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 inheritance of 23 protein polymorphisms was compared with the inheritance of a DNA restriction fragment length polymorphism (RFLP) of a strongly cross-hybridizing erbB-related sequence, epidermal growth factor receptor-like-1 (EGFRL1), in Xiphophorus clemenciae X X. milleri-derived backcross hybrids. Two polymorphic bands were noted in this cross with a v-erbB probe after PstI digestion: a 10-kilobase (kb) band in X. clemenciae and a 9-kb band in X. milleri. Joint segregation analysis of the RFLPs and protein polymorphisms indicate that this erbB-related sequence can be assigned to Xiphophorus linkage group VI, which also comprises genes coding for glutamine synthetase (GLNS), nucleoside phosphorylase-2 (NP2), and transferin (TF). We have designated this RFLP as alleles at a locus called EGFRL1 because of very strong cross-hybridization with the v-erbB probe, known to be homologous to the mammalian EGFR gene. This mapping assignment is the first autosomal linkage of an oncogene sequence reported in fish, which provide a large number of genetically controlled experimental tumor models.
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PMID:Assignment of an erbB-like DNA sequence to linkage group VI in fishes of the genus Xiphophorus (Poeciliidae). 197 44

Epidermal growth factor (EGF) stimulates the growth of several types of epithelial tissues and possesses a strong mitogenic activity that is mediated through its cell surface receptor (EGFR). The aim of this study was to characterize EGFR and measure its levels in head and neck tumors biopsies (70 patients); use of a simplified competition technique with a radiolabeled ligand allowed evaluation of functional EGFR. Five samples (4 tumors and 1 control) were used to characterize EGF binding. Graphic representation identified a single family of binding sites. Kd values revealed high affinity for EGF binding: mean Kd, 0.156 +/- 0.108 nM (0.095-0.347 nM). EGF-binding characteristics (Kd) were similar in nontumoral tissue samples (controls) and in tumor material. In 59 of 60 cases, EGFR levels were higher in the tumor than in the corresponding controls. A significant correlation was found between EGFR levels and tumor size and stage. Controls exhibited a trend toward higher EGFR levels in elevated sizes and stages. According to a cutoff EGFR value of 100 fmol/mg protein, which separated all controls from tumors, EGFR-positive tumors (greater than 100 fmol/mg protein) had a greater probability of complete response to chemotherapy than EGFR-negative tumors; other tumor characteristics, such as the degree of tumoral differentiation, tumor size, or stage, were unable to operate such a discrimination in the response to chemotherapy. EGFR may thus be an interesting biological marker for head and neck cancer.
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PMID:Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas. 202 78

EGFR gene transcription in rat embryo and adult tissues were analysed by RNA Northern and Dot hybridization using 2.4 Kb human EGFR cDNA pE 7 as probe. In Northern hybridization (Fig. 1), the normal rat liver RNA showed a major 5.6 Kb RNA band which was a common EGFR mRNA present in human normal and cancer cells. For the comparison of EGFR gene transcription in embryo of different stages and different tissues, the density scanning data of dot hybridization signals are shown as bars in accompanying figures. The results indicated that the highest level of EGFR transcription was seen in rat embryo at 10th to 12th day during neonatal development (Fig. 2 and Fig. 3). In adult rat tissues, EGFR gene was commonly expressed with some variation in different tissues, for example, much more expressed in kidney than in liver, heart, brain and spleen, and moderately expressed in testis and lung (Fig. 4). The EGFR gene transcription could be induced in liver by hepatectomy. Fig. 5 showed the increase of EGFR gene transcripts at the 2-8 th hour of liver regeneration and the decrease after the 8th hour, even reaching a value lower than that of normal liver after the 24th hour. The results suggest that EGFR gene transcripts are commonly present in a wide range of normal tissues and may be involved in the control of proliferation and differentiation in embryo and adult tissues.
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PMID:[Analysis of EGFR gene transcription in rat embryo and adult tissues]. 203 13

The presence of gene amplification was determined in 66 fresh head-and-neck SCC specimens using a battery of 9 different probes. Amplification of at least one gene was found in 12 samples (18%), of which 7 were amplified at multiple loci (58%). We observed amplifications for EGFR (10% of samples) and c-myc (9%), as well as co-amplification of bcl-1/int-2 (7%). No amplifications were demonstrated for c-Ha-ras-1, TGF alpha, c-mos, c-erbB-2, or c-erbA-2. The incidence of proto-oncogene amplification in head-and-neck SCC patients is comparable to that reported for other solid tumours. There was no statistically significant difference in survival between patients with or without gene amplification. However, the presence of multiple amplifications in several patients with advanced primary tumours suggests that the accumulation of genetic changes may correlate more closely with tumour size than with inherent biologic aggression.
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PMID:Analysis of gene amplification in head-and-neck squamous-cell carcinoma. 204 98

