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)

The mouse biliary glycoprotein 1 gene (bgp1) encodes several multifunctional glycoprotein isoforms. These glycoproteins represent members of the carcinoembryonic antigen (CEA) family which belongs to the immunoglobulin superfamily. The Bgp1 glycoproteins function as cell adhesion molecules and receptors for the mouse hepatitis viruses. In contrast to CEA, whose overexpression has been correlated with cancer progression, the human and mouse Bgp proteins are generally down-regulated upon tumor formation. In this study, we report on the mouse bgp1 gene organization and transcriptional activation. We have isolated phage and cosmid clones encompassing the entire bgp1 coding region. This gene consists of nine exons, some of which are subjected to alternative splicing producing a minimum of four splice variants. A comparison of the murine bgp1 proximal promoter with the human BGP and mouse cea10/bgp3 genes revealed sequence conservation of 66% and 95%, respectively. RNase protection assays and primer extension analyses indicated that the mouse bgp1 transcriptional start site is positioned 240 nucleotides upstream of the ATG translational initiation codon, which is 140 nucleotides further upstream than in any other CEA family member. The bgp1 promoter is transcriptionally active in reporter gene activation in vitro transfection studies and in vivo using a bgp1-containing cosmid clone. We identified three putative AP-2 or AP-2-like sites and an upstream stimulatory factor (USF) recognition sequence within the proximal mouse bgp1 promoter region at positions similar to those used by the human BGP promoter region. These data suggest that the regulation of the mouse and human BGP genes may follow some common spatial and temporal expression. Interestingly, the bgp1 proximal promoter and coding region are also well conserved throughout evolution.
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PMID:Characterization and transcriptional activity of the mouse biliary glycoprotein 1 gene, a carcinoembryonic antigen-related gene. 762 60

We examined expression of prostate-specific membrane antigen (PSM) mRNA in normal prostate using reverse transcription-PCR and sequencing. An alternatively spliced variant, PSM', along with the previously described PSM form, was found in normal prostate. PSM' cDNA is shorter (2387 nucleotides) than PSM (2653 nucleotides). The cDNAs are identical except for a 266-nucleotide region near the 5' end of PSM cDNA (nucleotide 114-380) that is absent from PSM'. This deleted region includes the translation initiation codon and codons for the putative transmembrane domain of PSM. Thus, PSM' RNA codes for a protein that has no apparent signal sequence. We verified the existence of spliced mRNA variants in human primary tissue specimens by RNase protection assay. In LNCaP human prostatic cancer cells and in primary prostate tumors, PSM is the dominant form. In contrast, normal human prostate expressed more PSM' than PSM. Benign prostatic hypertrophy samples showed about equal expression of both variants. We quantified the relative expression of each variant by densitometry and compiled a tumor index, which is the ratio of PSM:PSM' level. LNCaP has an index ranging from 9-11, carcinoma of the prostate from 3-6, benign prostatic hypertrophy from 0.75-1.6, and normal prostate from 0.075-0.45. The index reflects the increased expression of PSM over PSM' following the progression from normal to tumor state. This tumor index may be a useful indicator for the measurement of tumor progression. PSM and PSM' may be functionally different proteins as a result of differences in structure or cellular location. We are investigating the prevalence of one form over the other and how it may influence tumor progression.
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PMID:Alternatively spliced variants of prostate-specific membrane antigen RNA: ratio of expression as a potential measurement of progression. 788 49

Neuregulin, the putative ligand of the c-neu receptor tyrosine kinase, can induce differentiation or growth of epithelia and other cells. To gain insight into the biological role of this factor, we have analyzed the expression of neuregulin during mouse embryogenesis and in the perinatal animal by a combination of in situ hybridization and RNase protection experiments. We identify sites of expression that correspond to mesenchymal cells of various parenchymal organs. Our finding implies a function of neuregulin as a mesenchymal factor that acts on epithelia. The mesenchymal expression of neuregulin could thus provide a molecular basis for the biological phenomenon of mesenchymal-epithelial interactions. It also has implications on the molecular mechanism by which amplification of c-neu can affect tumor progression of carcinomas. In addition, neuregulin expression is found in neuronal cells during development. We show by RNase protection experiments that distinct isoforms of neuregulin are expressed in the brain. Therefore, our data indicate in vivo a dual role for neuregulin as mesenchymal and neuronal factor.
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PMID:Distinct isoforms of neuregulin are expressed in mesenchymal and neuronal cells during mouse development. 830 32

Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell growth and tumor progression. Previous work has shown that loss of functional TGF-beta type II receptor (RII) due to a frameshift mutation in the 5' half of the RII gene leads to TGF-beta resistance in a highly progressed, RER+ human colon carcinoma cell line designated HCT116. Expression of this mutated RII gene was highly repressed in RER+ cell lines such as HCT116 and RKO, as analyzed by RNase protection assays. Nuclear run-on and RII promoter-reporter (CAT) assays showed that the transcriptional levels of the RII gene in these RER+ cells were not reduced, compared to RII-expressing cells. However, the half-lives of the RII mRNA, as analyzed by RNase protection assays following actinomycin D treatment, were significantly decreased. This suggested that the decreased expression of the RII gene mutant was due to decreased mRNA stability. Furthermore, RII mRNA from HCT116 transfected with wild-type RII had a longer half-life than the endogenous mutated RII mRNA. A dominant negative RII mutant, which encodes a similarly truncated RII protein as HCT116 but lacks the extensive 3' untranslated region of RII mRNA, gave the same half-life as endogenous wild-type RII mRNA. We conclude that the frameshift mutation which results in a premature stop codon in the 5' half of the mRNA transcript accounts for the reduced RII mRNA levels in RER+ cells.
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PMID:Decreased Stability of Transforming Growth Factor beta Type II Receptor mRNA in RER+ Human Colon Carcinoma Cells 939 99

Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell growth and tumor progression. Previous work has shown that loss of functional TGF-beta type II receptor (RII) due to a frameshift mutation in the 5' half of the RII gene leads to TGF-beta resistance in a highly progressed, RER+ human colon carcinoma cell line designated HCT116. Expression of this mutated RII gene was highly repressed in RER+ cell lines such as HCT116 and RKO, as analyzed by RNase protection assays. Nuclear run-on and RII promoter-reporter (CAT) assays showed that the transcriptional levels of the RII gene in these RER+ cells were not reduced, compared to RII-expressing cells. However, the half-lives of the RII mRNA, as analyzed by RNase protection assays following actinomycin D treatment, were significantly decreased. This suggested that the decreased expression of the RII gene mutant was due to decreased mRNA stability. Furthermore, RII mRNA from HCT116 transfected with wild-type RII had a longer half-life than the endogenous mutated RII mRNA. A dominant negative RII mutant, which encodes a similarly truncated RII protein as HCT116 but lacks the extensive 3' untranslated region of RII mRNA, gave the same half-life as endogenous wild-type RII mRNA. We conclude that the frameshift mutation which results in a premature stop codon in the 5' half of the mRNA transcript accounts for the reduced RII mRNA levels in RER+ cells.
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PMID:Decreased stability of transforming growth factor beta type II receptor mRNA in RER+ human colon carcinoma cells. 940 53

RNA decay in IFN-treated cells is controlled by 2'5'-linked oligoadenylate (2-5A)-dependent RNase (RNase L), a uniquely regulated endoribonuclease that requires short 5'-phosphorylated, 2-5A for its activity. Because RNase L is also implicated in the regulation of cell proliferation, we monitored its expression in colorectal adenocarcinomas and noncancerous polyps from familial adenomatous polyposis patients. Elevated levels of RNase L mRNA and activity were found in 17 of 20 tumors compared with corresponding normal mucosa. An mAb against RNase L revealed elevated amounts of this RNase in sections of the tumors, largely in the base of the villi. The occurrence of elevated levels of RNase L seems to be an early event in colorectal tumorigenesis, suggesting that control of RNA turnover is an important step in tumor progression. These data also indicate that regulating RNase L activity may be a useful strategy in treating colorectal carcinomas.
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PMID:Elevated levels of 2',5'-linked oligoadenylate-dependent ribonuclease L occur as an early event in colorectal tumorigenesis. 981 40

