Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-beta (TGF-beta) superfamily members are multifunctional cytokines that exert their effects via heteromeric complexes of two distinct serine and threonine kinase receptors. Drosophila mothers against decapentaplegic and related genes in Caenorhabditis elegans, Xenopus, and mammals were shown to function downstream in the intracellular signaling pathways of TGF-beta superfamily members. Here we report the cloning of a Mad-related protein, termed Sma- and Mad-related protein 2 (Smad2). TGF-beta stimulated the phosphorylation and nuclear translocation of Smad2 in nontransfected Mv1Lu cells. In addition, we demonstrated that TGF-beta and activin mediated phosphorylation of Smad2 after its overexpression with appropriate type I and II receptors in COS cells. Smad2 and Smad1 were found to be broadly expressed in human tissues. Smad2 is closely linked to DPC4 on chromosome 18q21.1, a region often deleted in human cancers. Cells that lack Smad2 may escape from TGF-beta-mediated growth inhibition and promote cancer progression.
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PMID:Identification of Smad2, a human Mad-related protein in the transforming growth factor beta signaling pathway. 900 34

A cDNA encoding a new member of the membrane-type (MT) matrix metalloproteinase (MMP) family has been identified and cloned from a human brain cDNA library. The isolated cDNA encodes a polypeptide of 645 amino acids that displays a similar domain organization as other MMPs, including a predomain with the activation locus, a zinc-binding site, and a hemopexin domain. The deduced amino acid sequence contains a COOH-terminal extension, rich in hydrophobic residues and similar in size to the equivalent domains identified in MT-MMPs. Immunofluorescence and Western blot analysis of COS-7 cells transfected with the isolated cDNA revealed that the encoded protein is localized in the plasma membrane. On the basis of these features, this novel human MMP has been called MT5-MMP because it represents the fifth member of the MT-MMP subfamily of MMPs. Fluorescent in situ hybridization experiments showed that the human MT5-MMP gene (MMP-24) maps to 20q11.2, a region frequently amplified in tumors from diverse sources. Northern blot analysis demonstrated that MT5-MMP is predominantly expressed in brain, kidney, pancreas, and lung. In addition, MT5-MMP transcripts were detected at high levels compared to normal brain tissue in a series of brain tumors, including astrocytomas and glioblastomas. The catalytic domain of MT5-MMP, produced in Escherichia coli as a fusion protein with glutathione S-transferase, exhibits a potent proteolytic activity against progelatinase A, leading to the generation of the Mr 62,000 active form of this enzyme. These data suggest that MT5-MMP may contribute to the activation of progelatinase A in tumor tissues, in which it is overexpressed, thereby facilitating tumor progression.
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PMID:Identification and characterization of human MT5-MMP, a new membrane-bound activator of progelatinase a overexpressed in brain tumors. 1036 75

The localization of proteolytic enzymes at the cell surface is a widely used strategy for facilitating tumor invasion. In this study, we have cloned a new member of the membrane-type subfamily of matrix metalloproteinases (MT-MMPs), a group of enzymes associated with tumor progression. The cloned cDNA encodes a protein of 562 amino acids with a domain organization similar to that of other MT-MMPs, including a prodomain with a cysteine switch, a catalytic domain with the zinc-binding site, a hemopexin-like domain, and a COOH-terminal extension rich in hydrophobic residues. The predicted protein sequence also contains a short insertion of basic residues located between the propeptide and the catalytic domain and involved in the proteolytic activation of MT-MMPs by furin-like enzymes. Furthermore, immunofluorescence and Western blot analysis of COS-7 cells transfected with the isolated cDNA revealed that the encoded protein is localized at the cell surface. Based on these properties, this novel human matrix metalloproteinase has been called MT6-MMP because it is the sixth identified member of this subfamily of matrix metalloproteinase. Cotransfection of expression plasmids encoding MT6-MMP and progelatinase A resulted in activation of COS-7-secreted progelatinase A, as demonstrated by gelatin zymography. In contrast, transfection of progelatinase A cDNA alone did not lead to the activation of the proenzyme. Northern blot analysis of polyadenylated RNAs isolated from human tissues demonstrated that MT6-MMP is predominantly expressed in leukocytes, lung, and spleen. MT6-MMP was also detected at high levels in SW480 colon carcinoma cells as well as in some anaplastic astrocytomas and glioblastomas, but not in normal colon or brain or in meningiomas. On the basis of these results, we propose that MT6-MMP may facilitate tumor progression through its ability to activate progelatinase A at the membrane of cells from colon carcinomas or brain tumors.
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PMID:Human MT6-matrix metalloproteinase: identification, progelatinase A activation, and expression in brain tumors. 1070 98

