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)

Ongoing studies in our laboratory have demonstrated that dietary energy restriction (DER) inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced AP-1 transcription factor binding to DNA in the epidermis of SENCAR mice. To dissect the specific signal transduction pathways through which DER inhibits the AP-1:DNA binding, we analyzed the activities of three major MAP kinases that lead to the induction of AP-1. The changes in ERK1 and ERK2 protein expression and phosphorylation were further characterized by western blot analysis. Female SENCAR mice were pre-fed ad libitum (AL) or 40% DER diet for 8-10 weeks. The kinase activities in mouse epidermis were determined by immune complex kinase assays at 0.5, 1, 4, or 6 h following treatment with 3.2 nmol TPA to the shaved dorsal backs. ERK activity at 1 h post-TPA treatment was nearly 5-fold (P< 0.005) above basal levels in AL mice while the increase was abolished in DER mice. The TPA-induced ERK activity in AL mice was accompanied by increased phosphorylation of ERK1 and ERK2 (P< 0.05), which was abrogated in DER mice. In addition, DER mice exhibited reduced expression of total ERK1 and ERK2 and higher proportions of ERK1 and ERK2 phosphorylation in comparison with AL mice (P<0.05). JNK activity was decreased at 1 and 6 h but increased at 4 h (P<0.05) post-TPA treatment. TPA did not change p38 kinase activity at the time points tested. Neither JNK nor p38 activity was altered by DER. Taken together, our results indicated for the first time that DER blocked the TPA stimulation of ERK activity and suggested that the inhibition of TPA-induced AP-1 activity by DER is likely through inhibition of ERK but not JNK or p38 kinase pathway.
Carcinogenesis 2001 Apr
PMID:Dietary energy restriction inhibits ERK but not JNK or p38 activity in the epidermis of SENCAR mice. 1128 96

The roles of the MYC, ERBB2, and CCND1 genes in thyroid carcinogenesis are poorly known. We used real-time quantitative polymerase chain reaction (PCR) assays based on fluorescent TaqMan methodology to quantify MYC, ERBB2, and CCND1 gene amplification and expression in 24 benign tumors (adenomas and goiter nodules) and 12 carcinomas (9 papillary, 2 follicular, and 1 anaplastic) of the thyroid. Real-time PCR is a recently developed method for nucleic acid quantification in homogeneous solutions, and has the potential to become a reference in terms of performance, accuracy, sensitivity, wide dynamic range, excellent interlaboratory agreement, and high throughput capacity, while avoiding the need for tedious post-PCR processing. Overexpression (>5 standard deviations above mean for normal thyroid tissues) of the ERBB2 and CCND1 genes was observed (3.2- to 5.2-fold and 3.8- to 8.4-fold, respectively) in 5 (14%) and 13 (36%) of 36 neoplastic thyroid RNA samples, respectively. Overexpression of the CCND1 gene was observed in both the benign and malignant thyroid tumors, whereas the ERBB2 gene was mainly overexpressed in malignant thyroid tumors. None of the neoplastic thyroid samples overexpressed MYC. No MYC, ERBB2, or CCND1 gene amplification was identified. These results suggest that the CCND1 gene plays an early role and the ERBB2 gene a later role in thyroid tumorigenesis.
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PMID:Analyses of MYC, ERBB2, and CCND1 genes in benign and malignant thyroid follicular cell tumors by real-time polymerase chain reaction. 1128 83

Colorectal carcinogenesis is a complex, multistep process involving genetic alterations and progressive changes in signaling pathways regulating intestinal epithelial cell proliferation, differentiation, and apoptosis. Although cyclooxygenase-2 (COX-2), gastrin-releasing peptide (GRP), and its receptor, GRP-R, are not normally expressed by the epithelial cells lining the human colon, the levels of all three proteins are aberrantly overexpressed in premalignant adenomatous polyps and colorectal carcinomas of humans. Overexpression of these proteins is associated with altered epithelial cell growth, adhesion, and tumor cell invasiveness, both in vitro and in vivo; however, a mechanistic link between GRP-R-mediated signaling pathways and increased COX-2 overexpression has not been established. We report that bombesin, a homolog of GRP, potently stimulates the expression of COX-2 mRNA and protein as well as the release of prostaglandin E(2) from a rat intestinal epithelial cell line engineered to express GRP-R. Bombesin stimulation of COX-2 expression requires an increase in [Ca(2+)](i), activation of extracellular signal-regulated kinase (ERK)-1 and -2 and p38(MAPK), and increased activation and expression of the transcription factors Elk-1, ATF-2, c-Fos, and c-Jun. These data suggest that the expression of GRP-R in intestinal epithelial cells may play a role in carcinogenesis by stimulating COX-2 overexpression through an activator protein-1-dependent pathway.
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PMID:Activator protein-1 transcription factor mediates bombesin-stimulated cyclooxygenase-2 expression in intestinal epithelial cells. 1129 36

