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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This subject interests the practitioner as it will enable him to predict, at the time of diagnosis, what are the chances for the treatment being successful, how long will the survival be, etc.? Unquestionable factors are the extent of the tumour expressed as stage, the number of metastasis sites and the histological nature of the cancer. Possible factors are: 1) In non-small cell carcinomas: Stage 1: P 53 mutation, satellite nodules found at surgery, tumour size less than 2 cm in diameter. Operated cancers: absence of invaded lymph nodes, small size of the tumour, mutation on P 185 Neu, codon 12 mutation of the cancer ras, mutation of P 53. Effectiveness of chemotherapy: positive NSE labeling. 2) Small cell carcinomas: extent of the lesions, number of metastasis sites and performance index. When these prognostic factors are known, they must be taken into account for the attempted treatments. On the other hand, factors of poor prognosis may influence the therapeutic approach.
...
PMID:[Prognostic factors of lung cancer]. 839 27

Mitogen-activated protein kinases (MAPKs) are rapidly phosphorylated and activated in response to a variety of extracellular stimuli in many different cell types. The kinases that activate MAPK, the MAPK/ERK Kinases (MEKs), are also activated by phosphorylation. We have studied the influence of specific oncogenes on the regulation of MEK activity in NIH3T3 and Rat1a fibroblasts. We show that a similar MEK activity phosphorylates and activates MAPK in both growth factor-stimulated (epidermal growth factor and thrombin) and oncogene (gip2, v-src, and v-raf)-transfected cells. Gip2 and v-Src activated MEK-1 in transfected Rat 1a cells, whereas v-Raf activated MEK-1 in transfected NIH3T3 cells. These cell-selective differences in MEK activation parallel constitutive MAPK activation in these cell lines. Stable expression of the v-ras oncogene resulted in little constitutive MEK activation in either cell line, even though both were highly transformed. The growth factor and oncoprotein regulated MEK activity co-fractionated by Mono S chromatography with the 45-kDa MEK-1 protein. We further demonstrate in NIH3T3 and Rat 1a cells that Raf-1 is activated, as measured by its ability to phosphorylate MEK-1, in response to epidermal growth factor but not thrombin. Thus, the regulatory network of protein kinases that activate MAPK converges at MEK but diverges with the kinases that phosphorylate and activate MEK.
...
PMID:Activation of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase by G protein and tyrosine kinase oncoproteins. 839 52

Raf-1 is a serine/threonine kinase which is essential in cell growth and differentiation. Tyrosine kinase oncogenes and receptors and p21ras can activate Raf-1, and recent studies have suggested that Raf-1 functions upstream of MEK (MAP/ERK kinase), which phosphorylates and activates ERK. To determine whether or not Raf-1 directly activates MEK, we developed an in vitro assay with purified recombinant proteins. Epitope-tagged versions of Raf-1 and MEK and kinase-inactive mutants of each protein were expressed in Sf9 cells, and ERK1 was purified as a glutathione S-transferase fusion protein from bacteria. Raf-1 purified from Sf9 cells which had been coinfected with v-src or v-ras was able to phosphorylate kinase-active and kinase-inactive MEK. A kinase-inactive version of Raf-1 purified from cells that had been coinfected with v-src or v-ras was not able to phosphorylate MEK. Raf-1 phosphorylation of MEK activated it, as judged by its ability to stimulate the phosphorylation of myelin basic protein by glutathione S-transferase-ERK1. We conclude that MEK is a direct substrate of Raf-1 and that the activation of MEK by Raf-1 is due to phosphorylation by Raf-1, which is sufficient for MEK activation. We also tested the ability of protein kinase C to activate Raf-1 and found that, although protein kinase C phosphorylation of Raf-1 was able to stimulate its autokinase activity, it did not stimulate its ability to phosphorylate MEK.
...
PMID:Reconstitution of the Raf-1-MEK-ERK signal transduction pathway in vitro. 841 57

We have recently reported that about 50% of papillary thyroid carcinomas harbor an activated TRK or RET oncogene. Two retroviral vectors containing the activated TRK or RET/PTC oncogene have been used to infect a differentiated rat thyroid epithelial cell line, namely the PC Clone 3 cell line. Upon infection with the TRK virus, the PC Clone 3 cells lost only the ability to trap iodide and to express the thyroperoxidase gene. Conversely, when infected with the PTC virus, the PC Clone 3 cells completely lost all of their differentiated functions. However, both the PC-TRK and PC-PTC cell lines were unable to grow in soft agar, and they were not tumorigenic when injected into nude mice. A completely undifferentiated and malignant phenotype was obtained by the cooperation between the TRK or RET and the viral Ha-ras or Ki-ras oncogenes.
...
PMID:The TRK and RET tyrosine kinase oncogenes cooperate with ras in the neoplastic transformation of a rat thyroid epithelial cell line. 849 86

