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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our recent studies have implicated the TGF-alpha/epidermal growth factor receptor pathway in the genesis of testosterone (T) and estradiol-17 beta (E2)-induced dysplasia in the dorsolateral prostate (DLP) of Noble rats. This pathway was also found to be markedly up-regulated in the androgen-independent transplantable carcinoma that arose from the DLP of a Noble rat. In the current study, we investigated the expression of mitogen-activated protein kinase (MAP-kinase) and mitogen-activated kinase phosphatase-1 (MKP-1), key downstream regulators of growth factor-activated signal transduction in the DLP of castrated, castrated T-supplemented, and T+E2-treated rats and in the androgen-independent transplantable carcinoma. Both MAP-kinase and MKP-1 expression in the DLP were found to be dependent on androgen stimulation. Immunoblots of DLP from T+E2 treated rats demonstrated a selective decline in MKP-1 levels with no alteration in MAP-kinase expression. These findings suggest that the dual hormone treatment induces changes in the signal transduction pathway, which favors the protracted mitogenic action of MAP-kinase. In situ hybridization and immunohistochemistry findings corroborated the immunoblot data but also revealed that both MAP-kinase and MKP-1 were strongly expressed in severely dysplastic lesions, which may indicate the presence of transformed cells in these foci. In this regard, both proteins were strongly expressed in samples of the androgen-independent transplantable carcinoma. Taken together, results from this and our recent study suggest that alterations in a growth factor-MAP-kinase pathway may be important events in the initiation and progression of prostatic carcinoma.
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PMID:Mitogen-activated protein kinase and mitogen-activated kinase phosphatase-1 expression in the Noble rat model of sex hormone-induced prostatic dysplasia and carcinoma. 880 59

Faciogenital dysplasia (FGDY; MIM 305400), or Aarskog syndrome, is an X-linked developmental disorder that adversely affects the formation of specific skeletal structures including elements of the face, the cervical vertebrae, and the distal extremities. FGD1, the gene responsible for faciogenital dysplasia, encodes a guanine nucleotide exchange factor that specifically activates Cdc42, a member of the Rho (Ras homology) family of p21 GTPases. By activating Cdc42, FGD1 stimulates fibroblasts to form filopodia, cytoskeletal elements involved in cellular signaling and migration, and through Cdc42, FGD1 also activates the stress-activated protein kinase/c-Jun N-terminal kinase signaling cascade, a pathway that regulates cell growth and differentiation. Here, we report a detailed characterization of the genomic organization of the FGD1 gene. The FGD1 gene is composed of 18 exons that range in size from 31 to 1240 bp. These exons span over 51 kb of genomic DNA within region Xp11.21. Flanking intronic sequences and the sequence of the 5' and 3' untranslated regions were determined to facilitate the detection of FGDY patient mutations. Analyses show that FGD1 transcripts are differentially spliced; in brain and placenta an alternatively spliced form of the FGD1 transcript removes part of the Cdc42GEF domain to encode a null Cdc42 activator.
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PMID:Genomic organization of the faciogenital dysplasia (FGD1; Aarskog syndrome) gene. 926 45

Thanatophoric dysplasia (TD) is a lethal skeletal disorder caused by recurrent mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene. The mitogenic response of fetal TD I chondrocytes in primary cultures upon stimulation by either FGF 2 or FGF 9 did not significantly differ from controls. Although the levels of FGFR 3 mRNAs in cultured TD chondrocytes were similar to controls, an abundant immunoreactive material was observed at the perinuclear level using an anti-FGFR 3 antibody in TD cells. Transduction signaling via the mitogen-activated protein kinase pathway was assessed by measuring extracellular signal-regulated kinase activity (ERK 1 and ERK 2). Early ERKs activation following FGF 9 supplementation was observed in TD chondrocytes (2 min) as compared with controls (5 min) but no signal was detected in the absence of ligand. By contrast ligand-independent activation of the STAT signaling pathway was demonstrated in cultured TD cells and confirmed by immunodetection of Stat 1 in the nuclei of hypertrophic TD chondrocytes. Moreover, the presence of an increased number of apoptotic chondrocytes in TD fetuses was associated with a higher expression of Bax and the simultaneous decrease of Bcl-2 levels. Taken together, these results indicate that FGFR 3 mutations in TD I fetuses do not hamper chondrocyte proliferation but rather alter their differentiation by triggering premature apoptosis through activation of the STAT signaling pathway.
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PMID:Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia. 958 36