The trkA proto-oncogene encodes a high-affinity NGF receptor that is essential for the survival, differentiation and maintenance of many neural and non-neural cell types. Altered expression of the trkA gene or trkA receptor malfunction have been implicated in neurodegeneration, tumor progression and oncogenesis. We have cloned and characterized the 5' region of the mouse trkA gene and have identified its promoter. trkA promoter sequences are GC-rich, lack genuine TATA or CAAT boxes, and are contained within a CpG island which extends over the entire first coding exon. The mouse trkA transcription start site is located 70/71 bp upstream to the AUG translation initiation codon. Sequence analysis showed that the gene encoding the insulin receptor-related receptor, IRR, is located just 1.6 kbp upstream to the trkA gene and is transcribed in the opposite direction. We have used trkA-CAT transcriptional fusions to study trkA promoter function in transient transfection experiments. RNase protection assays and CAT protein ELISA analyses showed that a 150 bp long DNA segment, immediately upstream to the start site, is sufficient to direct accurate transcription in trkA-expressing cells. Dissection of this fragment allowed us to identify a 13 bp cis-regulatory element essential for both promoter activity and cell-type specific expression. Deletion of this 13 bp segment as well as modification of its sequence by site-directed mutagenesis led to a dramatic decline in promoter activity. Gel mobility shift assays carried out with double-stranded oligonucleotides containing the 13 bp element revealed several specific DNA-protein complexes when nuclear extracts from trkA-expressing cells were used. Supershift experiments showed that the Sp1 transcription factor was a component of one of these complexes. Our results identify a minimal trkA gene promoter, located very close to the transcription start site, and define a 13 bp enhancer within this promoter sequence.
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PMID:Molecular cloning and characterization of the 5' region of the mouse trkA proto-oncogene. 1052 65

Angiogenesis is essential for tumor growth and metastasis. It is regulated by numerous angiogenic factors, one of the most important being vascular endothelial growth factor (VEGF). Recently, VEGF-C, a new VEGF family member, has been identified that binds to the tyrosine kinase receptors flt-4 [VEGF receptor (VEGFR) 3] and KDR (VEGFR2). Although the importance of VEGF has been shown in many human tumor types, the contribution of VEGF-C and its primary receptor flt-4 to tumor progression is less well understood. We have therefore measured the level of VEGF-C, flt-4, and KDR mRNA by RNase protection assay and the pattern of VEGF-C expression by immunohistochemistry in 11 normal breast tissue samples and 61 invasive breast cancers. No significant difference in VEGF-C expression was observed between normal and neoplastic breast tissues (P = 0.11). There was a significant correlation between VEGF-C and both flt-4 (P = 0.02) and KDR (P = 0.0002), but no association was seen between VEGF-C and either lymph node status (P = 0.66) or number of involved nodes (P = 0.88), patient age (P = 0.83), tumor size (P = 0.20), estrogen receptor status (P = 0.67), or tumor grade (P = 0.35). No significant relationship was present between VEGF-C and vascular invasion (P = 0.30), tumor vascularity (P = 0.21), VEGF-A (P = 0.62), or thymidine phosphorylase expression (P = 1.00). VEGF-C was expressed predominantly in the cytoplasm of tumor cells, although occasional stromal components including fibroblasts were also positive. We could demonstrate no association between lymph node metastasis and either VEGF-C (P = 0.66) or flt-4 (P = 0.4). However, we did observe a significant loss of the long but not the short isoform of flt-4 in tumors compared with normal tissues (P = 0.02 and P = 0.25, respectively), and this difference was largely accounted for by the reduction of long flt-4 in node-positive tumors. These findings strongly support a role for VEGF-C/flt-4 signaling in tumor growth by enhancement of angiogenesis and/or lymphangiogenesis and suggest that differential regulation of these processes may be controlled via flt-4 isoform transcription. They further suggest that the measurement of flt-4 isoform expression may identify a patient group that is likely to have node-positive disease and therefore benefit from additional treatment and also emphasize an additional ligand interaction that could be exploited by anti-VEGFR therapy.
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PMID:The short form of the alternatively spliced flt-4 but not its ligand vascular endothelial growth factor C is related to lymph node metastasis in human breast cancers. 1110 44

