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)

Mitogen-activated protein kinase (MAPK) or extracellular signal-regulated kinase are ubiquitous kinases conserved from fungi to mammals. Their activity is regulated by phosphorylation on both threonine and tyrosine, and they play a crucial role in the regulation of proliferation and differentiation. We report here the cloning of the murine p44 MAP kinase (extracellular signal-regulated kinase 1) gene, the determination of its intron/exon boundaries, and the characterization of its promoter. The gene spans approximately eight kilobases (kb) and can be divided into nine exons and eight introns, each coding region exon containing from one to three of the highly conserved protein kinase domains. Primer extension analysis reveals the existence of two major start sites of transcription located at -183 and -186 base pairs (bp) as well as four discrete start sites for transcription located at -178, -192, -273, and -292 bp of the initiation of translation. However, the start site region lacks TATA-like sequences but does contain initiator-like sequences proximal to the major start sites obtained by primer extension. 1 kb of the promoter region has been sequenced. It contains three putative TATA boxes far upstream of the main start sites region, one AP-1 box, one AP-2 box, one Malt box, one GAGA box, one half serum-responsive element, and putative binding sites for Sp1 (five), GC-rich binding factor (five), CTF-NF1 (one), Myb (one), p53 (two), Ets-1 (one), NF-IL6 (two), MyoD (two), Zeste (one), and hepatocyte nuclear factor-5 (one). To determine the sites critical for the function of the p44 MAPK promoter, we constructed a series of chimeric genes containing variable regions of the 5'-flanking sequence of p44 MAPK gene and the coding region for luciferase. Activity of the promoter, measured by its capacity to direct expression of a luciferase reporter gene, is strong, being comparable with the activity of the Rous sarcoma virus promoter. Progressive deletions of the approximately 1 kb (-1200/-78) promoter region allowed us to define a minimal region of 186 bp (-284/-78) that has maximal promoter activity. Within this context, deletion of the AP-2 binding site reduces by 30-40% the activity of the promoter. Further deletion of this minimal promoter that removes the major start sites (-167/-78) surprisingly preserves promoter activity. This result implicates a major role of this region that contains the Sp1 sites.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The mouse p44 mitogen-activated protein kinase (extracellular signal-regulated kinase 1) gene. Genomic organization and structure of the 5'-flanking regulatory region. 759 46

Ras proteins function through the formation of specific complexes with Raf-1, B-raf, PI-3 kinase and RalGDS. These interactions all require Ras-GTP with an intact effector binding domain (Switch I region). We have examined the requirements of the Switch II region (amino acids 60-72) for the production of stable interactions between Ras and its downstream effectors. A point mutation at position 65 or 64 combined with additional mutations at either position 65 or 71 rendered nucleotide-free Ras protein unable to stably interact with Ras specific guanine nucleotide exchange factors. Ha-Ras containing point mutations at positions 65 and 71 possessed a twofold higher affinity for B-raf and consequently MEK1. The point mutation at 64, in combination with additional point mutations at either position 65 or 71, resulted in a protein which failed to interact with either PI-3 kinase or neurofibromin, though these Ras mutants effectively bound both Raf-1 and B-raf. An activated form of Ras, Q61L-Ras, associated with all effector proteins independent of the bound guanine nucleotide. Q61L-Ras-GDP was almost as effective as wild type Ras-GMPPNP in the in vitro activation of MEK1 and MAP kinase. Competitive studies with the catalytic domain if neurofibromin, NF1-GRD, demonstrated that its interaction with Ras-GMPPNP is mutually exclusive with both Raf-1 and B-raf. These data suggest that rasGAP and neurofibromin are unable to downregulate Ras-GTP complexed to Raf-1 or B-raf.
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PMID:Different structural requirements within the switch II region of the Ras protein for interactions with specific downstream targets. 763 Jun 28

The mitogenic action of cytokines such as epidermal growth factor (EGF) or platelet derived growth factor (PDGF) involves the stimulation of a signal cascade controlled by a small G protein called Ras. Mutations of Ras can cause its constitutive activation and, as a consequence, bypass the regulation of cell growth by cytokines. Both growth factor-induced and oncogenic activation of Ras involve the conversion of Ras from the GDP-bound (D-Ras) to the GTP-bound (T-Ras) forms. T-Ras activates a network of protein kinases including c-Mos, c-Raf-1 and MAP kinase. Eventually the activation of MAP kinase leads to the activation of the elongation factor 4E and several transcription factors such as c-Jun, c-Myc and c-Fos. There are several modulators of Ras activity, such as the GTPase activating proteins (GAP1 and NF1), which stimulate the conversion of T-Ras to D-Ras. A series of small NF1 fragments, which bind T-Ras, as well as truncated forms of derivatives of c-Raf-1, c-Jun and c-Myc, are capable of blocking the T-Ras-activated mitogenesis in a competitive manner. These agents offer a unique opportunity to control the proliferation of T-Ras-associated tumors, which represent more than 30% of total human carcinomas.
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PMID:Regulation of the Ras signalling network. 794 77

