Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The RAS guanine nucleotide binding proteins activate multiple signaling events that regulate cell growth and differentiation. In quiescent fibroblasts, ectopic expression of activated H-RAS (H-RASV12, where V12 indicates valine-12) induces membrane ruffling, mitogen-activated protein (MAP) kinase activation, and stimulation of DNA synthesis. A mutant of activated H-RAS, H-RASV12C40 (where C40 indicates cysteine-40), was identified that was defective for MAP kinase activation and stimulation of DNA synthesis, but retained the ability to induce membrane ruffling. Another mutant of activated H-RAS, H-RASV12S35 (where S35 indicates serine-35), which activates MAP kinase, was defective for stimulation of membrane ruffling and induction of DNA synthesis. Expression of both mutants resulted in a stimulation of DNA synthesis that was comparable to that induced by H-RASV12. These results indicate that membrane ruffling and activation of MAP kinase represent distinct RAS effector pathways and that input from both pathways is required for the mitogenic activity of RAS.
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PMID:Stimulation of membrane ruffling and MAP kinase activation by distinct effectors of RAS. 862 98

SAF-1, a zinc finger transcription factor, is activated by a number of inflammatory agents, including interleukin-1 (IL-1) and IL-6. It is involved in the cytokine-mediated transcriptional induction of serum amyloid A, an acute-phase plasma protein that is associated with the pathogenesis of reactive amyloidosis, rheumatoid arthritis, and atherosclerosis. Here, we show that the mitogen-activated protein (MAP) kinase signaling pathway regulates cytokine-mediated induction of the DNA-binding activity and transactivation potential of SAF-1. Phosphorylation of endogenous SAF-1 in response to IL-1 and IL-6 was markedly inhibited by the addition of MAP kinase inhibitors. Consistent with this finding, we show that a consensus MAP kinase phosphorylation site, PPTP, within SAF-1 could be phosphorylated by MAP kinase in vitro. To analyze the contribution of MAP kinase in the activation of SAF-1, we prepared two independent mutant proteins in which the threonine residue of the PPTP motif was altered to either valine or alanine. These mutant proteins lost the ability to be phosphorylated by MAP kinase both in vivo and in vitro and exhibited a significantly reduced ability to promote expression of the SAF-1-regulated promoter. While the DNA-binding activity of wild-type SAF-1 protein was markedly increased upon phosphorylation with MAP kinase, no such increase could be detected with the mutant SAF-1 proteins. Further analysis with the GAL-4 reporter system showed that mutation of the MAP kinase phosphorylation site considerably lowers the transactivation potential of SAF-1. Together, these results show that activation of SAF-1 in response to IL-1 and -6 is mediated via MAP kinase-regulated phosphorylation.
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PMID:Cytokine-responsive induction of SAF-1 activity is mediated by a mitogen-activated protein kinase signaling pathway. 1180 95

Colorectal cancer is believed to progress through an adenoma-carcinoma sequence. However, recent evidence increasingly supports the existence of an alternative route for colorectal carcinogenesis through serrated polyps, a group that encompasses a morphological spectrum, including hyperplastic polyp (HP), admixed hyperplastic polyp/adenoma (HP/AD), and serrated adenoma (SA; the latter two manifest epithelial dysplasia). We have studied a large series of serrated polyps for BRAF and KRAS mutations. BRAF mutations were detected in 18 of 50 (36%) HPs, 2 of 10 (20%) HP/ADs, and 9 of 9 (100%) SAs. Twenty-six of 29 mutations caused amino acid substitutions at valine 599, the known hotspot. KRAS mutations were detected in 9 of 50 (18%) HPs, 6 of 10 (60%) HP/ADs, and 0 of 9 (0%) SAs. BRAF and KRAS mutations are mutually exclusive (P = 0.001). The associations of BRAF mutations with SAs (P < 0.001) and KRAS mutations with HP/ADs (P = 0.005) are statistically significant. A majority (90%) of the serrated polyps showing dysplasia had mutations in either BRAF or KRAS, significantly different from those without dysplasia (54%; P = 0.014). Our data highlight the important role of activation of the RAS-RAF-mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase-mitogen-activated protein kinase pathway in the initiation and progression of serrated neoplasms. Acquisition of a BRAF mutation appears to be associated with the progression of HP to SA, whereas progression to HP/AD is predominantly associated with acquisition of a KRAS mutation. The high incidence of BRAF mutations in HPs and SAs is consistent with the notion that the group of colorectal cancers carrying BRAF mutations may harbor most that have progressed through the HP-SA-carcinoma pathway.
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PMID:BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. 1294 9

