Cloning and characterization of hcKrox, a transcriptional regulator of extracellular matrix gene expression

Widom, Russell L.; Culic, Ivana; Lee, John Y.; Korn, Joseph H.

doi:10.1016/s0378-1119(97)00360-0

Cited by 56 publications

(56 citation statements)

References 41 publications

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“…The absence of tissuespecific elements within the first intron extend results obtained by Hormuzdi et al (8). They also showed the absence of tissuespecific elements in this intron by generating knock-in mice lacking most of it (12). Analysis of heterozygous mice showed that it was important for maintaining normal levels of expression of the pro-␣1(I) collagen gene in lung and muscle during adult life.…”

Section: ␦Ef1 Represses Pro-␣1(i) Collagen Gene Expressionmentioning

confidence: 99%

“…Moreover, deletion of most of the first intron did not increase the levels of expression of the pro-␣1(I) collagen gene in vivo (8). A member of the Krü ppel-like family of transcription factors named cKrox is the only transcription factor that has been reported as being able to down-regulate the level of expression of the pro-␣1(I) collagen gene (12). Nevertheless, its role in modulating the transcription of this gene remains controversial (12,13).…”

mentioning

confidence: 99%

“…A member of the Krü ppel-like family of transcription factors named cKrox is the only transcription factor that has been reported as being able to down-regulate the level of expression of the pro-␣1(I) collagen gene (12). Nevertheless, its role in modulating the transcription of this gene remains controversial (12,13). In transient transfection experiments, overexpression of the mouse cKrox gene enhanced the transcription of a reporter gene cloned downstream of a promoter containing three copies of a cKrox binding site (13), while overexpression of a truncated form of the human cKrox gene had an inhibitory effect on the expression of the pro-␣1(I) collagen gene (12).…”

mentioning

confidence: 99%

“…Nevertheless, its role in modulating the transcription of this gene remains controversial (12,13). In transient transfection experiments, overexpression of the mouse cKrox gene enhanced the transcription of a reporter gene cloned downstream of a promoter containing three copies of a cKrox binding site (13), while overexpression of a truncated form of the human cKrox gene had an inhibitory effect on the expression of the pro-␣1(I) collagen gene (12).…”

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confidence: 99%

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δEF1 Binds to a Far Upstream Sequence of the Mouse Pro-α1(I) Collagen Gene and Represses Its Expression in Osteoblasts

Terraz¹,

Toman²,

Delauche³

et al. 2001

Journal of Biological Chemistry

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The transcription of type I collagen genes is tightly regulated, but few cis-acting elements have been identified that can modulate the levels of expression of these genes. Generation of transgenic mice harboring various segments of the mouse pro-␣1(I) collagen promoter led us to suspect that a repressor element was located between ؊10.5 and ؊17 kilobase pairs. Stable and transient transfection experiments in ROS17/2.8 osteoblastic cells confirmed the existence of such a repressor element at about ؊14 kilobase pairs and showed that it consisted in an almost perfect three-time repeat of a 41-base pair sequence. This element, which we named COIN-1, contains three E2-boxes, and a point mutation in at least two of them completely abolished its repressor effect. In gel shift assays, COIN-1 bound a DNAbinding protein named ␦EF1/ZEB-1, and mutations that abolished the repressor effect of COIN-1 also suppressed the binding of ␦EF1. We also showed that the repressor effect of COIN-1 was not mediated by chromatin compaction. Furthermore, overexpression of ␦EF1 in ROS17/ 2.8 osteoblastic cells enhanced the inhibitory effect of COIN-1 in a dose-dependent manner and repressed the expression of the pro-␣1(I) collagen gene. Thus, ␦EF1 appears to repress the expression of the mouse pro-␣1(I) collagen gene, through its binding to COIN-1.Type I collagen is a fibrillar collagen composed of two ␣1 chains and one ␣2 chain coiled around each others in a triple helix. It is the most abundant protein of mammalian bodies, and a major component of most extracellular matrices. In the extracellular space, type I collagen molecules self-assemble into highly organized fibrils and then fibers, which largely contribute to the high tensile strength of the structural framework supporting body structures (reviewed in Ref.

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Section: ␦Ef1 Represses Pro-␣1(i) Collagen Gene Expressionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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δEF1 Binds to a Far Upstream Sequence of the Mouse Pro-α1(I) Collagen Gene and Represses Its Expression in Osteoblasts

Terraz¹,

Toman²,

Delauche³

et al. 2001

Journal of Biological Chemistry

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“…A retroviral packaging cell line (hFasL-PA317) carrying the hfasl gene and control packaging cell line Krox-PA317 carrying the human ckrox were prepared according to the method of A. D. Miller (38) and have been described previously (36,39). A vesicular stomatitis virus G glycoprotein pseudotyped, vector-packaging cell line carrying the hfasl gene was prepared according to the method described by Burns et al (40).…”

