Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.2.1.23 (beta-galactosidase)
14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p53 induction and cell cycle arrest occur following DNA damage, possibly to allow repair prior to replication. p21WAF1/CIP1, a cyclin-cyclin-dependent kinase inhibitor and proliferating cell nuclear antigen-interacting protein, is induced by p53 and mediates the cell cycle arrest. To investigate a role for p21 in DNA repair in vivo, we studied the expression of in vitro damaged reporter DNA transfected into p21 +/+ or -/- HCT116 human colon cancer cells. Introduction of UV-damaged or cisplatinum-damaged cytomegalovirus-driven beta-galactosidase reporter DNA into tumor cells revealed a significant decrease (2-5-fold) in reporter expression in p21 -/- versus +/+ cells. In the absence of DNA damage, there was a significant increase (2-3-fold) in the number of 6-TG-resistant colonies derived from p21 -/- versus +/+ cells. Reintroduction of wild-type p21, but not a p21 C-terminal truncation mutant which lacks the proliferating cell nuclear antigen interaction domain, stimulated (2-3-fold) the repair capacity of the p21-deficient cells. We conclude that p21 deficiency is associated with a defect in DNA repair, which could lead to an increased sensitivity of tumor cells to DNA damage.
...
PMID:Repair Defect in p21 WAF1/CIP1 -/- human cancer cells. 862 93

Attainment of cell type-specific cytotoxicity with minimal side effects is the ultimate goal of cancer therapy. By employing the prostate-specific antigen promoter (PSAP), we investigated (1) whether PSAP-driven antisense genetic constructs targeting DNA polymerase-alpha and topoisomerase II alpha (Top II alpha), designated PSAP-antipol and PSAP-antitop respectively, could induce death of prostate cancer cells, and (2) whether the cytotoxicity is restricted to cells of prostate origin. A PSAP-driven beta-galactosidase gene, PSAP-LacZ, was also used to estimate the expression of the PSAP-driven transcripts. Lipofection-mediated gene transfers were performed with these 3 constructs and a control plasmid, pCDNA3, in 3 human prostate cancer cell lines (LNCaP, DU-145, PC-3) and 5 other cell lines (Cos-1 [monkey kidney], HL-60 [human myeloid leukemia], Hep G2 [human hepatoma], NCI H460 [human lung cancer] and SW 480 [human colon cancer]). On transfection with PSAP-LacZ, LNCaP, DU-145, and PC-3 showed a 10.8, 1.8, and 1.6 fold increase in beta-galactosidase activity, respectively. The remaining 5 cell lines showed no changes after transfection. Corresponding to the levels of the induced beta-galactosidase activity, LNCaP showed the strongest growth inhibition by the antisense constructs: 36% by PSAP-antipol, 39% by PSAP-antitop and 80% by PSAP-antipol+PSAP-antitop. DU-145 and PC-3 had minimal growth inhibition with PSAP-antipol alone or PSAP-antitop alone. However, when cotransfected with PSAP-antipol and PSAP-antitop, DU-145 and PC-3 displayed 42% and 55% growth inhibition, respectively. In contrast, no cytotoxicity was observed in the remaining 5 cell lines when transfected with PSAP-antipol, PSAP-antitop or both. Therefore, PSAP-driven antisense gene therapy targeting DNA polymerase-alpha and Top II alpha inhibits the growth of human prostate cancer cells and the cytotoxic effect is restricted in cells of prostate origin.
...
PMID:Prostate-specific antigen promoter driven gene therapy targeting DNA polymerase-alpha and topoisomerase II alpha in prostate cancer. 871 4