The most ominous development in tumor progression is the transition to an invasive and metastatic phenotype. Little is known, however, about the molecular alterations that cause a tumor to become invasive. In view of this, we have used microarray expression analysis to evaluate the expression profiles of a unique panel of human DU145 prostate cancer sublines that vary in their invasive potential. The three DU145 sublines expressed epidermal growth factor (EGF) receptors that differed in their ability to activate phospholipase C-gamma (PLC gamma). Three-way analyses yielded 11 genes out of 4608 genes screened that associated directly or inversely with invasive potential. The gene whose expression correlated most strongly with lack of invasion was identified as a potential invasion suppressor and called prostin-1. Pharmacological inhibition of PLC gamma (U73122) confirmed that PLC gamma signaling suppressed prostin-1 in that U73122 treatment caused induction of prostin-1 in PLC gamma competent cells. The prostin-1 gene, conserved through phylogeny, is induced by androgen in LNCaP cells and encodes a 92 amino acid protein. The protein shares no extensive homologies with other known genes, yet was recently identified as a small stabilizer subunit of the dolichol-phosphate-mannose (DPM) synthase complex. That DPM3/prostin-1 might suppress tumor progression was supported by the finding that exogenous expression in COS cells leads to apoptosis. These findings support the use of model cell lines to identify putative tumor suppressors and promoters.
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PMID:Dolichol-phosphate-mannose-3 (DPM3)/prostin-1 is a novel phospholipase C-gamma regulated gene negatively associated with prostate tumor invasion. 1142 Jun 90

Suppression subtractive hybridization, comparing mRNA expression profiles of common nevocellular nevi and melanoma metastases, was used to identify potential markers of melanoma progression. From the metastases we isolated XAGE-1b, a 470 bp transcript of the XAGE-1 gene. In general, expression of XAGE-1b was much more prominent than expression of the longer XAGE-1 transcript, isolated from Ewing's sarcoma. The XAGE-1b open-reading frame codes for a putative protein of 81 amino acids, harboring a functional bipartite nuclear localization signal and a C-terminal acidic transcription-activation-like domain. On the nucleotide level, XAGE-1b has a 50% homology with members of the GAGE family. However, homology between the corresponding proteins is weak. Expression of XAGE-1b in normal tissues was mainly restricted to testis, while placenta and brain were sporadically positive. In human tumor cell lines as well as in human tumor lesions, expression was most frequently found in melanocytic tumors and Ewing's sarcoma. In the different stages of melanocytic tumor progression, expression was exclusively seen in melanoma metastases (38%; n = 61), while all tested common and atypical nevi (n = 10) as well as primary melanomas (n = 8) were negative. Upregulation of expression after treatment with demethylating agent 5-aza-2'-deoxycytidine was detected in 1 of 4 human melanoma cell lines tested. The XAGE-1 gene consists of 4 exons and is located on chromosome Xp11.21-Xp11.22. After transfection into COS cells, the corresponding protein can direct the coupled fluorescent protein to the nucleus, showing a distinct speckled staining aspect. Our data imply the nuclear cancer/testis-associated XAGE-1b to be a marker for late melanocytic tumor progression.
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PMID:Characterization of XAGE-1b, a short major transcript of cancer/testis-associated gene XAGE-1, induced in melanoma metastasis. 1177 64

