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)

Several proto-oncogenes have been reported to be expressed in normal and malignant hematopoietic cells. Since these studies have been done almost exclusively by Northern and dot-blot analyses using mixed populations of cells, any conclusions concerning quantitative changes in gene expression are difficult to document. We have developed a rapid and sensitive RNA-in situ hybridization technique permitting detection of as few as 5 copies of mRNA per individual cell. Using this technique we have studied the expression levels of several oncogenes including MYC, SIS, FMS, p53, FOS and RAF in both normal hematopoietic cells and bone marrow (BM) cells obtained from acute myelogenous leukemia (AML) patients at presentation, at relapse and in complete remission (CR). Two of these oncogenes, MYC and SIS, are expressed at levels at least 2-5-fold higher in hematopoietic cells obtained from leukemia patients than in any normal hematopoietic cell examined, including cells obtained from regenerating bone marrow. The proportion of abnormal cells correlated well with the percentage of blast cells determined by morphological examination. In 7 out of 10 AML patients in morphological remission, a subpopulation of cells is detectable with abnormally high levels of MYC and/or SIS mRNA. These high levels of MYC expression are similar to those found in BM cells obtained from AML patients at presentation or relapse, but the percentage of cells with this abnormality is generally much lower. Continued follow-up of these patients has shown that 5 of them relapsed within 8 months. At this time, none of the 3 patients which were negative for MYC overexpression has relapsed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Detection of minimal residual disease in acute myelogenous leukemia by RNA-in situ hybridization. 265 88

EGF and related polypeptides are involved in the regulation of cell growth and differentiation of continuously regenerating tissues, in tissue repair processes and in placental and fetal development. Their initial mode of action generally constitutes binding to specific plasma membrane localized receptors, transduction of the signal across the plasma membrane, subsequent activation of signalling pathways in the cell, and the induction of early nuclear gene expression. EGF-induced signal transmission from the plasma membrane to the nucleus has been studied in microgravity in order to gain insight in the molecular mechanisms that constitute the effects of gravity on cell growth. Exposure of human A431 cells to microgravity strongly suppresses EGF- and PMA-induced c-fos and c-jun expression. In contrast, forskolin- and A23187-induced c-fos expression and constitutive beta-2 microglobulin expression remain unaffected. This suggests that microgravity differentially modulates EGF-induced signal transduction pathways. Since both EGF and PMA are known to be activators of PKC, which is not the case for forskolin and A23187, PKC-mediated signal transduction may be a cellular target for microgravity. Inhibition of EGF-induced c-fos expression by microgravity occurs downstream of the initiation of EGF-induced signal transduction, i.e., EGF binding and EGFR redistribution. In addition to PKC signaling, actin microfilament organization appears to be sensitive to microgravity. Therefore, the inhibition of signal transduction by microgravity may be related to alterations in actin microfilament organization. The fact that early gene expression is affected by agents that alter the organization of the actin microfilament system supports this hypothesis. The decrease in c-fos and c-jun expression in microgravity may result in the decreased formation of the FOS and JUN proteins. Consequently, a short-term reduction in gene expression in microgravity may have a more dramatic effect over the long term, since both the JUN and FOS protein families are required for normal cell cycle progression. However, since more than 20 years of manned spaceflight have shown that humans can survive in microgravity for prolonged periods, it appears that cells in the human body can partly or completely overcome gravitational stress. Although some insight in the molecular basis on human cells has been obtained, future studies will be needed for a better understanding of the grounds for alterations in the cellular biochemistry due to altered gravity conditions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of gravity on the cellular response to epidermal growth factor. 775 50

Transcripts coding for transcription factors (RB, P53, FOS, MYC, MYB, ERBA, REL), growth factors (FGF1, FGF2, INT2, TGFA, TGFB, PDGF, IGF1, IGF2), interleukins, (IL1, IL2, IL3, IL4, IL6, TNF), growth-factor receptors or cytosolic protein kinases (RAF, PIM, FES, MET, SRC, ROS, TRK, KIT, CSFR, IGFR, PDGFR, EGFR, NEU) were quantified in cultured human mammary fibroblasts from normal tissues, benign tumours, carcinomas and post-radiation fibrosis lesions by slot-blot autoradiography and image analysis. The effects of a differentiating agent (cholera toxin) and of a tumour promoter (12-O-tetradecanoyl-phorbol-13-acetate) were also examined. The drugs modulated the levels of the anti-oncogene transcripts (RB, P53) and of ERBA, REL, RAF, MET, ROS, TRK, CSFR, EGFR, NEU, FGF1, INT2, IGF1, IL1, IL2, IL4 and IL6. Apart from this variation, there were multiple differences in gene expression among normal and pathological cells (concerning all but P53, TGFB and interleukin transcripts) and between sub-types defined by the presence of alpha-sm-actin (myofibroblasts) or EDB-fibronectin (RAF, ROS, FES, KIT, IGFR, NEU, INT2, TGFB, PDGF, IGFs, ILs). It appears, therefore, that mammary stroma progress irreversibly along with the epithelium during tumoral development, and that breast cancer is not only a multi-gene but also a multi-tissue phenotype.
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PMID:Quantitative variation of proto-oncogene and cytokine gene expression in isolated breast fibroblasts. 776 44

