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

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human adenovirus E1A 243R protein (243 residues) transcriptionally represses a set of cellular genes that regulate cellular growth and differentiation. We describe two lines of evidence that E1A repression does not require cellular protein synthesis but instead involves direct interaction with a cellular protein(s). First, E1A 243R protein represses an E1A-repressible promoter in the presence of inhibitors of protein synthesis, as shown by cell microinjection-in situ hybridization. Second, E1A 243R protein strongly represses transcription in vitro from promoters of the E1A-repressible genes, human collagenase, and rat insulin type II. Repression in vitro is promoter-specific, and an E1A polypeptide containing only the N-terminal 80 residues is sufficient for strong repression both in vivo and in vitro. By use of a series of E1A 1-80 deletion proteins, the E1A repression function was found to require two E1A sequence elements, one within the nonconserved E1A N terminus, and the second within a portion of conserved region 1 (40-80). These domains have been reported to possess binding sites for several cellular transcription regulators, including p300, Dr1, YY1, and the TBP subunit of TFIID. The in vitro transcription-repression system described here provides a powerful tool for the further analysis of molecular mechanism and the possible role of these cellular factors.
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PMID:Transcriptional repression by human adenovirus E1A N terminus/conserved domain 1 polypeptides in vivo and in vitro in the absence of protein synthesis. 755 79

The transforming E1A 12S and E1A 13S proteins of human adenovirus type 5 (Ad5) contain two and three conserved regions, respectively. In the present study, the contribution of sequences in the nonconserved N-terminal region of the E1A proteins to morphological transformation and to down-regulation of a number of mitogen-inducible genes was investigated. As described previously, transformation of NRK cells (an established normal rat kidney cell line) results in denser cell growth and a cuboidal cellular morphology. None of the cells expressing N-terminally mutated E1A proteins, however, show these transformed properties, which suggests an important role for sequences in that domain. The decrease in cyclin D1 levels requires exactly the same sequences. The ability to transform NRK cells and to reduce cyclin D1 levels does not correlate with the presence in the E1A proteins of binding domains for p300, CBP, p107, pRb, cyclin A, or cdk2. In contrast, down-regulation of expression of the JE gene in NRK cells and repression of transcription of the collagenase gene in human HeLa cells does correlate with the presence in the E1A proteins of an intact binding domain for p300 and CBP. The results suggest that the N-terminal domain of the E1A proteins can repress expression of cellular genes by at least two different mechanisms.
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PMID:The N-terminal region of the adenovirus type 5 E1A proteins can repress expression of cellular genes via two distinct but overlapping domains. 770 22

Adenovirus E1A proteins modulate the expression of a large variety of genes in transformed cells by either stimulating or repressing their promoters. For example, the E1A proteins inhibit the collagenase promoter, whereas they activate the c-jun promoter. Both effects are mediated through AP-1/ATF-binding sites. Repression of transcription of the collagenase gene requires the amino-terminus and conserved region 1 (CR1) of Ad5 E1A, two regions that are also crucial for interaction of E1A with the recently isolated transcriptional adaptor protein p300. We show here that overexpressed p300 can counteract the repressive effect of E1A on the collagenase promoter. Using the CREB-binding protein (CBP), which is highly homologous to p300, the same results were obtained. The domains in E1A required for binding to p300 are also essential for E1A-mediated cell transformation. We therefore tested the effect of p300 and CBP on the transforming potential of Ad5 E1 in baby rat kidney (BRK) cells. It was found that E1A-induced focus formation was strongly inhibited by overexpression of p300 or CBP. Moreover the BRK cell colonies, obtained after cotransfection with Ad5E1 and p300, could not be established. These results indicate that one of the mechanisms by which E1A modulates transcription and transforms cells is via transcriptional adaptors like p300 and CBP.
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PMID:The adenovirus E1A-associated 300 kDa adaptor protein counteracts the inhibition of the collagenase promoter by E1A and represses transformation. 862 69

Transcription factors and cofactors play critical roles in cell growth and differentiation. Alterations of their activities either through genetic mutations or by viral oncoproteins often result in aberrant cell growth and tumorigenesis. The transcriptional cofactor p300 has recently been shown to be complexed with transcription factors YY1 and CREB. Adenovirus E1A oncoproteins target these transcription complexes via physical interactions with p300, resulting in alterations of transcription mediated by these transcription factors. Here we show that p300 is also critical for repression by E1A of the activities of cJun and JunB, two members of the AP-1 transcriptional complexes. This repressive effect of E1A is dependent on the p300-binding domain of E1A and can be relieved by overexpression of p300. These results suggest that p300 serves as a mediator protein for downregulation of AP-1 activity by E1A. This hypothesis was further supported by the following observations: (i) in the absence of E1A, overexpression of p300 stimulated transcription both through an AP-1 site present in the collagenase promoter and through Jun proteins in GAL4 fusion protein-based assays; and (ii) overexpression of a mutant p300 lacking the E1A-interacting domain reduced the responsiveness of Jun-dependent transcription to E1A repression. As predicted from the functional results, p300 physically interacted with the Jun proteins. These findings thus established that p300 is a cofactor for cJun and JunB. We propose that p300 is a common mediator protein through which E1A gains control over multiple transcriptional regulatory pathways in the host cells.
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PMID:Adenovirus E1A downregulates cJun- and JunB-mediated transcription by targeting their coactivator p300. 875 32

