Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To glean biological differences and similarities of peripheral T-cell lymphoma-not otherwise specified [PTCL-NOS] to diffuse large B-cell lymphoma (DLBCL), a transcriptosome analysis was done on five PTCL-NOS and four DLBCL patients and validated by quantitative real-time reverse transcription-PCR on 10 selected genes. Normal peripheral blood T cells, peripheral blood B cells, and lymph node were used as controls. The resultant gene expression profile delineated distinct "tumor profile signatures" for PTCL-NOS and DLBCL. Several highly overexpressed genes in both PTCL-NOS and DLBCL involve the immune network, stroma, angiogenesis, and cell survival cascades that make important contributions to lymphomagenesis. Inflammatory chemokines and their receptors likely play a central role in these complex interrelated pathways: CCL2 and CXCR4 in PTCL-NOS and CCL5 and CCR1 in DLBCL. Highly overexpressed oncogenes unique to PTCL-NOS are SPI1, STK6, alpha-PDGFR, and SH2D1A, whereas in DLBCL they are PIM1, PIM2, LYN, BCL2A1, and RAB13. Oncogenes common to both lymphomas are MAFB, MET, NF-kappaB2, LCK, and LYN. Several tumor suppressors are also down-regulated (TPTE, MGC154, PTCH, ST5, and SUI1). This study illustrates the relevance of tumor-stroma immune trafficking and identified potential novel prognostic markers and targets for therapeutic intervention.
Mol Cancer Ther 2005 Dec
PMID:Transcript profiling in peripheral T-cell lymphoma, not otherwise specified, and diffuse large B-cell lymphoma identifies distinct tumor profile signatures. 1637 2

The Methoprene-tolerant (Met) bHLH-PAS gene in Drosophila melanogaster is involved in the molecular action of juvenile hormone (JH), and mutants result in resistance to the toxic and morphogenetic effects of JH and JH agonist insecticides such as methoprene. A detailed study of Met mutants can shed light on the poorly understood action of JH as well as the molecular basis of Met resistance to JH insecticides. Nine mutant alleles bearing point mutations in Met were examined for penetrance and expressivity of three phenotypic characters: resistance, defective oogenesis, and a novel eye defect. The collection ranged from two weak alleles having less severe phenotypes to strong alleles with severe phenotypes similar to that of a null allele. The point mutations were located in both conserved and nonconserved domains. Both the eye defect, seen as severely malformed ommatidial facets in the posterior margin of the compound eye, and the oogenesis phenotype are nonconditional, whereas expression of the resistance phenotype requires treatment with JH or JH analogs (JHAs) during early metamorphosis. A proposed basis for all the phenotypic characters centers on MET action as a transcriptional regulator of ecdysone secondary-response target genes during metamorphosis. Disruption of MET function either by mutation or by JHA presence during early metamorphosis results in transcriptional misregulation of different target genes, resulting in the pathology seen in either instance. The variety of amino acid changes in MET that resulted in resistance may portend a rapid rise in resistance in response to increased use of JH insecticides in field insect populations.
Mol Genet Genomics 2006 Sep
PMID:Wide mutational spectrum of a gene involved in hormone action and insecticide resistance in Drosophila melanogaster. 1680 58

Methionine and metabolites such as S-adenosylmethionine (AdoMet) are of vital importance for eukaryotes; AdoMet is the main donor of methyl groups and is involved in expression control of the methionine biosynthesis genes (MET genes). Genome-wide expression profiling of protein kinase CK2 deletion strains of the budding yeast Saccharomyces cerevisiae has indicated a function for CK2 in MET gene control. Deletion of the regulatory CK2 subunits leads to MET gene repression, presumably due to an impaired phosphorylation of the ubiquitin-conjugating enzyme Cdc34, which controls the central MET gene transcription factor Met4. We show that CK2 phosphorylates Cdc34 at two sites and one of these, Ser282, has a significant impact on MET gene expression in vivo, and that high AdoMet levels inhibit CK2. The data provide evidence for a control of MET gene expression by protein kinase CK2-mediated phosphorylation of Cdc34, and appear to suggest a feedback control loop in which high AdoMet-levels are limiting CK2 activity and thus MET gene expression.
Cell Mol Life Sci 2006 Sep
PMID:Control of methionine biosynthesis genes by protein kinase CK2-mediated phosphorylation of Cdc34. 1695 51