Most studies of the clonal origin of the underlying lesion(s) and all investigations using X-inactivation, have concluded that the myelodysplastic syndromes arise from a multipotent stem cell. Non-random chromosomal abnormalities, particularly deletions of 5q and 7q, are common, most notably in therapy related MDS. Progression to AML is also frequently accompanied by increased genomic instability as evidenced by the emergence of multiple karyotypic abnormalities. While some evidence hints at the presence of tumour suppressor genes on chromosomes 5, 7, 20 and 12, no such genes have yet been identified. The search for point mutations in known oncogenes has concentrated on two oncogenes RAS and c-FMS. Point mutation frequency generating active forms of RAS oncogenes is approximately 40% in MDS overall, up to 80% in studies of CMML. 60% of all MDS RAS mutation involves a G to A transition, producing a substitution of aspartate for glycine at a frequency of 50% (of total ras mutants). RAS mutation is associated with progression to AML, although the presence of a RAS point mutation alone is neither necessary nor sufficient for leukaemic transformation. Mutation of c-FMS is also more common in CMML in comparison to other MDS subtypes and, as yet, point mutation potentiating the response of the receptor to CSF-1 (codon 969) has been found more frequently than point mutation resulting in permanently activated receptor (codon 301). However, recent work has identified additional mutations which produce transforming proteins, and mutation rates at these sites may be relevant in MDS.
...
PMID:Myelodysplastic syndromes: from morphology to molecular biology. Part II. The molecular genetics of myelodysplasia. 849 99

Vulval induction in C. elegans is controlled by a highly conserved signaling pathway similar to the RTK-Ras-MAPK cascade in mammals. By screening for suppressors of the Multivulva phenotype caused by an activated let-60 ras allele, we isolated mutations in a gene, ksr-1, that acts as a positive modifier of vulval induction and is required for at least two other let-60 ras-mediated processes. Although ksr-1 mutations do not perturb vulval induction in an otherwise wild-type background, they have very strong effects on vulval induction in genetic backgrounds where Ras pathway activity is constitutively activated or compromised, suggesting that ksr-1 activity is required for maximal stimulation of vulval fates by the Ras pathway. Genetic epistasis analysis suggests that ksr-1 acts downstream of or in parallel to let-60 ras. We cloned ksr-1 and have shown that it encodes a novel putative protein kinase related to the Raf family of Ser/Thr kinases.
...
PMID:The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction. 852 6

The activated neu (HER2/c-erbB-2) oncogene is extremely potent in inducing mammary cancer. For example, neu induces greater than 200 times as many tumors as the activated ras oncogene when directly introduced into in situ rat mammary epithelial cells using replication-defective retroviral vectors. In order to characterize mechanisms underlying this potency, we sought to identify uniquely overexpressed genes in neu-initiated tumors that were not overexpressed in tumors induced by weaker initiating agents, including activated ras and the chemical carcinogens dimethylbenz[a]anthracene and N-nitroso-N-methylurea. Several genes, including those encoding keratin K7 and the u haplotype of MHC class I RT1-A, were found to be overexpressed in neu-initiated carcinomas as well as in mammary carcinomas induced by other agents, when compared to their expression in normal mammary tissue. One gene, however, encoding a member of the lipocalin and calycin protein families, was 12-fold overexpressed in neu mammary tumors and was not overexpressed in ras or chemically induced carcinomas. This uniquely overexpressed gene was termed neu-related lipocalin (NRL). NRL protein was produced in a baculovirus system, purified and used to generate polyclonal antibodies. Western blot analysis indicate that neu-initiated mammary carcinomas express abundant NRL protein when compared to other mammary tumors.
...
PMID:Overexpression of neu-related lipocalin (NRL) in neu-initiated but not ras or chemically initiated rat mammary carcinomas. 857 Jan 73

Cancer is a multistep phenomenon, and multiple cellular genetic lesions are involved in the emergence of the malignant neoplasm. Several early events, including ras mutations in follicular thyroid carcinoma and RET gene rearrangement in papillary tumors, have been implicated in the neoplastic transformation of thyrocytes. The stepwise array of mutations or deletions described to date in candidate oncogenes and tumor suppressor genes that are necessary for the advance to malignancy and for tumor progression await further investigation. The identification of additional, thyroid-cancer-specific lesions in these pathways is being further studied also.
...
PMID:Genetics of follicular thyroid cancer. 860 82

