Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumour suppressor ING1 shares many biological functions with p53, such as cell cycle arrest, DNA repair, apoptosis, and chemosensitivity. Since p53 inhibits invasion and angiogenesis of melanoma cells, we sought to investigate if p33ING1 (one of ING1 isoforms) is also involved in these biological processes. We first overexpressed p33ING1 in melanoma cells and assessed the protein levels in MMP-1, MMP-2, and MMP-9. Results from Western blot analysis showed no significant difference in these matrix metalloproteinase levels between cells transfected with vector, p33ING1, and antisense p33ING1. Wound healing assay was performed to examine if p33ING1 plays a role in migration and invasion. Results showed that there was no difference between vector, p33ING1, and antisense p33ING1 groups in melanoma cell migration across the wound. Western blot analysis also indicated that there is no difference in the levels of proteins which are directly involved in angiogenesis, such as VEGF, Flt-1, and Flk-1, between cells transfected with vector, p33ING1, and antisense p33ING1. Furthermore, functional studies indicated that cultured medium derived from p33ING1-transfected melanoma cells did not stimulate the growth of HUVEC cells, compared to controls, providing support to the lack of functional role of p33ING1 in angiogenesis. In conclusion, we demonstrate in vitro that p33ING1, unlike p53, does not play a role in angiogenesis and migration in melanoma cells.
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PMID:The tumour suppressor p33ING1 does not regulate migration and angiogenesis in melanoma cells. 1242 89

Arsenic trioxide (As2O3) has been implicated as a promising anticancer agent for treatment of many cancers including acute promylocytic leukemia. However, the molecular mechanisms are not yet fully defined in solid tumor cells, especially cervical cancer cells carrying human papillomavirus (HPV) genome. To analyze detailed mechanisms in vitro, we treated As2O3 to transformed HeLa cells, a well-studied cervical cancer cell line carrying HPV-18 sequence, and investigated its antiproliferative, antiviral and antimetastatic effects. As2O3 reduced survival and growth of HeLa cells in a dose- and time-dependent manner. Several indicatives of apoptosis were demonstrated by DNA fragmentation assay, DAPI nuclear staining and FACS analysis, respectively. Protein levels of p53 and cleavage of poly(ADP)-ribose polymerase were increased in a dose-dependent manner following treatment of As2O3. In parallel, semi-quantitative reverse transcription-polymerase chain reaction showed that the treatment inhibited HPV-18 E6/E7 viral gene expression in HeLa cells. Using transient transfection and CAT ELISA, we also found that AP-1 sites, located proximal to HPV-18 upstream regulatory region (URR) promoter, could be the major target sites for As2O3. Furthermore, As2O3-treated HeLa cells showed lesser capacity of invasion than those of untreated cells by in vitro invasion assay. Taken together, we proposed that antiviral effect, i.e. down-regulation of HPV E6/E7 oncogenes through targeting for AP-1 sites located in HPV URR might be associated with antiproliferative effect, i.e. induction of apoptosis as be resulted from the accumulation of p53, and that antimetastatic effect could be due to the targeted inactivation of AP-1, a transcription factor required for the expression of MMP-1 and -3. Therefore, our finding may provide a logical basis for the development of a new agent treating HPV-associated cervical neoplasia.
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PMID:Down-regulation of human papillomavirus E6/E7 oncogene by arsenic trioxide in cervical carcinoma cells. 1243 Jan 74