The fibroblast growth factor receptor (FGFR) family members mediate a number of important cellular processes, and are mutated or overexpressed in several forms of human cancer. Mutation of Lys650-->Glu in the activation loop of the FGFR3 kinase domain causes the lethal human skeletal disorder thanatophoric dysplasia type II (TDII) and is also found in patients with multiple myeloma, bladder and cervical carcinomas. This mutation leads to constitutive activation of FGFR3. To compare the signaling activity of FGFR family members, this activating mutation was generated in FGFR1, FGFR3, and FGFR4. We show that the kinase domains of FGFR1, FGFR3, and FGFR4 containing the activation loop mutation, when targeted to the plasma membrane by a myristylation signal, can transform NIH3T3 cells and induce neurite outgrowth in PC12 cells. Phosphorylation of Shp2, PLC-gamma, and MAPK was also stimulated by all three 'TDII-like' FGFR derivatives. Additionally, activation of Stat1 and Stat3 was observed in cells expressing the activated FGFR derivatives. Finally, we demonstrate that FGFR1, FGFR3, and FGFR4 derivatives can stimulate PI-3 kinase activity. Our comparison of these activated receptor derivatives reveals a significant overlap in the panel of effector proteins used to mediate downstream signals. This also represents the first demonstration that activation of FGFR4, in addition to FGFR1 and FGFR3, can induce cellular transformation. Moreover, our results suggest that Stat activation by FGFRs is important in their ability to act as oncogenes.
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PMID:Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. 1091 87

The t(4;14) translocation occurs frequently in multiple myeloma (MM) and results in the simultaneous dysregulated expression of 2 potential oncogenes, FGFR3 (fibroblast growth factor receptor 3) from der(14) and multiple myeloma SET domain protein/Wolf-Hirschhorn syndrome candidate gene 1 from der(4). It is now shown that myeloma cells carrying a t(4;14) translocation express a functional FGFR3 that in some cases is constitutively activated by the same mutations that cause thanatophoric dysplasia. As with activating mutations of K-ras and N-ras, which are reported in approximately 40% of patients with MM, activating mutations of FGFR3 occur during tumor progression. However, the constitutive activation of ras and FGFR3 does not occur in the same myeloma cells. Thus the activated forms of these proteins appear to share an overlapping role in tumor progression, suggesting that they also share the signaling cascade. Consistent with this prediction, it is shown that activated FGFR3-when expressed at levels similar to those seen in t(4;14) myeloma-is an oncogene that acts through the MAP kinase pathway to transform NIH 3T3 cells, which can then generate tumors in nude mice. Thus, FGFR3, when overexpressed in MM, may be not only oncogenic when stimulated by FGF ligands in the bone marrow microenvironment, but is also a target for activating mutations that enable FGFR3 to play a ras-like role in tumor progression.
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PMID:Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. 1151 Apr 69

Since apoptosis was described as a process distinct from necrosis, there have been many studies of programmed cell death in diseases, especially immunological diseases. Because cardiac myocytes are terminally differentiated cells, they have typically been assumed to die exclusively by necrosis. However, during the last six to seven years this view has been challenged by several studies demonstrating that a significant number of myocytes undergo apoptosis in myocardial infarction, heart failure, myocarditis, arrhythmogen right ventricular dysplasia, and immune rejection after cardiac transplantation, as well as in other conditions of stress. These are potentially very important observations, because apoptosis--unlike necrosis--can be blocked or reversed at early stages. The tracking of cytoprotective and apoptotic signal transduction pathways has proceeded rapidly with important new insights into the roles of mitochondria-dependent pathway, Bcl-2 protein family, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase and c-Jun N-terminal kinase in cell fate. New studies have demonstrated that specific inhibition of apoptosis and activation of cytoprotective mechanisms, based on the better understanding of the intracellular signaling pathways, can significantly protect cardiac myocytes. This review will assess progress in cardiac myocyte apoptosis research and report on the current status of anti-apoptotic therapy in acute and chronic heart diseases.
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PMID:[Molecular regulation of myocardial apoptosis]. 1157 6

Various human skeletal disorders are thought to be caused by mutations in fibroblast growth factor receptor 3 (FGFR3). These result in chronic FGFR3 hyperactivation and inhibition of bone growth. One such disorder, thanatophoric dysplasia, the most common form of sporadic, lethal dwarfism, is associated frequently with cysteine substitutions (G370C, S371C, and Y373C) in the extracellular juxtamembrane region of the receptor. These mutations have been suggested to induce disulfide-mediated receptor dimerization and constitutive activation. An adjacent cysteine substitution (G375C) leads to a less severe form of human dwarfism, achondroplasia, suggesting that the intensity of FGFR3 activation by these cross-links may be position dependent. To test this hypothesis, we have sequentially replaced each amino acid at positions 370-375 of FGFR3 with cysteine. Expression of each of these mutant forms in 293T cells led to their spontaneous, ligand-independent dimerization and increased basal phosphorylation. Wild-type (WT) FGFR3 became dimerized and phosphorylated only on FGF stimulation. Among the mutants, only two (G370C and S371C) caused high basal phosphorylation with significantly increased constitutive levels of mitogen-activated protein kinase (MAPK) phosphorylation and c-fos transcription. This activity was probably caused by mutant homodimer pairs, because WT-mutant heterodimers were observed only in the presence, but not in the absence, of FGF1. The high spontaneous activity of the mutants in positions 370-371, unlike those in 372-375, affirms their known involvement with thanatophoric dysplasia. We conclude that the G370C and S371C mutant receptors spontaneously dimerize in the correct spatial orientation required for effective signal transduction, whereas the 372-5 mutants, like the WT receptor, may achieve this orientation only on ligand binding.
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PMID:Differential activation of cysteine-substitution mutants of fibroblast growth factor receptor 3 is determined by cysteine localization. 1200 17