Amino acid residues associated with functional specificity of cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), glycogen synthase kinases (GSKs), and CDK-like kinases (CLKs), which are collectively termed the CMGC group, were identified by categorizing and quantifying the selective constraints acting upon these proteins during evolution. Many constraints specific to CMGC kinases correspond to residues between the N-terminal end of the activation segment and a CMGC-conserved insert segment associated with coprotein binding. The strongest such constraint is imposed on a "CMGC-arginine" near the substrate phosphorylation site with a side chain that plays a role both in substrate recognition and in kinase activation. Two nearby buried waters, which are also present in non-CMGC kinases, typically position the main chain of this arginine relative to the catalytic loop. These and other CMGC-specific features suggest a structural linkage between coprotein binding, substrate recognition, and kinase activation. Constraints specific to individual subfamilies point to mechanisms for CMGC kinase specialization. Within casein kinase 2alpha (CK2alpha), for example, the binding of one of the buried waters appears prohibited by the side chain of a leucine that is highly conserved within CK2alpha and that, along with substitution of lysine for the CMGC-arginine, may contribute to the broad substrate specificity of CK2alpha by relaxing characteristically conserved, precise interactions near the active site. This leucine is replaced by a conserved isoleucine or valine in other CMGC kinases, thereby illustrating the potential functional significance of subtle amino acid substitutions. Analysis of other CMGC kinases similarly suggests candidate family-specific residues for experimental follow-up.
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PMID:Evolutionary constraints associated with functional specificity of the CMGC protein kinases MAPK, CDK, GSK, SRPK, DYRK, and CK2alpha. 1527 6

We investigated the effects of branched-chain amino acids on DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. Of the branched-chain amino acids, only leucine (10(-5)-10(-3) M) induced hepatocyte DNA synthesis and proliferation in a time- and dose-dependent manner. The addition of valine or isoleucine on its own had no significant effects on the hepatocyte DNA synthesis and proliferation. When combined, isoleucine competitively antagonized leucine-stimulated hepatocyte mitogenesis. U73122 (10(-6) M), AG1478 (10(-7) M), wortmannin (10(-7) M), PD98059 (10(-6) M) and rapamycin (10 ng/ml) inhibited the ability of leucine to stimulate the hepatocyte DNA synthesis and proliferation, suggesting that phospholipase C, tyrosine kinase, phosphatidylinositol 3-kinase, mitogen-activated protein (MAP) kinase, and p70 S6 kinase are involved in leucine signaling. The mitogenic effects of leucine are completely abolished by the addition of anti-transforming growth factor-alpha (TGF-alpha) antibody to the culture medium. Furthermore, leucine stimulated TGF-alpha secretion into the culture medium and the leucine effect was inhibited by U73122. Isoleucine alone had no significant effect on TGF-alpha secretion but this agent blocked leucine-induced TGF-alpha secretion. The results suggest that leucine triggers TGF-alpha secretion through a putative leucine receptor. The secreted TGF-alpha then stimulates hepatocyte DNA synthesis and proliferation through activation of TGF-alpha receptor to induce tyrosine kinase/MAP kinase activity and other downstream growth-related signal transducers.
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PMID:Effects of branched-chain amino acids on DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. 1576 40

The BRAF gene, one of the human isoforms of RAF, is activated by ras, leading to cooperative effects in cells responsive to growth factor signals. We studied the frequency of BRAF and k-ras-2 mutations in primary neuroendocrine gastroenteropancreatic (GEP) tumors. Mutation analysis of the BRAF and k-ras-2 genes was performed in 40 primary neuroendocrine tumors of the GEP system. The expression of extracellular signaling-related kinase (ERK) 1/2, an important downstream point of convergence in the ras-RAF-mitogen-activated protein-ERK pathway was analyzed immunohistochemically. We detected one 1796 T-->A BRAF mutation that led to a substitution of valine by glutamic acid at position 599 (V599E) in 40 primary neuroendocrine GEP tumors (3%). We failed to detect specific mutation of the k-ras-2 gene. We identified constitutively activated ERK in almost all neuroendocrine tumor tissues tested irrespective of BRAF mutation or localization or functional activity. These results suggest that BRAF mutations do not have a role in tumorigenesis of neuroendocrine tumors. Nevertheless, activation of the RAF/mitogen-activated protein kinase pathway might have a causative role in the development of neuroendocrine tumors, independent of BRAF or k-ras-2 mutation.
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PMID:BRAF gene mutations are rare events in gastroenteropancreatic neuroendocrine tumors. 1584 51