To gain insight into the transformation of epidermal cells into squamous carcinoma cells (SCC), we compared the response to ultraviolet B radiation (UVB) of normal human epidermal keratinocytes (NHEK) versus their transformed counterpart, SCC, using biological and molecular profiling. DNA microarray analyses (Affymetrix), approximately 12000 genes) indicated that the major group of upregulated genes in keratinocytes fall into three categories: (i). antiapoptotic and cell survival factors, including chemokines of the CXC/CC subfamilies (e.g. IL-8, GRO-1, -2, -3, SCYA20), growth factors (e.g. HB-EGF, CTGF, INSL-4), and proinflammatory mediators (e.g. COX-2, S100A9), (ii). DNA repair-related genes (e.g. GADD45, ERCC, BTG-1, Histones), and (iii). ECM proteases (MMP-1, -10). The major downregulated genes are DeltaNp63 and PUMILIO, two potential markers for the maintenance of keratinocyte stem cells. NHEK were found to be more resistant than SCC to UVB-induced apoptosis and this resistance was mainly because of the protection from cell death by secreted survival factors, since it can be transferred from NHEK to SCC cultures by the conditioned medium. Whereas the response of keratinocytes to UVB involved regulation of key checkpoint genes (p53, MDM2, p21(Cip1), DeltaNp63), as well as antiapoptotic and DNA repair-related genes - no or little regulation of these genes was observed in SCC. The effect of UVB on NHEK and SCC resulted in upregulation of 251 and 127 genes, respectively, and downregulation of 322 genes in NHEK and 117 genes in SCC. To further analyse these changes, we used a novel unsupervised coupled two-way clustering method that allowed the identification of groups of genes that clearly partitioned keratinocytes from SCC, including a group of genes whose constitutive expression levels were similar before UVB. This allowed the identification of discriminating genes not otherwise revealed by simple static comparison in the absence of UVB irradiation. The implication of the changes in gene profile in keratinocytes for epithelial cancer is discussed.
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PMID:Genome-wide comparison of human keratinocyte and squamous cell carcinoma responses to UVB irradiation: implications for skin and epithelial cancer. 1277 51

TNF-alpha is known to play an important role in UV-induced immunomodulation and photodamage. It plays a role in UVB-mediated induction of apoptosis and is a strong inducer of the c-Jun N-terminal kinase (JNK) pathway, which eventually leads to the loss of dermal collagen and elastin content. Recently chimeric anti-TNF-alpha has been introduced as a therapy for rheumatoid arthritis. The aim of the present study was to investigate the effect of anti-TNF-alpha treatment on UV-induced DNA damage, apoptosis, and induction of matrix metallo proteinases. Twelve patients with rheumatoid arthritis were included and irradiated with 2 MED broadband UVB before and after administration of 0.5 mg/kg anti-TNF-alpha monoclonal antibody. Twenty-four hours after irradiation biopsies were taken. Frozen and paraffin sections were stained for p53, c-Jun, phosphorylated c-Jun, sunburn cells and MMP-1. No significant changes were observed in the expression of p53 and sunburn cells and MMP-1 content after treatment with anti-TNF-alpha, whereas a slight but significant decrease in c-Jun and phosphorylated c-Jun expression was noted (P = 0.0250 and P = 0.0431, respectively). Our results showed no influence of anti-TNF-alpha on UV response at therapeutic doses in patients with rheumatoid arthritis.
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PMID:Adalimumab, a fully human anti-TNF-alpha monoclonal antibody, treatment does not influence experimental UV response in the skin of rheumatoid arthritis patients. 1293 Mar 3

The human T-cell leukemia virus type I (HTLV-I)-encoded Tax protein activates transcription from the viral promoter via association with the cellular basic leucine zipper factor cAMP-response element-binding protein-2. Tax is also able to induce cellular transformation of T lymphocytes probably by modulating transcriptional activity of cellular factors, including nuclear factor-kappaB, E2F, activator protein-1 (AP-1), and p53. Recently, we characterized in HTLV-I-infected cells the presence of a novel viral protein, HBZ, encoded by the complementary strand of the HTLV-I RNA genome (Gaudray, G., Gachon, F., Basbous, J., Biard-Piechaczyk, M., Devaux, C., and Mesnard, J.-M. (2002) J. Virol. 76, 12813-12822). HBZ is a nuclear basic leucine zipper protein that down-regulates Tax-dependent viral transcription by inhibiting the binding of cAMP-response element-binding protein-2 to the HTLV-I promoter. In searching for other cellular targets of HBZ, we identified two members of the Jun family, JunB and c-Jun. Co-immunoprecipitation and cellular colocalization confirmed that HBZ interacts in vivo with JunB and c-Jun. When transiently introduced into CEM cells with a reporter gene containing the AP-1 site from the collagenase promoter, HBZ suppressed transactivation by c-Jun. On the other hand, the combination of HBZ with Jun-B had higher transcriptional activity than JunB alone. Consistent with the structure of its basic domain, we demonstrate that HBZ decreases the DNA-binding activity of c-Jun and JunB. Last, we show that c-Jun is no longer capable of activating the basal expression of the HTLV-I promoter in the presence of HBZ in vivo. Our results support the hypothesis that HBZ could be a negative modulator of the Tax effect by controlling Tax expression at the transcriptional level and by attenuating activation of AP-1 by Tax.
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PMID:The HBZ factor of human T-cell leukemia virus type I dimerizes with transcription factors JunB and c-Jun and modulates their transcriptional activity. 1293 77