DNA copy number changes represent molecular fingerprints of solid tumors and are as such relevant for better understanding of tumor development and progression. In this study, we applied genome-wide array comparative genomic hybridization (aCGH) to identify gene-specific DNA copy number changes in chromosomal (CIN)- and microsatellite (MIN)-unstable sporadic colorectal cancers (sCRC). Genomic DNA was extracted from microdissected, matching normal colorectal epithelium and invasive tumor cells of formalin-fixed and paraffin-embedded tissues of 22 cases with colorectal cancer (CIN = 11, MIN = 11). DNA copy number changes were determined by aCGH for 287 target sequences in tumor cell DNAs, using pooled normal DNAs as reference. aCGH data of tumor cell DNAs was confirmed by fluorescence in situ hybridization (FISH) for three genes on serial tissues as those used for aCGH. aCGH revealed DNA copy number changes previously described by metaphase CGH (gains 7, 8q, 13q, and 20q; losses 8p, 15q, 18q, and 17p). However, chromosomal regions 20q, 13q, 7, and 17p were preferentially altered in CIN-type tumors and included DNA amplifications of eight genes on chromosome 20q (TOP1, AIB1, MYBL2, CAS, PTPN1, STK15, ZNF217, and CYP24), two genes on chromosome 13q (BRCA2 and D13S25), and three genes on chromosome 7 (IL6, CYLN2, and MET) as well as DNA deletions of two genes on chromosome 17p (HIC1 and LLGL1). Finally, additional CIN-tumor-associated DNA amplifications were identified for EXT1 (8q24.11) and MYC (8q24.12) as well as DNA deletions for MAP2K5 (15q23) and LAMA3 (18q11.2). In contrast, distinct MIN-tumor-associated DNA amplifications were detected for E2F5 (8p22-q21.3), GARP (11q13.5-q14), ATM (11q22.3), KAL (Xp22.3), and XIST (Xq13.2) as well as DNA deletions for RAF1 (3p25), DCC (18q21.3), and KEN (21q tel). aCGH revealed distinct DNA copy number changes of oncogenes and tumor suppressor genes in CIN- and MIN-type sporadic colorectal carcinomas. The identified candidate genes are likely to have distinct functional roles in the carcinogenesis and progression of CIN- and MIN-type sporadic CRCs and may be involved in the differential response of CIN- and MIN-type tumor cells to (adjuvant) therapy, such as 5-fluorouracil.
J Mol Med (Berl) 2007 Mar
PMID:Array CGH identifies distinct DNA copy number profiles of oncogenes and tumor suppressor genes in chromosomal- and microsatellite-unstable sporadic colorectal carcinomas. 1714 21

The multifunctional growth factor scatter factor/hepatocyte growth factor and its tyrosine kinase receptor, c-MET, have been implicated in the genesis and malignant progression of numerous human malignancies, including hepatocellular carcinomas. The incidence of hepatocellular carcinomas in the United States has increased noticeably over the past two decades and is listed as the fifth major cancer in men worldwide. In this study, we used a choline-deficient l-amino acid (CDAA)-defined rat hepatocarcinogenesis model to visualize increased in vivo expression of the c-MET antigen in neoplastic lesion formation with the use of a super paramagnetic iron oxide (SPIO)-anti-c-MET molecularly targeted magnetic resonance imaging (MRI) contrast agent. SPIO-anti-c-MET was used for the first time to detect overexpression of c-MET in neoplastic nodules and tumors within the livers of CDAA-treated rats, as determined by a decrease in MRI signal intensity and a decrease in regional T(2) values. Specificity for the binding of the molecularly targeted anti-c-MET contrast agent was determined using rat hepatoma (H4-II-E-C3) cell cultures and immunofluorescence microscopic imaging of the targeting agents within neoplastic liver tissue 1 to 2 hours following intravenous administration of SPIO-anti-c-MET and MRI investigation. This method has the ability to visualize in vivo the overexpression of c-MET at early developmental stages of tumor formation.
Mol Imaging
PMID:In vivo detection of c-MET expression in a rat hepatocarcinogenesis model using molecularly targeted magnetic resonance imaging. 1731 62