Alterations in gene expression represent key events in carcinogenesis. We have studied HPV-induced cervical carcinogenesis, using an HPV-33-positive cell line (UT-DEC-1) established from a low-grade vaginal dysplasia (VAIN-I). Early-passage cells contained HPV-33 in episomal form, but these were superseded at later passages by cells carrying only integrated virus. To gain insight into the biologic significance of HPV integration, we compared the level of gene expression in normal vaginal keratinocytes, early-passage and late-passage UT-DEC-1 cells, using cDNA microarrays. Total RNA was isolated from cells by CsCl-gradient centrifugation, reverse-transcribed with MMLV reverse transcriptase and labeled with alpha-(32)P ATP. A cDNA microarray expression profile analysis was performed with Clontech's Human Cancer 1.2 cDNA expression array kit. The 16 upregulated genes (cut-off 2-fold), identified by comparing both cell types to control keratinocytes, appeared to support cell-cycle progression or to be functional in mitosis. These included, e.g., MCM4 DNA replication licensing factor, cdc2p34 and chromatin assembly factor 1 p48 subunit. Downregulated genes (44 altogether) interfered with apoptosis and cell adhesion, including the apoptosis-inducing genes FRAP, Bik and caspase-9 precursor. The most significant differences between the late and early passages (29 and 46 constantly up- and downregulated genes without any fluctuation) were overexpression of the transcription factors E2F5 with its dimerization partner DP1, NF-kappa B and serine/threonine kinases and underexpression of enzymes of the MAPK pathway. Acquisition of a selective growth advantage after viral integration might be explained by a major shift from a MAPK pathway to cell-cycle dysregulation (G(2)/M).
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PMID:Transcriptional profiling of a human papillomavirus 33-positive squamous epithelial cell line which acquired a selective growth advantage after viral integration. 1211 47

Bony abnormalities are common findings in cases of neurofibromatosis 1. We might hypothesize that neurofibromin, the protein encoded by the neurofibromatosis 1 gene, plays important roles in bone development. Loss of function of oligodendrocyte-myelin glycoprotein gene and increased activity of ras p21 might increase the level of c-fos proto-oncogene in bones with formation of fibrous dysplasia-like tissue. Also, increased ras p21 might disturb collagen I synthesis by osteoblasts. Moreover, increased ras activity might increase the mitogenic signals to the nucleus through mitogen-activated protein kinase (MAPK) and disturb the level of the transcription factor core-binding factor alpha(1) (Cbfa1). Abnormal fibrous tissue and neurofibromas formed at the site of pseudarthrosis might represent abnormal response of periosteal fibroblasts for injury, an effect simulating the response of skin fibroblasts in neurofibromatosis 1 to injury.
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PMID:Bone development in neurofibromatosis 1. 1261

Auxiliary beta1 subunits of voltage-gated sodium channels (NaChs) critically regulate channel activity and may also act as cell adhesion molecules (CAMs). In a recent study we have shown that the expression of beta1 NaCh protein is increased in reactive astrocytes in a rat epilepsy model of mesial temporal lobe epilepsy. The present study was undertaken to examine whether changes of NaCh beta1 subunit protein expression are also associated with structural changes occurring in human reactive astrocytes under different pathological conditions in vivo, as well as in response to changing environmental conditions in vitro. Strong beta1 astroglial immunoreactivity was present in human brain tissue from patients with astrogliosis. The over-expression of beta1 protein in reactive glia was observed in both epilepsy-associated brain pathologies (temporal lobe epilepsy, cortical dysplasia), as well as non-epileptic (cerebral infarction, multiple sclerosis, amyotrophic lateral sclerosis, meningo-encephalitis) disorders. The up-regulation of beta1 subunit protein in astrocytes can be reproduced in vitro. beta1 protein is highly expressed in human astrocytes cultured in the presence of trophic factors, under conditions in which they show morphology similar to the morphology of cells undergoing reactive gliosis. The growth factor-induced overexpression of beta1 protein was abrogated by PD98059, which inhibits the mitogen-activated protein kinase pathway. These findings demonstrate that the expression of NaCh beta1 subunit protein in astrocytes is plastic, and indicate a novel mechanism for modulation of glial function in gliosis-associated pathologies.
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PMID:Expression and regulation of voltage-gated sodium channel beta1 subunit protein in human gliosis-associated pathologies. 1267 53


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