Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transformation of secondary Sprague-Dawley rat embryo (RE) cells with type 5 adenovirus (Ad5) results in morphologically transformed cells which can undergo a series of sequential changes resulting in enhanced expression of the transformed phenotype, a process termed progression. Selection for a progressed phenotype often occurs after growth in agar or tumor formation in nude mice, and this process is reversible following treatment of cells with 5-azacytidine. In the present study we have analyzed a series of clonal populations of Ad5-transformed RE cells representing different stages in a defined progression lineage. Progression was not associated with alterations in the steady-state levels of mRNA produced by the viral transforming genes, E1A and E1B, or the cellular gene, c-myc. In addition, the tumor-promoting agent 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which induces expression of a progressed phenotype in Ad5-transformed RE cells, did not significantly alter the RNA transcription rates of the Ad5 E1A or E1B genes, the TPA-inducible gene TPA-S1 or the TPA-responsive genes Pro1 or protein kinase C. TPA did, however, increase by 1 h the steady-state level of c-fos mRNA, but this effect was similar in both progressed and unprogressed cells. Progression also did not involve a change in the RNA transcription rate of a number of cellular and viral genes, including actin, c-Ha-ras, c-myc, v-fos, erbB, TGF-alpha, TGF-beta, Pro-2, transin, TPA-R1, v-myb and c-mos, or other adenovirus genes in addition to E1A and E1B, including E2A and E4. Immunoblotting analysis using E1B polyclonal antiserum further indicated that progression was not associated with changes in the levels of an Mr 21,000 polypeptide encoded by E1B. Similarly, immunoprecipitation analysis with an Ad2 E1A monoclonal antibody indicated similar levels of the Mr 55,000 and 48,000 E1A polypeptides, as well as coprecipitated proteins of Mr 300,000, 107,000 and 105,000 [which is the retinoblastoma (Rb) protein], in E11 and E11-NMT cells. Immunoprecipitation of cell lysates with a monoclonal antibody specific for the Mr 105,000 Rb protein further demonstrated that progression also was not associated with a change in the level or state of phosphorylation of the Rb protein. However, transfection of a human Rb gene (also containing a neomycin resistance gene) into Ad5-transformed RE cells was more inhibitory, with respect to formation of G418-resistant colonies, in unprogressed than in progressed Ad5-transformed RE cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Analysis of viral and cellular gene expression during progression and suppression of the transformed phenotype in type 5 adenovirus-transformed rat embryo cells. 192 6

It has been proposed that tumor progression is a selective process and that only a minority of tumor cells survive this selection because they possess the phenotypic traits necessary for metastasis and organ colonization. Both proteases and extracellular matrix proteins have been implicated in invasion and metastasis formation. To examine the nature of the selection process, we transformed 10T1/2 fibroblasts with T24 H-ras and the neoR gene and selected a clonal line expressing the mutant ras gene. After i.v. injection of this line into syngeneic C3H/HeN mice, tumor cells were recovered from lungs by enzymatic treatment and selective outgrowth in G418. Less than one of 10(3) cells survived in the lung 30 min after inoculation, and these exhibited a unique phenotype. This was characterized by a propensity to lodge in the lung on reinjection; markedly enhanced mRNA levels of procollagen alpha 2(I), procollagen alpha 1(III), and fibronectin; and decreased levels of laminin, major excreted protein (procathepsin L), transin, and H-ras. Between 1 and 9 days after tumor injection, the phenotype of the cells surviving in the lung changed dramatically and exhibited a pattern of gene expression with increased protease and low matrix protein mRNA levels. This coincided with a 26-fold increase in the ability to colonize lungs on i.v. injection. Both the phenotype characterized by its propensity to arrest in the lung and that showing enhanced metastatic ability were unstable on prolonged in vitro culture. We hypothesize that two selection events have occurred. The first is for lung arrest and implantation of variants of the injected tumor with high matrix protein and low protease levels. A second selection then occurs for tumor cells that carry a favorable phenotype for invasion and proliferation which is associated with low matrix protein and high protease gene expression. These two phenotypes are represented within a clonal population of recently transformed tumor cells.
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PMID:Transient alterations in the expression of protease and extracellular matrix genes during metastatic lung colonization by H-ras-transformed 10T1/2 fibroblasts. 219 71

A conditional expression system was established whereby the human K-ras, v-src, and v-mos genes were cloned into a conditional expression vector downstream of the dexamethasone-inducible mouse mammary tumor virus long terminal repeat. Rat-1 fibroblasts were transfected with these constructs and selected in medium containing G418. Cloned transfectants were isolated and characterized for absolute dependence on dexamethasone for expression of oncogene products and anchorage-independent growth in soft agar. Expression of activated p21K-ras(val12) enabled the fibroblasts to degrade extracellular matrix collagen secreted by murine microvessel endothelial cells. Concurrent with p21K-ras(val12) induction a proteinase with the characteristic size and substrate specificity of transin, the murine homologue of the human matrix metalloproteinase stromelysin, was expressed and secreted. Induction of v-mos and v-src oncogenes resulted in little or no detectable transin expression respectively coinciding with a relative or absolute failure to increase degradation of extracellular matrix collagen. This study suggests that in this system the expression of the ras oncogene can contribute to the in vitro invasive behavior of tumor cells by upregulating the production of a metalloproteinase capable of degrading collagen synthesized by vascular endothelial cells.
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PMID:Degradation of endothelial cell matrix collagen is correlated with induction of stromelysin by an activated ras oncogene. 760 86