Vimentin exhibits a complex pattern of developmental- and tissue-specific expression. Since it is aberrantly expressed in metastatic tumors, which have progressed through the epithelial-mesenchymal transition, it has been cited as a marker for tumor progression. Previous studies have indicated that the transcription factor activator protein (AP1) is important in tumor progression. The stable transformation of the MCF7 cell line with the oncogene c-Jun resulted in a cell line (MCF7Jun), which displayed a change in morphology, enhanced migratory and invasive properties, and metastatic behavior. Of the 21 genes whose expression levels were altered in the MCF7Jun cell line, the greatest change in expression occurred for the vimentin gene. Previously, tandem AP1 sites in the promoter were reported to be important for the serum and TPA inducibility of the vimentin gene. However, we find that the AP1 elements only contribute in part to c-Jun activation. Moreover, this activation can be duplicated in COS-1 or S2 cells by expression of c-Jun or TAM67, and is dependent only on the leucine-zipper region of c-Jun. Transient transfection analyses, electrophoretic mobility shift assays, DNA precipitation assays, and coimmunoprecipitation studies suggest that c-Jun is able to synergize with the activator protein Sp1 in binding to GC-box1 to enhance vimentin gene expression.
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PMID:c-Jun and the dominant-negative mutant, TAM67, induce vimentin gene expression by interacting with the activator Sp1. 1465 85

The ARHGEF5/TIM oncogene belongs to the Dbl family of guanine nucleotide exchange factors (GEFs) for Rho GTPases. It is well established that Rho-GEFs play an important role in tumorigenesis and metastasis through the activation of their substrates, the Rho GTPases. Little is known about ARHGEF5/TIM oncogene expression and cellular functions. Because of its localization close to the common fragile site FRA7I, which has been shown to be responsible for an inverted duplication of the 7q34-q35 region in breast carcinoma cells, we examined the expression of the ARHGEF5/TIM oncogene in normal and tumoral breast tissue. We report here the identification of five novel ARHGEF5/TIM alternative transcripts specifically expressed in breast tumors. These variant transcripts were characterized by the absence of one or several exons, all coding for the catalytic Dbl-homology domain and generating modified or truncated predicted variant proteins. The variant transcripts were predominantly expressed in breast carcinoma cell lines and in the most aggressive primary breast carcinomas, suggesting they may play a role in breast tumor progression. Moreover, we demonstrate that the expression of recombinant ARHGEF5/TIM protein in transfected COS-7 and NIH-3T3 cells generated a loss of actin stress fibers and the formation of membrane ruffles and filopodia. This pattern suggests that ARHGEF5/TIM activates Rac1, Cdc42 or RhoG rather than RhoA, as previously demonstrated in in vitro guanine nucleotide exchange assays. We anticipate that the activation of the ARHGEF5/TIM oncogene, possibly by the variant isoforms detected here, may play an important role in proliferative breast disease.
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PMID:Expression and molecular characterization of alternative transcripts of the ARHGEF5/TIM oncogene specific for human breast cancer. 1466 53