Two ligand oligopeptides GV1 and GV2 were designed according to the putative binding region of VEGF to its receptors. GV1, GV2 and endosome releasing oligopeptide HA20 were conjugated with poly-L-lysine or protamine and the resulting conjugates could interact with DNA in a noncovalent bond to form a complex. Using pSV2-beta-galactosidase as a reporter gene, it has been demonstrated that exogenous gene was transferred into bovine aortic arch-derived endothelial cells (ABAE) and human malignant melanoma cell lines (A375) in vitro. In vivo experiments, exogenous gene was transferred into tumor vascular endothelial cells and tumor cells of subcutaneously transplanted human colon cancer LOVO, human malignant melanoma A375 and human hepatoma graft in nude mice. This system could also target gene to intrahepatically transplanted human hepatoma injected via portal vein in nude mice. These results are correlated with the relevant receptors (flt-1, flk-1/KDR) expression on the targeted cells and tissues.
...
PMID:A novel gene delivery system targeting cells expressing VEGF receptors. 1032 85

The enzyme cyclooxygenase-2 (COX-2) is abundantly expressed in colon cancer cells and plays a key role in colon tumorigenesis. Compounds inhibiting COX-2 transcriptional activity have therefore potentially a chemopreventive property against colon tumor formation. An assay method for estimating COX-2 transcriptional activity in human colon cancer cells was established using a beta-galactosidase reporter gene system, and examination was made of various medicinal herbs and their ingredients for an inhibitory effect on COX-2 transcriptional activity. We found that berberine, an isoquinoline alkaloid present in plants of the genera Berberis and Coptis, effectively inhibits COX-2 transcriptional activity in colon cancer cells in a dose- and time-dependent manner at concentrations higher than 0.3 microM. The present findings may further explain the mechanism of anti-inflammatory and anti-tumor promoting effects of berberine.
...
PMID:Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells. 1043 83

Circulating endothelial progenitor cells (EPCs) have been isolated in peripheral blood of adult species. To determine the origin and role of EPCs contributing to postnatal vasculogenesis, transgenic mice constitutively expressing beta-galactosidase under the transcriptional regulation of an endothelial cell-specific promoter (Flk-1/LZ or Tie-2/LZ) were used as transplant donors. Localization of EPCs, indicated by flk-1 or tie-2/lacZ fusion transcripts, were identified in corpus luteal and endometrial neovasculature after inductive ovulation. Mouse syngeneic colon cancer cells (MCA38) were implanted subcutaneously into Flk-1/LZ/BMT (bone marrow transplantation) and Tie-2/LZ/BMT mice; tumor samples harvested at 1 week disclosed abundant flk-1/lacZ and tie-2/lacZ fusion transcripts, and sections stained with X-gal demonstrated that the neovasculature of the developing tumor frequently comprised Flk-1- or Tie-2-expressing EPCs. Cutaneous wounds examined at 4 days and 7 days after skin removal by punch biopsy disclosed EPCs incorporated into foci of neovascularization at high frequency. One week after the onset of hindlimb ischemia, lacZ-positive EPCs were identified incorporated into capillaries among skeletal myocytes. After permanent ligation of the left anterior descending coronary artery, histological samples from sites of myocardial infarction demonstrated incorporation of EPCs into foci of neovascularization at the border of the infarct. These findings indicate that postnatal neovascularization does not rely exclusively on sprouting from preexisting blood vessels (angiogenesis); instead, EPCs circulate from bone marrow to incorporate into and thus contribute to postnatal physiological and pathological neovascularization, which is consistent with postnatal vasculogenesis.
...
PMID:Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. 1043 64