Enhanced production of matrix metalloproteinase-1 (MMP-1, collagenase-1) is implicated in pathological tissue destruction. Transforming growth factor-beta (TGF-beta) prevents cytokine-induced MMP-1 gene expression in fibroblasts. In these studies, we examined the hypothesis that repression of MMP-1 may be mediated through the Smad signaling pathway. The results showed that Smad3 and Smad4, but not Smad1 or Smad2, mimicked the inhibitory effect of TGF-beta and abrogated interleukin-1beta (IL-1beta)-induced stimulation of MMP-1 promoter activity and NFkappaB-specific gene transcription in dermal fibroblasts. Experiments with truncation mutants indicated that both MH1 and MH2 domains of Smad3 were necessary for inhibitory activity. Dominant negative mutants of Smad3 or Smad4 and antagonistic Smad7, which disrupts ligand-induced Smad3 phosphorylation, abrogated the repression of MMP-1 transcription by TGF-beta. Similar results were obtained using immunoblot and Northern analysis. Furthermore, TGF-beta failed to repress MMP-1 promoter activity in Smad3-deficient murine embryonic fibroblasts. These results implicated cellular Smads in mediating the inhibitory effects of TGF-beta. Overexpression of the transcriptional co-activator p300, but not its histone acetyltransferase (HAT)-deficient mutant, was able to relieve repression of MMP-1 gene expression, suggesting that Smad-dependent inhibition may be due to increased competition between Smad proteins and IL-1beta signaling pathways for limiting amounts of cellular p300. Together, these results demonstrate that MMP-1 is a target for negative regulation by TGF-beta through cellular Smad3 and Smad4. Smad-mediated repression of MMP-1 gene expression may be important for preventing excessive matrix degradation induced by inflammatory cytokines; disruption of Smad signaling, as occurs in certain cancer cells, may thus be causally linked to uncontrolled tissue destruction mediated through MMP-1.
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PMID:Transforming growth factor-beta repression of matrix metalloproteinase-1 in dermal fibroblasts involves Smad3. 1150 52

The adenovirus E1A protein regulates transcription of cellular genes via its interaction with the transcriptional coactivators p300/CBP. The collagenase promoter activated by the c-Jun protein is repressed by E1A. Here we show that E1A repression is specific for c-Jun, as E1A does not repress the collagenase promoter activated by the homologous transcription factor EB1. Using chimeras of c-Jun and EB1, we demonstrate that a 12 amino acid region in the basic region of the c-Jun DNA-binding domain is essential for repression by E1A. Since repression requires the binding of p300 to E1A, we studied the involvement of p300 acetyltransferase activity in the repression mechanism. We demonstrate that c-Jun is acetylated in vivo, and mutational analysis identified Lys271 in the c-Jun basic region to be essential for repression of the collagenase promoter by E1A. In addition, Lys271 is acetylated both in vitro and in vivo. These results suggest that the specific repression of the collagenase promoter by E1A involves acetylation of c-Jun.
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PMID:A specific lysine in c-Jun is required for transcriptional repression by E1A and is acetylated by p300. 1168 49

Extracellular matrix (ECM) production and turnover are tightly controlled under normal physiological conditions. Ets factors regulate matrix turnover by activating transcription of several metalloproteinases (MMPs) and are frequently overexpressed in aggressive tumors and arthritis. Because of the prominent role of transforming growth factor beta (TGF-beta) in ECM synthesis, this study was undertaken to determine the possible interactions between Ets1 and the TGF-beta pathway. Experiments using adenoviral delivery of Ets1 in human fibroblasts have established that Ets1 strongly suppresses TGF-beta induction of collagen type I and other matrix-related genes and reverses TGF-beta-dependent inhibition of MMP-1. Subsequent experiments utilizing COL1A2 promoter demonstrated that Ets1 in the presence of TGF-beta signaling interferes with the stimulatory role of p300. To gain further insight into the mechanism of Ets1 inhibition of the TGF-beta signaling, the protein levels and post-translational modifications of Ets1 after TGF-beta treatment were analyzed. The level of total Ets1 protein was not affected after 24 h of TGF-beta stimulation. Moreover, TGF-beta did not affect either serine or threonine phosphorylation levels of Ets1. However, TGF-beta induced rapid and prolonged lysine acetylation of Ets1. In addition, analyses of endogenous p300.Ets1 complexes revealed that acetylated Ets1 is preferentially associated with the p300/CBP complexes. TGF-beta treatment leads to dissociation of Ets1 from the CBP/p300 complexes. Together, these findings suggest that elevated expression of Ets1 in fibroblasts fundamentally alters their responses to TGF-beta in favor of matrix degradation and away from matrix deposition as exemplified by arthritis and cancer.
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PMID:Ets1 is an effector of the transforming growth factor beta (TGF-beta ) signaling pathway and an antagonist of the profibrotic effects of TGF-beta. 1191 90