Keloids are benign mesenchymal tumours, usually present at and extending beyond the margins of sites of previous injury. It is reported that keloids display aberrant expression of apoptotic genes: TGFB1 is activated, whereas caspase 8 and 3 are not, thus indicating a block upstream in the apoptosis cascade in keloids. Interferon-alpha 2b normalizes the excessive synthesis of collagen, glycosaminoglycans and collagenase by keloidal fibroblasts, reduces recurrences following keloid excision, and enhances the expression of native p53 and apoptosis. Imiquimod, a rapid and potent inducer of interferons locally at the site of application to the skin, reduces recurrences following keloid excision and alters gene expression of markers of apoptosis in basal cell carcinoma cells. We investigated the effects with respect to the expression of apoptotic genes in keloidal tissue compared with nontreated controls of imiquimod 5% cream applied topically to keloids. Total RNA was extracted from excised keloidal tissue, cDNA probes synthesized and then hybridized to gene-specific cDNA fragments spotted on membranes. The expression levels of 96 genes involved in apoptosis, relative to cyclophilin expression, were compared in the imiquimod-treated and untreated groups. The mean ratio of expression, relative to cyclophilin of caspase 3 and DFFA were significantly enhanced. Caspase 3 was significantly downregulated and DFFA was significantly upregulated in the group of imiquimod-treated keloids (P < 0.05) compared with the untreated group of keloids. Although imiquimod is capable of altering the expression of these markers of apoptosis in keloids, their role, if any, in the therapeutic response of keloids to imiquimod requires further investigation.
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PMID:Topical application of imiquimod 5% cream to keloids alters expression genes associated with apoptosis. 1461 55

C-terminal truncation of ADAMTS-4 from the p68 form to the p53 form is required for activation of its capacity to cleave the Glu(373)-Ala(374) interglobular domain bond of aggrecan. In transfected human chondrosarcoma cells, this process is not autoproteolytic because the same products form with an inactive mutant of ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin-like motif 4) and truncation is completely blocked by tissue inhibitor of metalloproteinase-1. Instead, activation can be mediated by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase (MT4-MMP, MMP-17) because co-transfection with the active form of MT4-MMP markedly enhanced activation, whereas an inactive mutant of MT4-MMP was ineffective. Treatment of co-transfected cells with phosphatidylinositol-specific phospholipase C liberated the complex of MT4-MMP and p68 ADAMTS4 from the cell membrane, but the p53 ADAMTS4 remained associated. Specific glycosaminoglycan lyase digestions, followed by product analyses using fluorescence-assisted carbohydrate electrophoresis and immunoprecipitation experiments, showed that the p53 form is associated with syndecan-1 through both chondroitin sulfate and heparan sulfate. We conclude that ADAMTS-4 activation in this cell system involves the coordinated activity of both glycosylphosphatidyl inositol-anchored MT4-MMP and the proteoglycan form of syndecan-1 on the cell surface.
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PMID:ADAMTS4 (aggrecanase-1) activation on the cell surface involves C-terminal cleavage by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase and binding of the activated proteinase to chondroitin sulfate and heparan sulfate on syndecan-1. 1470 64