The molecular mechanism of carcinogenesis is a multistep process that is characterized by both activation of oncogenes and inactivation of tumor suppressor genes. In the present study, mutations of N-ras, p53 and FMS-like tyrosine kinase 3 (FLT-3) genes and loss of expression of the deleted in colorectal carcinoma (DCC) gene were analyzed in 59 patients with myelodysplastic syndromes (MDS). Mutations of N-ras, p53, and FLT-3 genes were detected in 7, 7, 1 of the 59 patients with MDS, respectively. Loss of DCC expression was detected in 16 patients. Type of MDS patients with N-ras mutation were all refractory anemia with excess of blasts in transformation (RAEB-T). Abnormalities of p53 and DCC genes were significantly associated with survival time (p< 0.02, p< 0.004, respectively).
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PMID:[Abnormalities of the p53, N-ras, DCC and FLT-3 genes in myelodysplastic syndromes]. 1130 59

Epidermal growth factor (EGF) influences the cell by activation of its specific cell receptor (EGFR). It is regarded as one of the most effective mitogenic factors and plays a role in carcinogenesis. The aim of this study was the assessment of EGF expression in different types of cerebral neoplasms and searching for its correlation with histopathologic features of malignancy and presence of peritumoral oedema. Sixty seven samples of brain tumours were examined. Among them were 17 meningiomas, 34 gliomas and 16 metastases. Expression of EGF was estimated by a radioimmune assay. The authors found the presence of EGF in all types of tumours. No correlation was found between expression of EGF and histopathological signs of tumour malignancy, although a tendency appeared towards a higher level of that factor in anaplastic tumours. Also, no correlation was found between EGF and peritumoral oedema.
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PMID:[Epidermal growth factor expression in brain neoplasms]. 1131 93

Hepatocellular carcinoma (HCC) is the most frequently occurring liver carcinoma world-wide. Clinical and molecular medical analyses have produced a considerable amount of information about liver carcinogenesis. Loss of heterozygosity (LOH) analyses have revealed several chromosomal loci harboring potential tumor suppressors. These data support the idea that deletion or inactivation of tumor suppressors including RB, p53, BRCA2, E-cadherin and other candidate genes seem to be common events in HCC development. Factors associated with cell cycle regulation via the Wnt- and MAPK/ERK signaling pathways are frequently deregulated in hepatocarcinogenesis. Aberrant activation of telomerase also occurs in precancerous as well as cancerous lesions in HCC patients. To characterize the wide variety of genetic events that occur in HCC, mRNA expression has been compared in HCC and non-cancerous liver tissues, and several differentially expressed genes have been identified. Hepatitis B and C viruses are the main risk factors for HCC, and indeed some accessory functions of viral products seem to contribute to tumor development; however, whether they have a direct carcinogenic effect has not yet been established.
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PMID:Genetic and epigenetic events in human hepatocarcinogenesis. 1135 Dec 62

Specific point mutations of the RET proto-oncogene have been demonstrated to be responsible for multiple endocrine neoplasia (MEN) types 2A and 2B, for familial medullary thyroid carcinoma (MTC) syndromes, as well as for sporadic MTC. Here we show that nuclear factor (NF)-kappaB is activated in RET-associated C-cell carcinoma specimens. TT cells, a human MTC cell line expressing MEN 2A type RET, display transcriptionally active RelA(p65) in the nucleus. NF-kappaB activity in these cells is attributable to constitutive IkappaB kinase (IKK) activity and high turn over of IkappaBalpha. RET harboring the mutations C634R (MEN 2A) or M918T (MEN 2B), in contrast to wild-type RET, activates a NF-kappaB-dependent reporter construct upon transient transfection in HeLa cells. We show that the prototype RET mutation C634R enhances phosphorylation of IkappaBalpha by IKKbeta but not by IKKalpha. RET-induced NF-kappaB and IKKbeta activity requires Ras function but does neither involve the classical mitogen-activated protein kinase kinase/extracellular signal-regulated kinase nor the phosphoinositide 3-kinase/Akt pathways. In contrast, RET-induced NF-kappaB activity is dependent on Raf and MEKK1. Inhibition of constitutive NF-kappaB activity results in cell death of TT cells and blocks focus formation induced by oncogenic forms of RET in NIH 3T3 cells. These results suggest that RET-mediated carcinogenesis critically depends on IKK activity and subsequent NF-kappaB activation.
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PMID:Nuclear factor-kappaB is constitutively active in C-cell carcinoma and required for RET-induced transformation. 1138 85