Characteristic of Philadelphia (Ph)+ chronic myelogenous leukemia (CML) is the presence of the chimeric BCR/ABL (p210) protein possessing elevated protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Our previous studies demonstrated subtle differences in the growth, phenotypic and morphologic characteristics of the most primitive subpopulations of primary lin-Ph+ chronic phase CML blasts and comparable primary lin- normal blasts. Recently, in comparing proteins phosphorylated on tyrosine in these cell populations, we reported a prominent 62 kDa phosphotyrosyl (P-tyr) protein constitutively present in primary primitive lin- CML chronic phase blasts which was virtually undetectable in primary primitive lin- normal blasts. In the present studies, we demonstrate that this P-tyr p62 from primary primitive lin- chronic phase CML blasts co-immunoprecipitates with ras-GAP. Furthermore, in addition to the p210 protein, we show in whole cell lysates the presence of other clearly consistent but less prominent P-tyr proteins with molecular weights of approximately 155, 140, 110, 55 and 45 kDa as well as more minor P-tyr proteins of approximately 190, 85, 52, 42 and 39 kDa constitutively present in primary primitive lin- chronic phase CML blasts. In analyzing proteins tyrosine phosphorylated in primary primitive lin- normal blasts in response to various hematopoietic growth factors, we found a striking similarity in the phosphorylation of four major (approximately 140, 110, 62 and 56 kDa) and three minor (approximately 51, 45 and 42 kDa) P-tyr proteins after stimulation with c-kit ligand and the P-tyr proteins constitutively phosphorylated in primary primitive lin- chronic phase CML blasts. Other growth factors tested (ie GM-CSF, G-CSF, IL-3, FLT3 ligand and EPO) were much less active or stimulated phosphorylation of other proteins. It is provocative that at least seven proteins rapidly and transiently phosphorylated on tyrosine in the c-kit ligand signal transduction pathway in lin- normal blasts may be constitutive substrates for the p210 activated tyrosine kinase in comparable lin- chronic phase CML blasts. In addition, it is intriguing that some of the biological effects on hematopoietic progenitors attributed to the c-kit ligand may be similar to some of the observed biological consequences of the p210 protein, including survival and expansion of a more mature stem cell population, probably at the time of lineage commitment rather than at the level of the earliest self-renewing stem cell.
...
PMID:c-kit ligand stimulates tyrosine phosphorylation of a similar pattern of phosphotyrosyl proteins in primary primitive normal hematopoietic progenitors that are constitutively phosphorylated in comparable primitive progenitors in chronic phase chronic myelogenous leukemia. 863 31

The cervix is an ideal organ for chemoprevention studies and the study of squamous carcinogenesis. In chemoprevention trial design, four factors are important: high-risk cohorts must be identified; suitable agents must be selected; study designs should include Phase 1, II, and III; and studies should include the use of surrogate endpoint biomarkers. High-risk cohorts can be selected for Phase I, II and III trials in the cervix, for example, patients with high grade lesions such as cervical intraepithelial neoplasia (CIN) grade 3 and carcinoma in situ (CIS). A Phase III trial might also include patients with lesions infected with oncogenic HPV types. The cervix is accessible and can be safely followed with Papanicolaou (Pap) smears and colposcopy. Suitable agents include those likely to work in squamous lesions, including retinoids, difluoromethylornithine, beta-carotene, and others. In Phase I chemopreventive studies, does are de-escalated rather than escalated, determining toxicity and optimal dose schedule. Phase II studies looking at effectiveness need placebo control groups since regression of high-risk lesions is possible. Phase III studies, now multicentric, should be carefully designed and include wide patient representation in order to evaluate the risk-benefit ratio of therapy, focusing on cancer incidence reduction. Surrogate endpoint biomarkers include quantitative histopathology, biologic measures of proliferation, regulation, differentiation, genetic instability, and fluorescence emission. Quantitative histopathologic markers include nuclear grading (i.e., shape, area, optical density, texture), nuclear pleomorphism, ploidy, and nucleolar size and position. Biomarkers under study at the present time in the cervix include proliferation markers (PCNA), regulation marker (EGFR, ras, myc, p53, retinoic acid receptors, ODC, spermidine/spermine ratios), differentiation markers (involucrin, cornifin, keratins), and markers of genetic instability (chromosome polysomy). Fluorescent spectroscopy uses light to probe the biochemical properties of tissue. This technique provides an automated diagnosis in real time with comparable sensitivity and specificity to colposcopy and can be used to monitor lesions in chemoprevention trials. Recruitment designs for cervix studies need to include a large referral population and patients with sufficiently large lesions. Clinicians involved in such studies need to stress contraception and smoking cessation, deal with language barriers, and provide compensation for child care and parking to patients in order to increase compliance.
...
PMID:Chemoprevention trials in the cervix: design, feasibility, and recruitment. 874 84


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---