We have generated a recombinant baculovirus using the high expression vector pVL941 containing the complementary DNA encoding the intracellular domain of the human epidermal growth factor receptor (EGFR-IC). Upon infection of Spodoptera frugiperda insect cells, protein tyrosine kinase-active EGFR-IC was produced. The expressed protein has a molecular weight of 61,000 and is specifically recognized by antibodies directed against peptides representing different regions of human EGFR-IC. Upon sonication of infected cells, EGFR-IC was detected in both the soluble and insoluble fractions of the cell lysate. About 20-50% of the expressed EGFR-IC was soluble. Metabolic labeling and protein analyses showed that EGFR-IC comprised 7% of newly synthesized proteins in the cytoplasmic lysate and 0.1-0.2% of the total soluble protein. We have used a three-step purification procedure (fast-Q-Sepharose and phenyl-Sepharose column chromatographies and 30% ammonium sulfate precipitation) to purify EGFR-IC to 85% purity with 15-20% recovery from the initial soluble lysate. A yield of 3-4 mg of purified EGFR-IC has been consistently produced from 20 roller bottles with 2-4 x 10(8) infected cells/bottle. The tyrosine kinase activity was retained through purification. The enzyme demonstrated much higher autophosphorylation activity in the presence of Mn2+ than Mg2+. Phosphopeptide mapping revealed the same autophosphorylation sites utilized by EGFR-IC as those identified in wild-type EGFR. EGFR-IC-catalyzed phosphorylation of either a synthetic peptide representing the major autophosphorylation site or angiotensin II showed that the baculovirus-expressed EGFR-IC exhibits similar enzymatic kinetic characteristics to the intact activated EGFR kinase.
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PMID:Generation of recombinant cytoplasmic domain of epidermal growth factor receptor with intrinsic protein tyrosine kinase activity. 208 99

Oncogenic potential of herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) which are both associated with occurrence of cervical cancer and the mechanism of oncogenesis by these viruses were investigated by transformation experiments in vitro. The results were obtained as follows. 1) HSV-2 induced neoplastic transformation of normal diploid cells is a multistep process. Cervical cancer associated antigen AG-4 is encoded within the specific region of HSV-2 DNA which converts immortalized cells to tumorigenic lines. 2) Tumor cells express cellular oncogene at a final stage of neoplastic transformation induced by HSV-2 and "hit and run" theory is applicable to oncogenesis of this virus. 3) Complete carcinogenesis can be mediated by HPV-16 or HPV-18 DNA under collaboration with other cofactors such as HSV-2. 4) It is suggested that neoplastic transformation induced by HPV-18 DNA is based on "hit and run" oncogenesis. 5) HPV-16 or HPV-18 DNA can immortalize primary diploid cells and convert them to fully tumorigenic phenotype by repeating cell passage. 6) It has been experimentally proved that the difference in transforming potential exists between HPV 6/11 and HPV 16/18. 7) Amplification and overexpression of c-myc oncogene was detected in transformed cells obtained by HPV-16 transfection. While overexpression of c-myc was detected in transformed cells induced by HPV-18 DNA, but no amplification was observed. On the other hand, detection of HPV, DNA and amplification or overexpression of protooncogenes was performed in cervical intraepithelial neoplasias (CIN) and invasive cervical carcinomas. The results were summarized as follows. 1) HPV DNA was detected in approximately 70% of a population with CIN by in situ hybridization. CIN II showed the highest incidence of positive HPV DNA (91%), and the positive ratio decreased in CIN III (56%). 2) Immunohistochemical study of paraffin-embedded specimens with monoclonal antibodies to oncogene products revealed that only some of cervical invasive carcinomas expressed c-myc protein, ras p21 or EGFR. 3) HPV DNA was detected in 46% of invasive cervical carcinomas by Southern blot hybridization. The percentage of patients with positive results for HPV 16/18 was 29%. However, it increased up to 58% by use of polymerase chain reaction (PCR), suggesting that there are many cervical cancer tissues in which a number of cells lack viral DNA. 4) Northern blot hybridization analysis revealed overexpression of c-myc mRNA in 30% of cervical invasive carcinomas although amplification of c-myc oncogene was detected in only one of invasive carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[The possibility of viral etiology in cervical carcinogenesis]. 217 17