Cancers develop and progress via activation of oncogenes and loss of tumor suppressor genes, a progression that can be recapitulated through cross breeding mouse strains harboring genetic mutations. To define the role of RET/PTC3, p53 and Fhit in thyroid carcinogenesis, we intercrossed RET/PTC3 transgenics with p53-/- mice. This new strain, RET/PTC3p53-/-, succumb to rapidly growing and strikingly large multilobed thyroid tumors containing mixtures of both well and poorly differentiated, highly proliferative follicular epithelial cells. Interestingly, transplanted tumors from RET/PTC3p53-/- mice grew in SCID but not syngeneic immunocompetent mice indicating that these advanced tumors were immunogenic. RET/PTC3 protein expression was reduced to undetectable levels in tumors of older mice suggesting that the continued elevated expression of RET/PTC3 may not be necessary for tumor progression. Similarly, expression of Fhit protein was reduced in early tumors and undetected in older tumors irrespective of tumor histopathology. In contrast to RET/PTC3p53-/- mice, RET/PTC3Fhit-/- mice did not develop advanced thyroid carcinomas. These studies support a model of human thyroid cancer whereby thyroid epithelium expresses RET/PTC3 protein at early stages of tumor development, followed by the reduction of RET/PTC3 and loss of p53 function with progressive reduction of Fhit protein expression coincident with malignant progression.
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PMID:Altered gene expression in immunogenic poorly differentiated thyroid carcinomas from RET/PTC3p53-/- mice. 1142 73

The roles of p38 MAP kinases and ERK in UVB induced cox-2 gene expression were studied in a human keratinocyte cell line, HaCaT. UVB significantly increased cox-2 gene expression at both protein and mRNA levels. As we reported previously, p38 and ERK were significantly activated after UVB irradiation in HaCaT cells. In addition, treating the cells with p38 inhibitor SB202190 or MEK inhibitor PD98059 specifically inhibited UVB induced p38 or ERK activation, respectively. In this study, we further examined the roles of p38 and ERK in UVB induced cox-2 gene expression in HaCaT cells. We found that SB202190 strongly inhibited UVB induced COX-2 protein expression at different time points and various UVB doses. Furthermore, SB202190 markedly inhibited UVB induced cox-2 mRNA. Our data indicated that ERK did not play a role in UVB induced cox-2 gene expression in human keratinocytes since suppression of ERK did not significantly alter UVB induced increase of COX-2 protein and mRNA. These results suggested, for the first time, that activation of p38 is required for UVB induced cox-2 gene expression in human keratinocytes. Since cox-2 expression plays an important role in UV carcinogenesis, p38 could be a potential molecular target for chemoprevention of skin cancer.
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PMID:Role of p38 MAP kinases and ERK in mediating ultraviolet-B induced cyclooxygenase-2 gene expression in human keratinocytes. 1143 56

The molecular events leading to the development and progression of serous ovarian carcinoma are not completely understood. We performed a large scale survey for the identification of differentially expressed genes in serous ovarian carcinoma by using cDNA array analysis. Differences in gene expression between serous adenocarcinoma and benign serous adenoma, and between advanced and/or moderately or poorly differentiated and local, highly differentiated serous adenocarcinoma were assessed. The most striking difference between adenocarcinoma and benign adenoma was upregulation of RHOGDI2 in the carcinomas irrespective of the clinical tumor stage. Other changes in carcinoma were upregulation of MET and Ne-dlg, and downregulation of HGFAC, desmin, and PDGFA. The most prominent differences between advanced and local adenocarcinoma were upregulation of COL3A1, CFGR, and MET in advanced carcinoma, and downregulation of HGFAC, FZD3, and BFL1 in the same tumors. In conclusion, significant differences were found in the gene expression between benign and malignant serous ovarian tumors, and between local, highly differentiated and advanced and/or moderately or poorly differentiated serous adenocarcinomas. The differentially expressed genes may be related to the carcinogenesis and progression of the malignant growth.
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PMID:Changes in gene expression during progression of ovarian carcinoma. 1145 21


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