT immunoreactivity in TMAs was stronger in chromophobe RCC (1.93) and oncocytoma (2.07) than in other subtypes of renal tumors tested, including angiomyolipomas (0.17), papillary RCCs (0.05), and clear-cell RCCs (0.03). In conclusion, we found a significant elevation of c- kit mRNA by cDNA expression microarrays and overexpression of KIT protein by immunohistochemistry not only in chromophobe RCCs but also in oncocytomas. In contrast, immunohistochemical expression of KIT was not detected in most other types of renal cell tumors evaluated. The differential expression of c- kit in these renal tumors may have diagnostic and therapeutic implications.
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PMID:C-kit expression in renal oncocytomas and chromophobe renal cell carcinomas. 1579 70

The tyrosine kinase receptor KIT plays a major role in gastrointestinal stromal tumors (GISTs) oncogenesis. Indeed, 95% of GISTs express KIT protein, and about 70% exhibit activating mutations of the KIT gene. However, little is known about KIT overexpression mechanisms in these tumors, and the correlation with KIT mutations. GISTs with mutations within exon 11 (n=12) or 9 (n=1) of KIT were compared with GISTs without KIT mutations in exons 9, 11, 13, and 17 (n=10), two of them had PDGFRA mutations. KIT amplification was studied by real-time PCR of KIT and beta-ACTIN genes, and by fluorescence in situ hybridization (FISH) using KIT and chromosome 4 centromere specific probes. KIT transcripts and protein expression were quantified by reverse transcription real-time PCR and Western blot respectively. Genomic analysis revealed a single mutated GIST with KIT amplification. KIT protein and RNA levels were highly variable in GISTs but closely correlated (r=0.82, P<1.10(-5)), and were higher in GISTs with KIT mutations (P=0.07 and P=0.03 respectively). In conclusion, contrasting with the regulation of other tyrosine kinase receptors, KIT overexpression in GISTs is rarely related to a gene amplification, which suggests a deregulation of KIT gene transcription.
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PMID:KIT overexpression and amplification in gastrointestinal stromal tumors (GISTs). 1586 70


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