DNA probes for the NRAS, HRAS, KRAS2, LCK, RAF1, MET, MYCL1, MYCN, MYB, ERBB2, FOS, CSF1R, and SRC protooncogene loci; the retinoblastoma gene locus (RB1); the tumor virus integration sites INT2, PVT1, and MLV12; and the locus of the tumor-specific antigen T1A were used to screen mouse genomic DNAs from RF/J, CAST/Ei, MOLF/Ei, Mus musculus musculus, M. m. poschiavinus, and M. spretus. Polymorphic DNA fragments for the 18 DNA probes have been identified using Southern blot hybridization and restriction fragment length polymorphism (RFLP) analysis.
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PMID:Novel RFLPs at protooncogene and cancer-related gene loci on mouse chromosomes. 809 10

The c-MET proto-oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF), also known as scatter factor, a potent mitogen and motogen for epithelial cells. The level of the HGF receptor expressed by epithelial cells varies in different growth conditions, being lower in growth arrested confluent monolayers and higher in growing sparse cells. The amount of HGF receptor mRNA increases from 3- to 5-fold after stimulation of confluent monolayers by serum and up to 10-fold after stimulation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate (TPA). An increased level of the receptor mRNA was also observed after cell stimulation with nanomolar concentration of HGF itself. The effect was transient, dose, and time-dependent. Transcription of a reporter gene under control of the cloned 297 base pair c-MET promoter was also stimulated by serum, TPA, or HGF. The accumulation of specific mRNA is followed by appearance of the HGF receptor precursor protein, which is further processed to the receptor mature form. After HGF stimulation, HGF receptor expression follows c-FOS and c-JUN induction with a peak approximately 4 h. Pretreatment with the protein synthesis inhibitor puromycin strongly reduced the response to HGF, while cycloheximide alone increased the level of the receptor mRNA. These data show that c-MET behaves as a delayed early-response gene and suggest that the HGF response is autoamplified by inducing the specific receptor.
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PMID:Hepatocyte growth factor (HGF) receptor expression is inducible and is part of the delayed-early response to HGF. 817 99

There is considerable interest in the role of the TRK family of neuotrophin receptors in regulating growth and differentiation in normal and neoplastic nerve cells. A neuroblastoma is a common pediatric tumor derived from the neural crest, and the majority of favorable neuroblastomas express a high level of TRK-A mRNA. However, little is known about the expression or function of TRK-B in these tumors. TRK-B encodes a tyrosine kinase that binds to brain-derived neuotrophic factor (BDNF), as well as neurotrophin-3 (NT-3) and NT-4/5. We have studied the N-myc-amplified human neuroblastoma cell line, SMS-KCN, which expresses both TRK-B and BDNF. Exogenous BDNF induces tyrosine phosphorylation of TRK-B as well as phosphorylation of phospholipase C-gamma 1, the extracellular signal-regulated kinases 1 and 2, and phosphatidylinositol-3 kinase. BDNF also induces expression of the immediate-early genes c-FOS and NGFI-A but not NGFI-B or NGFI-C. In addition, BDNF appears to promote cell survival and neurite outgrowth. SMS-KCN cells also express TRK-A, which is phosphorylated in response to nerve growth factor. However, the downstream TRK-A signaling is apparently defective. Finally, we determined that in a series of 74 primary neuroblastomas, 36% express TRK-B mRNA, 68% express BDNF mRNA, and 31% express both. Truncated TRK-B appears to be preferentially expressed in more-differentiated tumors (ganglioneuromas and ganglioneuroblastomas), whereas full-length TRK-B is expressed almost exclusively in immature neuroblastomas with N-myc amplification. Our findings suggest that in TRK-B-expressing human neuroblastomas, BDNF promotes survival and induces neurite outgrowth in an autocrine or paracrine manner. The BDNF/TRK-B pathway may be particularly important for growth and differentiation of neuroblastomas with N-myc amplification.
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PMID:Expression and function of TRK-B and BDNF in human neuroblastomas. 826 43

