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

Transin mRNA encodes a secreted metalloprotease which is transcriptionally induced in Rat-1 cells by epidermal growth factor (EGF) and a number of oncogenes. A role for transin in tumor progression is suggested by its overexpression in malignant and metastatic tumors compared to their benign counterparts. In an effort to elucidate mechanisms by which elevated transin expression may be inhibited, it has been determined that both transforming growth factor type beta 1 (TGF beta 1) and increased levels of intracellular cyclic 5'-adenosine monophosphate (cAMP) inhibit EGF and oncogene induction of transin mRNA. The inhibition of transin mRNA occurred at the level of transcription as demonstrated by nuclear run-on assays. EGF binding studies in Rat-1 cells showed no significant effect of cAMP or TGF beta 1 on EGF receptor number or affinity. We have also examined the effects of cAMP and TGF beta 1 on oncogene-induced transin using Rat-1 cells transformed by temperature-sensitive mutants of v-src and K-ras oncogenes. Both inhibitors prevented the induction of transin RNA as well as decreased the levels of transin once elevated at the permissive temperature. Despite the similarities in the actions of TGF beta 1 and cAMP on transin gene expression, TGF beta 1 treatment did not significantly elevate intracellular cAMP levels, thus making it unlikely that cAMP is a second messenger system for TGF beta 1 action. These studies suggest that the inhibitory effects of cAMP and TGF beta 1 occur by distinct pathways at the level of gene regulation.
 ...
PMID:Transforming growth factor beta 1 and cAMP inhibit transcription of epidermal growth factor- and oncogene-induced transin RNA. 284 55

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.
 ...
PMID:Degradation of endothelial cell matrix collagen is correlated with induction of stromelysin by an activated ras oncogene. 760 86

In our previous study on the tumorigenesis of human functional adrenal tumors, we observed a high frequency of point mutation in the K-ras gene in clinical adrenal tumors. Therefore, we analyzed gene profiles of mutant K-ras transfected adrenocortical cells by DNA microarray to determine the expression pattern of genes related to cell cycle, signal transduction, apoptosis, tumorigenesis, steroidogenesis, and other expressed sequence tags (ESTs). Then we analyzed all of the significant differentially expressed genes by bioinformatics tools, "Matchminer" and "Gominer." The results revealed that expression of mutant K-ras gene induced by IPTG upregulated Ets1, which was mainly related to cell proliferation. After carefully being analyzed by software "DAVID" and "Pathart," Ets1 was found to be activated by being phosphorylated at theronine 38 by ERK1/2, and in turn, to regulate the following genes: uPA, MMP-3, and prolactin (Ling et al., 2003; Duffy and Daggan, 2004; Maupas-Schwalm et al., 2004; van Themsche et al., 2004). The result of Western blotting analysis confirmed that Ets1 was really phosphorylated when mutant K-ras was activated. On the other hand, the membrane blotting analyses indicated that the expression levels of uPA, MMP-3, and prolactin in human adrenocortical cells stably transfected with the mutant K-ras gene were significantly higher than those in normal control cells. Compared to control cells, the level of prolactin raised 1.4-fold, the level of MMP-3 raised 1.8-fold, and the level of uPA raised 2.1-fold in the transfected cells. From the results of this study, we proposed a mechanism of Ets1 in human adrenocortical cells expressing a mutated K-ras gene.
 ...
PMID:Ets1 was significantly activated by ERK1/2 in mutant K-ras stably transfected human adrenocortical cells. 1569 32