Gene activation in eukaryotes requires chromatin remodeling, in part via histone modifications. To study the events at the promoter of a mitogen-inducible gene, we examined the induction of expression of the collagenase gene. It has been established that the collagenase gene can be activated by c-Jun and c-Fos and that the transcriptional coactivator p300 is involved in the activation. As expected, we found histone acetyltransferase activity at the collagenase promoter during activation. Interestingly, we also found histone methyltransferase and kinase activity. Strikingly, the first modification observed is methylation of histone H3 lysine 4, which correlates with the binding of the SET9 methyltransferase and the assembly of a complex consisting of c-Jun, c-Fos, TATA binding protein, and RNA polymerase II. The assembly of the preinitiation complex also shows an ordered binding of the acetyltransferase p300, the RSK2 kinase, and the SWI/SNF component Brg-1. Our results suggest that collagenase gene activation involves a dynamic recruitment of different factors and that in addition to acetylation, histone H3 lysine 4 di- and trimethylation and histone H3 serine 10 phosphorylation are important steps in the activation of this gene.
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PMID:Cascade of distinct histone modifications during collagenase gene activation. 1258 98

CITED2 (CBP/p300-interacting transactivator with ED-rich tail 2) is a member of the Cited family of nuclear regulators, previously known as mrg1 (melanocyte-specific gene-related gene 1). CITED2 is inducible by varying stimuli including lipopolysaccharide, hypoxia, and cytokines such as interleukin 9 and interferon gamma. Using the immortalized human chondrocyte cell line, C-28/I2, we investigated whether CITED2 could be responsive to mechanical stimuli, and if so, whether CITED2 could mediate shear-driven regulation of matrix metalloproteinase (MMP) genes. The C-28/I2 cells were cultured under flow shear at 1-20 dyn/cm2, and the role of CIT-ED2 in regulation of MMPs was examined using the plasmids encoding sense and antisense CITED2 DNA sequences. The results showed that flow shear at 5 dyn/cm2 increased CITED2 mRNA and protein levels and down-regulated MMP-1 and MMP-13 mRNA and protein levels as well as enzyme activities. Consistent with the coordinated expression patterns of CITED2 and MMPs, overexpression of CITED2 repressed MMP-1 and MMP-13 mRNA levels and activities, whereas antisense CITED2 plasmids prevented the shear-induced down-regulation of MMP expression. Interleukin-1beta induced the formation of p300-Ets-1 complexes without affecting expression of CITED2. Transforming growth factor-beta as well as flow shear at 5 dyn/cm2 stimulated not only the expression of CITED2 but also the association of CIT-ED2 with p300 by dissociating Ets-1 from p300. These results indicate that CITED2 plays a major role in shear-induced down-regulation of MMP-1 and MMP-13 via a transforming growth factor-beta-dependent pathway.
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PMID:CITED2-mediated regulation of MMP-1 and MMP-13 in human chondrocytes under flow shear. 1296 Jan 75

The mechanisms of action of Ewing's sarcoma (EWS) associated EWS-ETS oncoproteins have largely remained unresolved. Here, we analyzed how two EWS-ETS proteins, EWS-ER81 and EWS-Fli-1, in vitro activate the matrix metalloproteinase (MMP)-1 promoter that is upregulated in a subset of EWSs. EWS-ER81 and EWS-Fli-1 interact with and thereby activate the MMP-1 promoter, which is potentiated by the cofactor p300 and the proto-oncoprotein c-Jun. Further, EWS-ER81 binds to c-Jun in vitro and in vivo. The interaction between c-Jun, p300 and EWS-ER81 or EWS-Fli-1 may also be relevant to the regulation of other yet-to-be-identified genes that are responsible for EWS formation.
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PMID:Upregulation of the matrix metalloproteinase-1 gene by the Ewing's sarcoma associated EWS-ER81 and EWS-Fli-1 oncoproteins, c-Jun and p300. 1455 May 55


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