Colon carcinoma accounts for 20% of deaths due to malignancies in the Western world. Once metastases occur, therapeutic options are limited, with an approximate 5-year survival of only 5%. To investigate the potential of new gene therapeutic approaches, a hepatic micrometastasis model of colon carcinoma in BALB/c mice was established. Inoculation of syngeneic MCA26 colon carcinoma cells into the spleens of 18- to 20-week-old mice resulted in the formation of multiple hepatic metastases. Selective transduction of developing hepatic metastases was demonstrated using a beta-galactosidase-expressing recombinant adenovirus. Cytosine deaminase (CD) can metabolize 5-fluorocytosine into the chemotherapeutic reagent 5-fluorouracil (5FU). The antitumoral potential of this suicide gene therapy approach was explored by systemic application of a recombinant replication-deficient adenovirus encoding for the bacterial CD gene under the control of the cytomegalovirus promoter (Ad.CMV-CD). Injection into the tail vein of tumor-bearing mice resulted in delayed tumor growth with significant reduction in hepatic metastases. The potential of this experimental approach for possible future clinical applications was evaluated by investigating adenoviral transduction efficiency, 5FU sensitivity, and 5-fluorocytosine-dependent Ad.CMV-CD toxicity in a variety of human colon cancer cell lines. Although the murine cell lines MCA26 and CC36 were highly sensitive to 5FU, the human colon cancer cell lines showed a 1-100 times higher resistance to 5FU. Specific Ad.CMV-CD toxicity correlates with 5FU toxicity. Transduction efficiency in human colon carcinoma cell lines was shown to be 10-1700 times higher compared with murine cell lines, thus compensating for 5FU resistance. In conclusion, suicide gene therapy using CD may be promising as an adjuvant treatment regimen for hepatic micrometastases of human colon carcinoma.
...
PMID:Gene therapy of metastatic colon carcinoma: regression of multiple hepatic metastases by adenoviral expression of bacterial cytosine deaminase. 1076 50

Cyclooxygenase-2 (COX-2) is abundantly expressed in colon cancer cells. It has been reported that inhibition of COX-2 enzyme activity is shown to prevent colon carcinogenesis. Thus, suppression of COX-2 expression may also be an effective chemopreventive strategy. In the present study, we constructed a beta-galactosidase reporter gene system in human colon cancer DLD-1 cells, and measured COX-2 promoter-dependent transcriptional activity in the cells. Interferon gamma suppressed this COX-2 promoter activity, while 12-O-tetradecanoylphorbol-13-acetate and transforming growth factor alpha (TGFalpha) exerted enhancing effects. We then tested the influence of 14 candidate cancer chemopreventive compounds on COX-2 promoter activity. Chemopreventive agents such as quercetin, kaempferol, genistein, resveratrol and resorcinol, all having a common resorcin moiety, were found to effectively suppress the COX-2 promoter activity with and without TGFalpha-stimulation in DLD-1 cells. Since all these compounds have a resorcin moiety as a common structure, a resorcin-type structure may play an active role in the inhibition of COX-2 expression in colon cancer cells.
...
PMID:Suppression of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells by chemopreventive agents with a resorcin-type structure. 1078 18

The majority of colonic neoplasias contain mutations in either the adenomatous polyposis coli or the beta-catenin (beta-cat) gene, both of which result in elevated levels of cytoplasmic beta-cat. The oncogenic activity of beta-cat has been explored in vivo and in vitro with conflicting results. We tested the hypothesis that beta-cat is capable of immortalizing and transforming cultured epithelial cells that represent the precursors to colon cancer. A truncated form of beta-cat (deltaN89) was stably expressed in murine colonic epithelial cells that were conditionally immortalized by temperature-sensitive T antigen expression and contained a mutant ApcMin allele [Immorto-Min colonic epithelium (IMCE)]. IMCE cells, grown under nonpermissive conditions, were immortalized by expression of the truncated beta-cat protein as determined by sustained growth in culture and escape from senescence as measured by endogenous beta-galactosidase activity. IMCE neo cells at nonpermissive conditions underwent extensive apoptosis, an effect that was blocked by the expression of deltaN89 beta-catenin. IMCE beta-cat cells had significantly lower p19 and p53 protein levels compared to IMCE neo cells, suggesting that alterations in these two key genes may mediate the effects of beta-cat on both cellular senescence and apoptosis. IMCE beta-cat cells were also transformed as determined by growth in the absence of serum, anchorage-independent growth, and sustained tumor growth in nude mice. Stable beta-cat-expressing populations could not be generated in conditionally immortalized colonic epithelia cells with a wild-type Apc background. These studies demonstrated the immortalizing activity of stabilized beta-cat for the first time and extend the transforming ability of mutated beta-cat to a cell line representing a precursor to colorectal cancer.
...
PMID:Stabilized beta-catenin immortalizes colonic epithelial cells. 1128 Jul 72