B-Raf(V600E), an oncogenic protein kinase, is the most frequent genetic alteration in papillary thyroid carcinomas (PTC). PTC represents 80-90% of all thyroid cancers and over the past five years, more than 200 manuscripts have been published about the relationship between "B-Raf(V600E) and thyroid cancer". B-Raf(V600E) genetically arises from a transversion point mutation (valine-to-glutamate substitution at amino acid residue-600, V600E) and leads to over activation of the mitogen-activated protein kinases (MAPK) signaling pathway. The MAPK pathway is essential for transmitting proliferation signals generated by cell surface receptors and cytoplasmic signaling elements to the nucleus. In many cancers, including thyroid cancer, B-Raf(V600E) appears to play a crucial role in cell proliferation, survival and de-differentiation. In thyroid cancer, the V600E mutation occurs with greater frequently in aggressive subtypes of PTC, and in individuals that present at advanced stages of disease with extra-thyroidal extension and/or lymph node metastases. B-Raf(V600E) is considered a marker of aggressive disease in both PTC (>1 cm) and micro-PTC (</=1 cm), and interestingly, is associated with both loss of I-131 avidity and PTC recurrence. Though treatment of patients with thyroid cancer is usually successful and most patients are rendered disease-free, to date there are no effective therapies for patients with invasive, non-radioiodine sensitive tumors or metastatic disease. In this article we will review the relation between B-Raf(V600E) and PTC, as well as both non-selective and selective pharmacological agents currently under investigation for treatment of B-Raf(V600E) positive PTC.
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PMID:Role of B-Raf(V600E) in differentiated thyroid cancer and preclinical validation of compounds against B-Raf(V600E). 1935 76

The papillary carcinoma is the most prevalent malignant neoplasm of the thyroid gland, representing 85-90% of all cases, and its incidence has been increasing in recent years. It is relatively indolent, however other types poorly differentiated or anaplastic, are more aggressive and usually associated with poor prognosis. Approximately half of these papillary carcinomas harbor a thymine-to-adenine transversion (T1799A) point mutation, in the gene encoding the serine/threonine-kinase B-type Raf kinase (BRAF), with substitution of valine by glutamate (V600E). Mutated BRAF, generates a constitutive activation of the mitogen-activated protein kinases (MAPK) signaling pathway, which plays a critical role in transmitting proliferative signals generated by cell surface receptors and cytoplasmic signaling elements, to the nucleus. BRAF mutation is mutually exclusive with other common genetic alterations, supporting its independent oncogenic role in cell proliferation, survival and tumor de-differentiation. The BRAFV600E occurs exclusively in papillary thyroid carcinoma and papillary carcinoma-derived anaplastic cancer, rising as a specific diagnostic marker for this tumor when identified in cytological / histological exams. This mutation has recently emerged, as a potential prognostic marker for papillary thyroid carcinoma, after several studies have found this mutation to be associated with some clinicopathological characteristics, known to predict tumor recurrence and progression, including, for instance, old patient age, extrathyroidal invasion and lymph node metastasis. It is therefore considered a marker of aggressive disease in these tumors, associated with increased cancer recurrence and even loss of radioiodine avidity. Several studies were not able to confirm these associations. It has become clearer that BRAF mutation will likely have significant impact on the clinical management of papillary thyroid carcinoma.
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PMID:[BRAF gene mutation in the natural history of papillary thyroid carcinoma: diagnostic and prognostic implications]. 2286 93

Proteins containing Valine-glutamine (VQ) motifs play important roles in plant growth and development, as well as in defense responses to both abiotic and biotic stresses. Blackleg disease, which is caused by Leptosphaeria maculans, is the most important disease in canola (Brassica napus L.) worldwide. H; however, the identification of B. napus VQs and their functions in response to blackleg disease have not yet been reported. In this study, we conducted a genome genome-wide identification and characterization of the VQ gene family in B. napus, including chromosome location, phylogenetic relations, gene structure, motif domain, synteny analysis, and cis-elements categorization of their promoter regions. To understand B. napus VQ gene function in response to blackleg disease, we overexpressed BnVQ7 (BnaA01g36880D, also known as the mitogen-activated protein kinase4 substrate1 (MKS1) gene) in a blackleg-susceptible canola variety Westar. Overexpression The overexpression of BnMKS1 in canola did not improve its resistance to blackleg disease at the seedling stage. H; however, transgenic canola plants overexpressing BnMKS1 displayed an enhanced resistance to L. maculans infection at the adult plant stage. Expression levels of downstream and defense marker genes in cotyledons increased significantly at the necrotrophic stage of L. maculans infection in the overexpression line of BnMKS1, suggesting that the SA salicylic acid (SA)- and jasmonic acid (JA )-mediated signaling pathways were both involved in the defense responses. Together, these results suggest that BnMKS1 might play an important role in the defense against L. maculans.
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PMID:Genome-Wide Identification and Analysis of VQ Motif-containing Gene Family in Brassica napus and Functional Characterization of BnMKS1 in Response to Leptosphaeria maculans. 3280 45