Phospholipase C-gamma (PLC-gamma) and GTPase activating protein (GAP) are substrates of EGF, PDGF and other growth factor receptors. Since either PLC-gamma or GAP also bind to the activated receptors it was suggested that their SH2 domains are mediating this association. We attempted to delineate the specific region of the EGF receptor that is responsible for the binding, utilizing EGF receptor mutants, PLC-gamma, and a bacterially expressed TRP E fusion protein containing the SH2 domains of GAP. As previously shown, tyrosine autophosphorylation of the wild-type receptor wsa crucial in mediating the association and in agreement, a kinase negative EGF receptor could bind PLC-gamma or TRP E GAP SH2, but only when cross tyrosine phosphorylated by an active EGF receptor kinase. The importance of autophosphorylation for association was confirmed by demonstrating that a carboxy-terminal deletion of the EGFR missing four autophosphorylation sites bound these proteins poorly. To study the role of EGF receptor autophosphorylation further, a 203 amino acid EGF receptor fragment was generated with cyanogen bromide that contained all known tyrosine autophosphorylation sites. This fragment bound both TRP E GAP SH2 and PLC-gamma but only when tyrosine phosphorylated. This data localizes a major binding site for SH2 domain containing proteins to the carboxy-terminus of the EGF receptor and points to the importance of tyrosine phosphorylation in mediating this association.
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PMID:The tyrosine phosphorylated carboxyterminus of the EGF receptor is a binding site for GAP and PLC-gamma. 217 51

The epidermal growth factor (EGF) receptor (EGFR) can efficiently couple with mitogenic signaling pathways when it is transfected into interleukin-3 (IL-3)-dependent 32D hematopoietic cells. When expression vectors for erbB-2, which is structurally related to EGFR, or its truncated counterpart, delta NerbB-2, were introduced into 32D cells, neither was capable of inducing proliferation. This was despite overexpression and constitutive tyrosine kinase activity of their products at levels associated with potent transformation of fibroblast target cells. Thus, EGFR and erbB-2 couple with distinct mitogenic signaling pathways. The region responsible for the specificity of intracellular signal transduction was localized to a 270-amino acid stretch encompassing their respective tyrosine kinase domains. Thus, tissue- or cell-specific regulation of growth factor receptor signaling can occur at a point after the initial interaction of growth factor with receptor. Such specificity in signal transduction may account for the selection of certain oncogenes in some malignancies.
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PMID:EGF receptor and erbB-2 tyrosine kinase domains confer cell specificity for mitogenic signaling. 218 68

We have studied mRNA levels for a variety of growth factors in biopsy specimens from malignant, benign and normal breast tissue. We found TGFb mRNA in all breast cancers and neoplastic breast tissues but the level of the TGFb mRNA were found to be higher in breast cancer (P = 0.01). TGFa mRNA was detected in a similar proportion of cancers as in neoplastic breast tissues but the TGFa receptor EGFR mRNA was detected in only 55% of breast cancers but in all non-neoplastic breast tissue tested. The presence of EGFR mRNA was inverted related to oestrogen receptor status and coexpression of TGFa and EGFR was observed in 28% of carcinomas, and significantly more commonly in ER negative tumours (P = 0.01). PDGF a and b chain transcripts coexisted in all normal and malignant breast tissue. Insulin-like growth factor II mRNA was present in all 15 samples of non-malignant breast tissue but in only 11 of 21 (52%) of carcinomas.
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PMID:Growth factor expression in breast tissue. 228 95

Two retroviral DNAs that encode the normal human epidermal growth factor (EGF) receptor hEGFR have been generated by inserting a hEGFR cDNA into two different retroviral vectors. One DNA (pCO11-EGFR-neo) also contained a linked selectable marker gene (neoR). The other (pCO12-EGFR) only expresses hEGFR. When introduced into NIH3T3 cells, the two DNAs and the viruses derived from them induced a fully transformed phenotype, including focal transformation and growth in agar or low serum, but transformation depended entirely upon EGF being present in the growth medium. Compared with pCO11-EGFR-neo, pCO12-EGFR induced EGF-dependent transformation 2-5 times more efficiently and expressed higher numbers of receptors (4 x 10(5) vs. 1 x 10(5) EGF receptors per cell). The results indicate that transforming potential is directly related to the number of EGF receptors. In defined, serum-free medium that contained only very low concentrations of insulin (0.6 microgram/ml) and transferrin (0.6 micrograms/ml), hEGFR-virus infected cells were able to grow with EGF as the only growth factor. Moreover, daily incubation of the cells with EGF for only 30 min was sufficient to induce growth. NR6 cells, which lack endogenous EGF receptors, were transformed as efficiently as NIH3T3 cells by the hEGFR virus. The dose-dependent growth response to EGF of infected NR6 cells grown in serum-free medium can be used as a highly sensitive bioassay for the quantitative assessment of EGF and transforming growth factor type alpha (TGF alpha). This bioassay is at least as sensitive as previously reported radioimmunoassays and can measure a much wider concentration range (10 pg-100 ng/ml). Uninfected NR6 cells or NR6 cells infected by helper virus alone can be used as controls for the EGF specificity of growth stimulation.
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PMID:Retroviruses expressing different levels of the normal epidermal growth factor receptor: biological properties and new bioassay. 256 8


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