Section: Methodsmentioning

confidence: 99%

Apoptosis-inducing Membrane Vesicles

Jodo

Xiao

Hohlbaum

et al. 2001

Journal of Biological Chemistry

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CD95 (Fas)1 is a type I transmembrane protein expressed by a variety of nucleated cells (1). The physiological ligand for Fas (FasL) is a type II transmembrane protein expressed by activated T cells and non-T cells under a variety of conditions (2-11). Cross-linking of Fas induces cells to undergo apoptosis (12)(13)(14). This apoptosis pathway has been implicated in immune response regulation, self-tolerance, graft rejection, tumor escape of immune surveillance, and maintenance of the immune privileged sites (2-6, 15-28).Regulation of FasL expression has been demonstrated at the transcriptional and post-transcriptional levels (4 -6, 29 -32).Recent studies have suggested that the level of cell surface FasL is regulated by a mechanism involving matrix metalloproteinase (MMP) cleavage that releases from cells soluble FasL (sFasL) lacking the transmembrane and cytoplasmic domains (29 -32). Compared with cell-associated FasL, sFasL is a relatively poor mediator of cytotoxicity. Indeed, under certain conditions, sFasL can actually inhibit the cytotoxicity of FasLexpressing cells (30, 31). Thus, sFasL release effectively downregulates the function of cell-associated FasL. Here, we demonstrate that there is a second mechanism responsible for FasL turnover. This mechanism involves the release of cell surface FasL in the form of vesicles, which contain full-length FasL and are bioactive. Although the presence of FasL-bearing vesicles was implicated in previous studies (33, 34), the FasL expression level was so low that a quantitative study to determine its contribution to cell membrane FasL turnover was difficult. We have generated retroviral packaging cell lines that produce large amounts of FasL-expressing vesicles; however, it is not clear whether the retroviral packaging process has influenced the production of FasL membrane vesicles (35-37).To determine whether normal FasL-expressing cells produce apoptosis-inducing vesicles, we generated FasL-expressing 3T3 cells that do not produce virus. We generated T cells that produce high levels of membrane FasL upon activation. In addition, we studied normal T cells for cell membrane FasL turnover upon activation. We demonstrated that these cells release of FasL-bearing vesicles capable of inducing apoptosis in target cells. Our quantitative analysis indicated that release of vesicles contributes to the turnover of cell-associated FasL, but the extent of contribution varies in different cell lines examined. Interestingly, the apoptosis-inducing vesicles display unique properties. In contrast to sFasL, FasL-bearing vesicles fully retained the target range of the FasL-expressing cells. However, there is a reduction of specific activity in comparison with cell-associated FasL. These observations suggest that release of vesicles is a physiologically significant process regarding both the turnover of cell-associated FasL and the impact on FasL function of the FasL-expressing cells. EXPERIMENTAL PROCEDURESProduction of FasL-expressing Cell Lines-We obtained an hfasl cDNA construct ...

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Species differences in cis-elements of the Pro?1(I) procollagen promoter and their binding proteins

et al. 1999

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Previous studies suggest that there may be species differences in the utilization of cis-elements of the type I collagen genes. The present study was designed to examine this possibility by focusing on two regions of the proalpha1(I) collagen promoter. One is the GC-rich A1 region (-194/168) that modulates transcriptional activity of the mouse promoter. The other contains a glucocorticoid response element (GRE) implicated in negative glucocorticoid regulation of the rat promoter. Unlike mouse A1 probes, probes representing the analogous human (-195/-168) and rat (-193/-179) regions failed to bind nuclear proteins in gel shift assays. Binding assays with mouse A1 probes containing base substitutions indicated that this behavior could be ascribed to five bases in the human, and two in the rat sequences. In addition, the pattern of expression of c-Krox, a protein that alters transcriptional activity via the mouse A1 element, differed in mouse and human tissues. Computer analysis revealed differences in the arrangement of GRE half-sites in human and rat proalpha1(I) collagen promoters. In a region of the human promoter (-700/673) analogous to the rat (-672/-633), there are three half-sites, each separated by two nucleotides, that cooperate in binding of glucocorticoid receptor. There also is a proximal half-site at position -335 of the human promoter that binds glucocorticoid receptor, but it is not present in the rat promoter. This study has defined several species-specific differences in the sequences and nuclear protein binding activity of regions involved in transcriptional activity of the proalpha1(I) collagen promoter. The results suggest that the A1 regions of the human and rat promoters examined here are unlikely to function as regulatory cis-elements, and they provide a framework for investigating the role of GREs in transcriptional regulation. They also suggest that species differences in cis-elements and transcription factors should be taken into consideration when using heterologous systems to study collagen gene regulation.

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Cloning and characterization of hcKrox, a transcriptional regulator of extracellular matrix gene expression

Cited by 56 publications

References 41 publications

δEF1 Binds to a Far Upstream Sequence of the Mouse Pro-α1(I) Collagen Gene and Represses Its Expression in Osteoblasts

δEF1 Binds to a Far Upstream Sequence of the Mouse Pro-α1(I) Collagen Gene and Represses Its Expression in Osteoblasts

Apoptosis-inducing Membrane Vesicles

Species differences in cis-elements of the Pro?1(I) procollagen promoter and their binding proteins

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