Much information has been reported on the genetic and genomic alterations in colorectal cancer (CRC) in literature; however, nonrandom chromosomal alterations in Chinese CRC patients have only one report in Hong Kong. To further identify genomic alteration in primary sporadic colorectal carcinomas (SCRC) in Chinese patients and understand the molecular mechanisms in CRC development, progress, and metastasis, we used comparative genomic hybridization to screen for losses and/or gains of DNA copies along chromosomes in 24 SCRC tissues from 24 patients. Comparative genomic hybridization was applied to investigate the genomic imbalance in 24 cases of primary SCRC and compared the differences between tumors in different loci and between tumors with and without metastasis. The common chromosomal alterations in the SCRC included gains of chromosomes 1q, 2q, 4q, 7q, 8q, 11q, 13q, 20q and also losses of chromosomes 9p, 16q, 17p, 18q. Among them, gains of 1q, 7q, 20q and losses of 17p, 18q were related with lymph node metastasis of SCRC (P<0.05). The gains of 4q, 7q, 20q and losses of 9p, 18q were related with the sites (P<0.05), colon and rectum, respectively; gain of 20q and loss of 9p were commonly found in the colon cancer; gain of 4q, 7q and loss of 18q were easily seen in the rectal cancer. There are multiple regions of chromosomes with copy-number changes in SCRC. The tumor suppressor genes and oncogenes on these regions may be involved in the development and progress of SCRC. The chromosome 1q, 2q, 4q, 7q, 8q, 11q, 13q, 20q regions may have oncogenes such as epidermal growth factor, MET, platelet-derived growth factor receptor A, and 9p, 16q, 17p, 18q regions may have tumor suppressor genes such as p53,DCC, IGFR1 associated with occurrence of SCRC. The chromosome 1q, 7q, 20q, 17p, 18q regions may have genes related with metastasis of SCRC. The development mechanisms of colon cancer and rectal cancer may not be completely similar. Additionally, gain of chromosome 1q was verified by the second technique-Real-time reverse transcription PCR.
Diagn Mol Pathol 2007 Jun
PMID:Chromosomal alteration in Chinese sporadic colorectal carcinomas detected by comparative genomic hybridization. 1752 79

Transforming growth factor beta (TGF-beta) receptor (TbetaR) signaling contributes to normal development as well as tumorigenesis. Here we report that RIN1, a RAB5 guanine nucleotide exchange factor (GEF) and down regulator of receptor tyrosine kinases (RTKs), promotes TbetaR signaling through enhanced endocytosis. TbetaR activation induces SNAI1 (Snail), a transcription repressor that reduces RIN1 expression, providing a negative feedback mechanism to control TbetaR trafficking and downstream signaling. Persistent RAS signaling disrupts this equilibrium by stabilizing SNAI1 protein, resulting in strong silencing of RIN1 and stabilization of RTKs. TGF-beta-induced RIN1 silencing in breast cancer cells prolonged sensitivity to hepatocyte growth factor, a ligand for the MET-type RTK, and enhanced growth factor-directed cell motility. We conclude that in some tumor cells TbetaR and RAS signals are integrated through the silencing of RIN1, leading to a reduction in RAB5-mediated endocytosis. These findings shed new light on the basis for distinct interpretations of TGF-beta signaling by normal versus transformed cells.
Mol Cell Biol 2008 Mar
PMID:Integration of transforming growth factor beta and RAS signaling silences a RAB5 guanine nucleotide exchange factor and enhances growth factor-directed cell migration. 1816 Jul 7