There is an urgent need for improved therapies for inoperable metastatic colon cancer. Gene-directed enzyme prodrug therapy (GDEPT) using adenovirus vectors works well in preclinical models of this disease, but successful clinical application is hampered by an inability to construct vectors that express at high levels in infected tumor cells but not in infected normal cells. Constitutive activation of beta-catenin-dependent gene expression is almost certainly a key causative event in the genesis of colon and some other cancers. Here we have exploited this oncogenic defect to design a synthetic promoter, CTP1, that, in contrast to currently available tumor-selective promoters, is both highly active in cancer cells and highly cancer-cell-specific. CTP1 directs high-level beta-galactosidase expression in freshly isolated biopsies of secondary colon cancer, but is not detectably active in associated normal liver tissue. We also demonstrate that CTP1 can direct high-level, tumor-specific therapeutic gene expression in vivo. Intratumoral injection of an adenovirus vector encoding Escherichia coli nitroreductase driven by CTP1 efficiently sensitized SW480 xenografts to the prodrug CB1954, whereas systemic vector and prodrug administration produced no apparent signs of toxicity. CTP1 may form the basis for effective, targeted gene therapy of metastatic colon cancer and other tumors with deregulated beta-catenin/T cell factor.
...
PMID:High-level, beta-catenin/TCF-dependent transgene expression in secondary colorectal cancer tissue. 1159 40

Although overexpression of E2F-1 can induce apoptosis in a variety of tumor cell lines, the mechanisms by which E2F-1 induces apoptosis remain ambiguous. In this study, we examine the ability of E2F-1 to induce apoptosis in colon cancer and the molecular mechanisms underlying E2F-1-mediated apoptosis. HT-29 and SW-620 colon adenocarcinoma cells (both mutant p53) were treated by mock infection or adenoviral vectors Ad5CMV (empty vector), Ad5CMVLacZ (beta-galactosidase), and Ad5CMVE2F-1 (E2F-1) at multiplicity of infection of 100. Western blot analysis confirmed marked overexpression of E2F-1 in both cell lines. By 5 days after infection, E2F-1 overexpression resulted in >25-fold reduction in cell growth and >90% loss of cell viability in both cell lines. Cell cycle analysis of Ad-E2F-1-infected cells revealed an increase in G(2)/M and sub-G(1) populations. By in situ terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling analysis, evidence of apoptosis was observed including internucleosomal DNA fragmentation and the formation of apoptotic bodies. In addition, caspase-3 and poly(ADP-ribose) polymerase apoptotic fragments were detected by 48 h after treatment with Ad-E2F-1. Of mechanistic importance, overexpression of E2F-1 caused a G(2)/M arrest followed by increased levels of c-Myc and p14(ARF) proteins. Additionally, expression of the antiapoptotic Bcl-2 family member Mcl-1 was down-regulated in E2F-1-overexpressing cells. In conclusion, E2F-1 overexpression initiates apoptosis and suppresses growth in HT-29 and SW620 colon adenocarcinoma cells. Overexpression of E2F-1 triggers apoptosis and is associated with up-regulation of c-Myc and p14(ARF) proteins and down-regulation of Mcl-1. Therefore, E2F-1 is a potentially active gene therapy agent for the treatment of colon cancer.
...
PMID:E2F-1 up-regulates c-Myc and p14(ARF) and induces apoptosis in colon cancer cells. 1170 81


1 2 3 Next >>

---