Maintenance of mammary epithelial differentiation and milk production during lactation is a consequence of milk removal and the presence of lactogenic hormones, particularly glucocorticoids, insulin and prolactin. After weaning the fall in lactogenic hormones and milk stasis lead to involution, a process that is mainly characterized by three events: (i) downregulation of milk protein gene expression, (ii) loss of epithelial cells by apoptosis and, (iii) tissue remodeling and preparation of the gland for a new pregnancy. Each of these processes is likely to depend on the activity of specific sets of transcription factors in the mammary epithelium and stroma that ensure the timely and spatially coordinated expression of critical gene products such as mediators of apoptosis (e.g., caspase-1 and regulators of tissue remodeling events (e.g., matrix metalloproteinases). Here we describe signal transduction events such as activation of protein kinase A and JNK and changes in the activity of several transcription factors including Stat5, Stat3, NF1, Oct-1, and AP-1 during the early and late phases of mammary gland involution. We discuss their possible role in regulating and coordinating involution with emphasis on the apoptotic process of involution.
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PMID:Transcription factor activities and gene expression during mouse mammary gland involution. 1042 93

N-methyl-d-aspartate receptors (NMDAR) mediate long-lasting changes in synapse strength via downstream signaling pathways. We report proteomic characterization with mass spectrometry and immunoblotting of NMDAR multiprotein complexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins organized into receptor, adaptor, signaling, cytoskeletal and novel proteins, of which 30 are implicated from binding studies and another 19 participate in NMDAR signaling. NMDAR and metabotropic glutamate receptor subtypes were linked to cadherins and L1 cell-adhesion molecules in complexes lacking AMPA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins and Ras with effectors including MAPK pathway components. Several proteins were encoded by activity-dependent genes. Genetic or pharmacological interference with 15 NRC proteins impairs learning and with 22 proteins alters synaptic plasticity in rodents. Mutations in three human genes (NF1, Rsk-2, L1) are associated with learning impairments, indicating the NRC also participates in human cognition.
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PMID:Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. 1086 88

Neurofibromatosis type 1(NF1), a pleiotrophic autosomal dominant disorder, was first described in 1882 by Friedrich Daniel von Recklinghausen. The cloning of the NF1 gene located at 17q11.2 revealed that the gene contains 60 exons and spans 350 kb of genomic DNA in 1990. The gene product of NF1 is neurofibromin. Neurofibromin is a major negative regulator of the Ras pathway in cells, which transmits mitogenic signals to the nucleus through the cascade of MAP kinase. Loss of neurofibromin in patients with NF1 leads to accumulation of activated Ras (bound to GTP), and thus increases downstream mitogenic signaling. Future understanding the neurofibromin's role will contribute to the development of agents and genetic therapies which modulate Ras-mediated signaling pathways.
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PMID:[Characterization of the neurofibromatosis type 1 gene and neurofibromin's role in cells]. 1092 17

Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type I (NF1), a disease characterized by the formation of cutaneous neurofibromas infiltrated with a high density of degranulating mast cells. A hallmark of cell lines generated from NF1 patients or Nf1-deficient mice is their propensity to hyperproliferate. Neurofibromin, the protein encoded by NF1, negatively regulates p21(ras) activity by accelerating the conversion of Ras-GTP to Ras-GDP. However, identification of alterations in specific p21(ras) effector pathways that control proliferation in NF1-deficient cells is incomplete and critical for understanding disease pathogenesis. Recent studies have suggested that the proliferative effects of p21(ras) may depend on signaling outputs from the small Rho GTPases, Rac and Rho, but the physiologic importance of these interactions in an animal disease model has not been established. Using a genetic intercross between Nf1(+/)- and Rac2(-)(/)- mice, we now provide genetic evidence to support a biochemical model where hyperactivation of the extracellular signal-regulated kinase (ERK) via the hematopoietic-specific Rho GTPase, Rac2, directly contributes to the hyperproliferation of Nf1-deficient mast cells in vitro and in vivo. Further, we demonstrate that Rac2 functions as mediator of cross-talk between phosphoinositide 3-kinase (PI-3K) and the classical p21(ras)-Raf-Mek-ERK pathway to confer a distinct proliferative advantage to Nf1(+/)- mast cells. Thus, these studies identify Rac2 as a novel mediator of cross-talk between PI-3K and the p21(ras)-ERK pathway which functions to alter the cellular phenotype of a cell lineage involved in the pathologic complications of a common genetic disease.
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PMID:Hyperactivation of p21(ras) and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro. 1143 72