Gamma-glutamylcysteine synthetase (gamma-GCS) is a heterodimer consisting of heavy (gamma-GCSh) and light (gamma-GCSl) subunits. gamma-GCS catalyzes the rate-limiting de novo biosynthesis of glutathione (GSH), an abundant physiological antioxidant that plays important roles for regulating oxidative stress. Expression of gamma-GCSh and gamma-GCSl are sensitive to oxidative stress. To investigate whether expression of gamma-GCS is correlated with tumor progression, we used immunohistochemical approaches to examine 16 human colorectal adenomas and resected 57 carcinomas from untreated patients. In adjacent normal colorectal epithelium, levels of gamma-GCSh expression were low. Strong cytoplasmic staining for gamma-GCSh was detected in 3 (18.8%) adenoma and 48 (84.2%) carcinomas. The frequency of gamma-GCSh expression in carcinoma was significantly higher than in adenoma (p<0.0001). We used RNase protation assay and Western blot to determine levels of gamma-GCSh mRNA and protein from 10 pairs of matched carcinomas with adjacent normal controls. Elevated expression of both gamma-GCSh mRNA and protein were found in 6 cases, suggesting that transcriptional and/or posttranscriptional regulation play an important role in the upregulation of gamma-GCS during colorectal carcinogenesis. We also examined the expression of another redox-regulated gene, multidrug resistance protein 1 (MRP1). Strong staining for MRP1 was detected in 1 (6.3%) adenoma and 40 (70.2%) carcinomas. The frequency of MRP1 expression in carcinoma was significantly higher than in adenoma ( p<0.0001). Nuclear p53 expression was detected in 30 (52.6%) of carcinomas. There is a significant correlation between gamma-GCSh and MRP1 expression (p=0.013) but not between gamma-GCSh and p53. Since gamma-GCS is a sensor of oxidative stress, these results are consistent with the notion that oxidative stress is associated with colorectal tumor progression.
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PMID:Expression of heavy subunit of gamma-glutamylcysteine synthetase (gamma-GCSh) in human colorectal carcinoma. 1177 39

We have found using differential display of mRNA that the growth factor heregulin beta 1 (HRG), a combinatorial ligand for human epidermal growth factor receptors (HERs), induced expression of G3BP, the Ras GTPase-activating protein SH3 domain-binding protein, in breast cancer cells. G3BP is a downstream effector protein of Ras signaling with ATP-dependent RNase and helicase activities, which may link Ras signaling with RNA turnover and cell cycle progression. In human breast cancer cells, HRG induced G3BP mRNA and protein expression. Up-regulation of G3BP was found in MCF7 breast cancer cells overexpressing HER2. G3BP was also overexpressed in human breast tumors in parallel with HER2 overexpression and in an estrogen-independent manner, suggesting a role for G3BP in cancer progression. In addition, HRG stimulation of breast cancer cells promoted phosphorylation of G3BP and increased the association of G3BP with GTPase-activating protein, both of which are essential for G3BP activity. G3BP ATPase activity was also significantly increased by HRG treatment. Furthermore, HRG treatment resulted in G3BP translocation to the nucleus and colocalization with acetylated histone H3, a hallmark of active transcription sites. G3BP induction, phosphorylation, ATPase activity, and relocalization after HRG treatment could all be blocked by pretreatment with the anti-receptor HER2 monoclonal antibody Herceptin (trastuzumab), which may suggest additional applications for this therapeutic antibody. These findings demonstrate for the first time the receptor-dependent regulation of G3BP, a downstream effector of Ras signaling, by HRG, a growth factor with diverse functions in breast cancer cells.
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PMID:Heregulin induces expression, ATPase activity, and nuclear localization of G3BP, a Ras signaling component, in human breast tumors. 1188 85


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