With the advancing widespread use of photodynamic therapy, questions have arisen about the necessity to protect the adjacent healthy skin from high-dose long-wave light. The aim of the present study was to investigate the effects of high dose visible light on the skin of healthy volunteers with focus on apoptosis, DNA damage, inflammation, melanogenesis and induction of matrix metalloproteinases (MMP). Fourteen healthy volunteers were included and irradiated daily on their buttocks with 1300 kJ/m2 long wave visible light (560-780 nm) on five consecutive days with a cumulative dose of 6500 kJ/m2. In each volunteer six biopsies were taken before and 24 h after irradiation on days 1, 2, 3 and 5 and on day 8 and 12. Frozen and paraffin sections were investigated by measuring parameters for photodamage (apoptosis, p53, phosphorylated c-Jun), skin ageing (phosphorylated c-Jun, MMP-1, elastin content) melanogenesis (Melan A). Although no sunburn cells were seen, a significant increase in perinuclear vacuolization was noted (P < 0.0003) from day 5 till 7 days after the last irradiation. There was no expression of phosphorylated c-Jun, whereas the expression of p53, Melan A, MMP-1 and elastin content did not change. High-dose visible light induces a significant increase in perinuclear vacuolization, but does not result in apoptosis, photodamage or early induction of skin ageing.
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PMID:High-dose long wave visible light induces perinuclear vacuolization in vivo but does not result in early photoageing and apoptosis. 1470 1

We have previously reported that human matrix metalloproteinase-1 (MMP1) is a p53 target gene subject to down-regulation (Sun et al. [1999]: J Biol Chem 274:11535-11540]. In the present study, we demonstrate that the down-regulation of the human -83MMP1 promoter fragment by p53 was abolished when the -72AP-1 site was eliminated and that a GAL4-cJun-mediated but not a GAL4-Elk1-mediated induction of pFR-luci was effectively inhibited by p53 suggesting an AP-1 dependent but AP-1 binding independent mechanism. Results from gel mobility shift assays were consistent with an AP-1 binding independent mechanism. We also demonstrate that both p300 and TATA box binding proteins cooperated with the transcription factor AP-1 to induce the promoter of MMP1; however, p53 only inhibited the p300-mediated induction of the MMP1 promoter and the inhibition was -72AP-1 dependent. Furthermore, the down-regulation of the MMP1 promoter and mRNA by p53 could be reversed by p300 and by a p53 binding p300 fragment that had no coactivator activity. Taken together, these results indicate that p53 down-regulates MMP1 mainly by disrupting the communications between the transactivator AP-1 and the basal transcriptional complex, which are partially mediated by p300. Finally, by using p53 truncated mutant constructs, we demonstrate that both the N-terminal activation domain and the C-terminal oligomerization domains of p53 were required for the down-regulation of MMP1 transcription.
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PMID:P53 down-regulates matrix metalloproteinase-1 by targeting the communications between AP-1 and the basal transcription complex. 1510 53

Cyclooxygenase 2 (COX-2) is known to be increased in aged cells. Recent studies suggest that the increased expression of COX-2 may be involved in the pathogenesis of age-associated diseases such as rheumatoid arthritis and cancer. We investigated the role of COX-2 in cell cycle arrest and collagen deficiency during the aging process. Using the replicative senescence model of dermal fibroblasts, we demonstrated the increased expression of COX-2 and increased PGE(2) levels associated with replicative senescence. Replicative senescent cells showed a decreased ability to induce cell proliferation, probably due to the increased expression of the p53 protein and the decreased expression of the PCNA protein, and also showed increased expression of MMP-1, and decreased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and procollagen. The selective COX-2 inhibitor, NS-398, can inhibit the senescence-associated increases of COX-2, PGE(2), p53 and MMP-1 expression, and the senescence-associated decreases of PCNA, TIMP-1 and procollagen expression. These results suggest that the increased level of COX-2 and higher level of PGE(2) in aged cells may play an important role in cellular senescence, and that selective COX-2 inhibitors may be useful for the intervention of skin aging.
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PMID:Selective COX-2 inhibitor, NS-398, inhibits the replicative senescence of cultured dermal fibroblasts. 1513 Jul 53


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