An important aspect of tumor progression is the ability of cancer cells to escape detection and clearance by the immune system. Recent studies suggest that several tumors express soluble factors interfering with the immune response. Here, we show that semaphorin-3A (Sema-3A), a secreted member of the semaphorin family involved in axonal guidance, organogenesis, and angiogenesis, is highly expressed in several tumor cells. Conditioned media of Sema-3A-transfected COS-7 cells or human recombinant Sema-3A inhibited primary human T-cell proliferation and cytokines production under anti-CD3 plus anti-CD28 stimulating conditions. Sema-3A also inhibited the activation of nonspecific cytotoxic activity in mixed lymphocyte culture (MLC), as measured against K-562 cells. In contrast, suppression of Sema-3A in tumor cells with a small interfering RNA (siRNA) augmented T-cell activation. The inhibitory effect of Sema-3A in T cells is mediated by blockade of Ras/mitogen-activated protein kinase (MAPK) signaling pathway. The presence of Sema-3A increased the activation of the Ras family small GTPase Rap1 and introduction of the dominant-negative mutant of Rap1 (Rap1N17) blunted the immunoinhibitory effects of Sema-3A. These results suggest that Sema-3A inhibits primary T-cell activation and imply that it can contribute to the T-cell dysfunction in the tumor microenvironment.
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PMID:Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function. 1638 Apr 53

Much of the ability of the MUC1 oncoprotein to foster tumorigenesis and tumor progression likely originates from the interaction of its cytoplasmic tail with proteins involved in oncogenic signaling. Many of these interactions are regulated by phosphorylation, as the cytoplasmic tail contains seven highly conserved tyrosines and several serine/threonine phosphorylation sites. We have developed a cell line-based model system to study the effects of tyrosine phosphorylation on MUC1 signaling, with particular emphasis on its effects on gene transcription. COS-7 cells, which lack endogenous MUC1, were stably infected with wild-type MUC1 or a MUC1 construct lacking all seven tyrosines (MUC1 Y0) and analyzed for effects on transcription mediated by the extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-kappaB (NF-kappaB) pathways. COS.MUC1 Y0 cells showed heightened active ERK1/2 with increased activator protein-1 (AP-1) and signal transducer and activator of transcription 3 (STAT3) transcriptional activity; there was also a simultaneous decrease in NF-kappaB transcriptional activity and nuclear localization. These changes altered the phenotype of COS.MUC1 Y0 cells, as this line displayed increased invasion and enhanced [(3)H]thymidine incorporation. Analysis of the three lines also showed significant differences in their cell cycle profile and bromodeoxyuridine incorporation when the cells were serum starved. These data support the growing evidence that MUC1 is involved in transcriptional regulation and link MUC1 for the first time to the NF-kappaB pathway.
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PMID:Tyrosines in the MUC1 cytoplasmic tail modulate transcription via the extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB pathways. 1684 24

The aryl hydrocarbon receptor (AhR) mediates transcriptional effects of a diverse array of ligands including environmental contaminants that have been linked to various cancers. The transcriptional activity of the AhR is modulated by different coregulators such as the p160 family members of coactivators and nuclear receptor coactivator 4 (NcoA4). In this study, we provide novel evidence that four and a half LIM only protein 2 (FHL2) interacts with and differentially modulates the transcriptional activity of AhR. Co-immunoprecipitation studies indicate that FHL2 interacts with AhR in a ligand-independent manner but not with its heterodimeric partner, AhR nuclear translocator (ARNT). Overexpression of FHL2 enhanced AhR-mediated expression of a luciferase reporter gene in a dose- and ligand-dependent manner in COS cells. Furthermore, FHL2 cooperated with NcoA4 to synergistically enhance AhR transcriptional activity in these cells. However, the impact of FHL2 on AhR transcriptional activity was cell-specific: FHL2 facilitated AhR action in MCF-7 and PC-3 cells, whereas it suppressed AhR activity in T47D and LNCaP cells. These results of reporter gene studies were corroborated by the impact of FHL2 overexpression on, an established target gene of AhR, cytochrome P450 (CYP1A1) expression. We also demonstrated a potential competition of AhR and androgen receptor (AR) for FHL2 availability in COS cells, as FHL2-facilitation was significantly decreased in the presence of liganded AR. These findings indicate a functional interaction between AhR and FHL2 that modulates the activity of AhR and therefore could affect its role in cancer progression or development.
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PMID:Modulation of aryl hydrocarbon receptor activity by four and a half LIM domain 2. 1901 43


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