Non-small cell lung carcinoma specimens of 173 previously untreated patients were analyzed for the expression of proteins encoded by the oncogenes c-myc, c-fos, c-jun, c-erbB-1, c-erbB-2, c-H-ras, c-K-ras and c-N-ras. Forty-six per cent of the tumors were positive for the c-MYC protein, 60% for c-FOS, 50% for c-JUN, 80% for c-ERBB-1, 55% for c-ERBB-2, 12% for c-H-RAS, 5% for c-K-RAS and 71% for c-N-RAS. Proteins encoded by c-fos and c-jun are overexpressed more frequently in carcinomas of smokers (c-fos: P < 0.005; c-jun: P < 0.01). When we grouped the patients according to their tumor histology the results became more evident. Squamous cell lung carcinomas of smokers showed a higher incidence of c-FOS (P = 0.01), c-JUN (P < 0.01) and c-ERBB-1 (P = 0.01) proteins than squamous cell lung carcinomas of non-smokers. The expression rate and the intensity of staining proved not to be influenced either by the number of cigarettes smoked daily or by cessation of smoking. In adenocarcinomas, however, we only found a trend for a more frequent overexpression of c-fos (P = 0.07) and c-jun (P = 0.14) encoded proteins in carcinomas of smokers and no correlation between the expression of c-erbB-1 products and smoking. No correlation was found between the expression of c-MYC, c-ERBB-2, c-H-RAS, c-K-RAS and c-N-RAS proteins and the smoking habits of the patients, neither in squamous cell carcinomas nor in adenocarcinomas of the lung.
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PMID:Overexpression of oncoproteins in non-small cell lung carcinomas of smokers. 838 72

Patients with previously untreated squamous cell lung carcinomas were evaluated to see if combining the expression of molecular and cellular factors with the most important clinical prognostic factors could improve the diagnostic ability to predict prognosis. For this reason, immunohistochemistry was used to examine the squamous cell lung carcinomas from 121 patients for their expression of ERBB-1, vascular endothelial growth factor (VEGF), cyclin A, FOS, JUN and MYC. Median survival was shorter for patients with ERBB-1-, VEGF-, cyclin A-, FOS-, or JUN-positive tumours. For those patients with positive lymph node involvement, the survival times were also shorter in the VEGF-positive, cyclin A-positive and FOS-positive groups. Multivariate analysis independently demonstrated a significant prognostic value for lymph node involvement, VEGF and FOS.
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PMID:Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN and MYC in patients with squamous cell lung carcinomas. 948 27

The FMS proto-oncogene encodes the cell surface receptor for colony stimulating factor-1 (CSF-1). Mutations of the FMS gene at codon 969, in the C-terminal region of the gene, have been detected in haematological malignancies. To ascertain the biological significance of a mutation at this codon, we have used a murine haematopoietic cell line, FDC-P1, containing a mutation at codon 969 that results in a phenylalanine replacing a tyrosine. FMS 969 mutant cells and v-fms transfected cells conferred interleukin 3 (IL-3) independent stimulation of FDC-P1 cells, whereas cells transfected with a wild-type FMS construct required exogenous IL-3 for growth. FDC-P1 cells containing a FMS 969 mutation and v-fms transfected cells were tumorigenic in nude mice. Binding studies with radioidonated CSF-1 revealed saturable specific binding in FMS wild-type cells with a Km of 0.9 mM; however, mutant FMS-containing cells did not display saturation kinetics, but instead exhibited a linear relationship between ligand concentration and amount bound. Constitutive expression of FOS was detected in 969 mutant cells in the absence of exogenous CSF-1, a phenotype that was only inducible in wild-type cells in response to CSF-1. FOS and JUNB expression by v-FMS transfected cells showed a similar pattern to FMS wild-type cells. This mutation has been detected in patients with haematological malignancies, and illustrates that the pathway of FMS 969 phenylalanine mutations and v-fms induced pathogenesis can be distinguished. These data indicate that there is a biological role for FMS codon 969 phenylalanine mutation which results in transformation of FDC-P1 cells.
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PMID:Biological consequences of a point mutation at codon 969 of the FMS gene. 966 41

Proliferation, differentiation, and apoptosis are tightly regulated during hematopoiesis, allowing amplification along specific lineages while preventing excessive proliferation of immature cells. The MCL1 member of the BCL2 family is up-regulated during the induction of monocytic differentiation (approximately 10-fold with 12-O-tetradecanoylphorbol 13-acetate (TPA)). MCL1 has effects similar to those of BCL2, up-regulation promoting viability, but differs from BCL2 in its rapid inducibility and its pattern of expression. Nuclear factors that regulate MCL1 transcription have now been identified, extending the previous demonstration of signal transduction through mitogen-activated protein kinase. A 162-base pair segment of the human MCL1 5'-flank was found to direct luciferase reporter activity, allowing approximately 10-fold induction with TPA that was suppressible upon inhibition of the extracellular signal-regulated kinase (ERK) pathway. Serum response factor (SRF), Elk-1, and Sp1 bound to cognate sites within this segment, SRF and Elk-1 acting coordinately to affect both basal activity and TPA inducibility, whereas Sp1 affected basal activity only. Thus, the mechanism of the TPA-induced increase in MCL1 expression seen in myelomonocytic cells at early stages of differentiation involves signal transduction through ERKs and transcriptional activation through SRF/Elk-1. This finding provides a parallel to early response genes (e.g. c-FOS and EGR1) that affect maturation commitment in these cells and therefore suggests a means through which enhancement of cell viability may be linked to the induction of differentiation.
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PMID:Regulation of MCL1 through a serum response factor/Elk-1-mediated mechanism links expression of a viability-promoting member of the BCL2 family to the induction of hematopoietic cell differentiation. 988 May 63


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