The Methoprene-tolerant (Met) gene of Drosophila melanogaster is involved in both juvenile hormone (JH) action and resistance to JH insecticides, such as methoprene. Although the consequences of Met mutations on development and methoprene resistance are known, no studies have examined Met+ overexpression. Met+ was overexpressed in transgenic lines with various promoters that drive overexpression to different levels. Flies expressing either genomic or cDNA Met+ transgenes showed higher susceptibility to both the morphogenetic and toxic effects of methoprene, consistent with the hormone-binding property of MET. Both the sensitive period and lethal period were the same as seen for non-overexpressing Met+ flies. However, continual exposure of high-overexpressing Met+ larvae to borderline-toxic or higher methoprene doses advanced the sensitive period from prepupae to first instar and the lethal period from pharate adults to larvae and early pupae. When expression of transgenic UAS-Met+ was driven to high levels by either an actin-GAL4 or tubulin-GAL4 promoter, larvae showed high mortality in the absence of methoprene, indicating that high MET titer is lethal, perhaps resulting from expression in an inappropriate tissue. Adults overexpressing Met+ did not show enhanced oogenesis, ruling out MET as a limiting factor for this hormone-driven physiology.
Insect Biochem Mol Biol 2008 Mar
PMID:Overexpression of Methoprene-tolerant, a Drosophila melanogaster gene that is critical for juvenile hormone action and insecticide resistance. 1825 48

The growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF) and its receptor MET, the tyrosine kinase encoded by the c-MET proto-oncogene, exert major roles in cancer invasion and metastasis and are key targets for therapy. NK1 is an alternative spliced variant of HGF/SF that consists of the N-terminal (N) and first kringle (K1) domains and has partial agonistic activity. NK1 crystallizes as a head-to-tail dimer with an extensive inter-protomeric interface resulting from contacts between the two short interdomain linkers and reciprocal contacts between the N and K1 domains. Here we show that a subset of mutants at the NK1 dimer interface, such as the linker mutants Y124A or N127A or the kringle mutant V140A:I142A, bind the MET receptor with affinities comparable to wild-type NK1 but fail to assemble a dimeric, signalling competent NK1-MET complex. These NK1 variants have no detectable agonistic activity on, behave as bona fide receptor antagonists by blocking cell migration and DNA synthesis in target cells and have strong prospects as therapeutics for human cancer.
J Mol Biol 2008 Mar 28
PMID:Engineering the NK1 fragment of hepatocyte growth factor/scatter factor as a MET receptor antagonist. 1829 18

Complex genetic disorders such as depression likely exhibit epistasis, but neural mechanisms of such gene-gene interactions are incompletely understood. 5-HTTLPR and BDNF VAL66MET, functional polymorphisms of the serotonin (5-HT) transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) gene, impact on two distinct, but interacting signaling systems, which have been related to depression and to the modulation of neurogenesis and plasticity of circuitries of emotion processing. Recent clinical studies suggest that the BDNF MET allele, which shows abnormal intracellular trafficking and regulated secretion, has a protective effect regarding the development of depression and in mice of social defeat stress. Here we show, using anatomical neuroimaging techniques in a sample of healthy subjects (n=111), that the BDNF MET allele, which is predicted to have reduced responsivity to 5-HT signaling, protects against 5-HTTLPR S allele-induced effects on a brain circuitry encompassing the amygdala and the subgenual portion of the anterior cingulate (rAC). Our analyses revealed no effect of the 5-HTTLPR S allele on rAC volume in the presence of BDNF MET alleles, whereas a significant volume reduction (P<0.001) was seen on BDNF VAL/VAL background. Interacting genotype effects were also found in structural connectivity between amygdala and rAC (P=0.002). These data provide in vivo evidence of biologic epistasis between SLC6A4 and BDNF in the human brain by identifying a neural mechanism linking serotonergic and neurotrophic signaling on the neural systems level, and have implications for personalized treatment planning in depression.
Mol Psychiatry 2008 Jul
PMID:Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. 1834 99


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