Neurofibromin is a tumor suppressor protein, which is similar in function to the GTPase activating protein (GAP), p120GAP, in that it accelerates inactivation of Ras. Mutations in the NF1 gene cause neurofibromatosis type 1, NF1, an autosomal dominant disease with a diverse spectrum of clinical manifestations, including neurofibromas. Ras activation (GTP binding) is induced by the GTP exchange factor Sos and its inactivation is regulated through the GAPs (p120GAP and neurofibromin). Strikingly, neurofibromin was nearly absent in MB-231 human breast cancer cells and present in the remaining four cell lines studied, with higher levels in BT-474 and MB-453 than in MCF-7 and BT-20 cells, as tested with polyclonal antibodies to both the N-terminal as well as the C-terminal peptides. Coordinated with the near absence of neurofibromin, these cells also presented with much greater levels of P-MAPK and activated Ras. Further, RT-PCR analysis demonstrated the absence of expression of NF1 mRNA type I isoform only in the MB-231 cell lines. This result documents for the first time an altered NF1 expression at the protein and mRNA levels in MDA-MB-231 breast cancer cells.
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PMID:Human breast cancer MDA-MB-231 cells fail to express the neurofibromin protein, lack its type I mRNA isoform and show accumulation of P-MAPK and activated Ras. 1156 91

The neurofibromatosis type 1 tumor suppressor protein neurofibromin, is a GTPase activating protein for H-, N-, K-, R-Ras and TC21/R-Ras2 proteins. We demonstrate that Schwann cells derived from Nf1-null mice have enhanced chemokinetic and chemotactic migration in comparison to wild-type controls. Surprisingly, this migratory phenotype is not inhibited by a farnesyltransferase inhibitor or dominant-negative (dn) (N17)H-Ras (which inhibits H-, N-, and K-Ras activation). We postulated that increased activity of R-Ras and/or TC21/R-Ras2, due to loss of Nf1, contributes to increased migration. Mouse Schwann cells (MSCs) express R-Ras and TC21/R-Ras2 and their specific guanine exchange factors, C3G and AND-34. Infection of Nf1-null MSCs with a dn(43N)R-Ras adenovirus (to inhibit both R-Ras and TC21/R-Ras2 activation) decreases migration by approximately 50%. Conversely, expression of activated (72L)TC21/R-Ras2, but not activated (38V)R-Ras, increases migration, suggesting a role of TC21/R-Ras2 activation in the migration of neurofibromin-deficient Schwann cells. TC21/R-Ras2 preferentially couples to the phosphatidylinositol 3-kinase (PI3-kinase) and MAP kinase pathways. Treatment with a PI3-kinase or MAP kinase inhibitor reduces Nf1-null Schwann cell migration, implicating these TC21 effectors in Schwann cell migration. These data reveal a key role for neurofibromin regulation of TC21/R-Ras2 in Schwann cells, a cell type critical to NF1 tumor pathogenesis.
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PMID:Role of TC21/R-Ras2 in enhanced migration of neurofibromin-deficient Schwann cells. 1472 65

S100A8 (A8) has roles in inflammation, differentiation and development and is associated with oxidative defense. Murine A8 (mA8) is up-regulated in macrophages, fibroblasts, and microvascular endothelial cells by LPS. Glucocorticoids (GCs) amplified LPS-induced mA8 in these cells. Relative to stimulation by LPS, GCs increased mA8 gene transcription and mRNA half-life. Enhancement required new protein synthesis, IL-10 and products of the cyclooxygenase-2 pathway, and both ERK1/2 and p38 MAPK. Protein kinase A positively and protein kinase C negatively regulated this process. Promoter analysis indicated element(s) essential for LPS and dexamethasone enhancement colocated within the region -178 to 0 bp. In the absence of glucocorticoid response elements, NF1 motif at -58 is a candidate for mediation of enhancement. Gel shift analysis detected no differences between LPS- and LPS/dexamethasone-treated complexes within this region. GCs increased constitutive levels of A8 and S100A9 (A9) mRNA in human monocytes. The synovial membrane of rheumatoid patients treated with high dose i.v. methylprednisolone contained higher numbers of A8/A9-positive macrophages than pre- or posttreatment samples. Results support the proposal that A8 has anti-inflammatory properties that may be independent of hetero-complex formation with A9 and may also enable localized defense in the absence of overriding deleterious host responses.
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PMID:Regulation of S100A8 by glucocorticoids. 1569 68


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