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

Terraz, Catherine; Toman, Dave; Delauche, Madeleine; Ronco, Pierre; Rossert, Jérôme

doi:10.1074/jbc.m104185200

Cited by 52 publications

(42 citation statements)

References 37 publications

(28 reference statements)

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“…It is known that ZEB1 contributes to maintaining the cell cycle because ZEB1 antisense RNA abrogates proliferation (24), apparently due to regulation of the p73 gene in muscle and neuronal cells (6,25). It is frequently observed that ZEB1 represses genes that are markers of terminal differentiation in skeletal muscle (10,12) and represses a1-collagen and collagen type II genes in osteoblasts (22,23) and vascular smooth muscle cells (26). ZEB1 has been suggested to function as a repressor of skeletal muscle differentiation based on the repression of myogenesis in cell lines in vitro (10-12); however, in vivo, it is highly expressed in actively differentiating myoblasts and myofibers (6) and there is no skeletal muscle defect in ZEB1-null embryos (19).…”

Section: Discussionmentioning

confidence: 99%

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The Transcription Factor ZEB1 Is Aberrantly Expressed in Aggressive Uterine Cancers

Spoelstra¹,

Manning²,

et al. 2006

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The transcription factor ZEB1 (DEF1 in mice) has been implicated in cellular processes during development and tumor progression including epithelial to mesenchymal transition. DEF1 null mice die at birth, but heterozygotes expressing a LacZ reporter inserted into the DEF1 gene live and reproduce. Using these mice, we observed ZEB1 promoter activity in the virgin myometrium, and stroma and myometrium of the pregnant uterus. ZEB1 protein is up-regulated in the myometrium and endometrial stroma after progesterone or estrogen treatment of ovariectomized mice. In the normal human uterus, ZEB1 protein is increased in the myometrium and stroma during the secretory stage of the menstrual cycle. ZEB1 is not expressed in the normal endometrial epithelium. In malignancies of the uterus, we find that ZEB1 (a) is overexpressed in malignant tumors derived from the myometrium (leiomyosarcomas), (b) is overexpressed in tumor-associated stroma of low-grade endometrioid adenocarcinomas, and (c) is aberrantly expressed in the tumor epithelial cells of aggressive endometrial cancers. Specifically, in grade 3 endometrioid adenocarcinomas and uterine papillary serous carcinomas, ZEB1 could be expressed in the epithelial-derived carcinoma cells as well as in the stroma. In malignant mixed Müllerian tumors, the sarcomatous component always expresses ZEB1, and the carcinomatous component can also be positive. In summary, ZEB1 is normally regulated by both estrogen and progesterone receptors, but in uterine cancers, it is likely no longer under control of steroid hormone receptors and becomes aberrantly expressed in epithelial-derived tumor cells, supporting a role for ZEB1 in epithelial to mesenchymal transitions associated with aggressive tumors. (Cancer Res 2006; 66(7): 3893-902)

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Section: Discussionmentioning

confidence: 99%

“…In addition to roles in lymphopoiesis (21) and skeletal patterning (17), ZEB1 is likely involved in chondrogenesis (22,23), neurogenesis, neural crest cell development (24), and tumorigenesis (13)(14)(15). Some of these roles seem to involve regulation of events at the crossroad between proliferation and differentiation (6,24).…”

Section: Discussionmentioning

confidence: 99%

The Transcription Factor ZEB1 Is Aberrantly Expressed in Aggressive Uterine Cancers

Spoelstra¹,

Manning²,

et al. 2006

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“…A number of GC-rich TATA-less promoters regulated by Sp1 and Sp3 have previously been shown to contain sequence elements that confer tissue-specific expression (33,34). Additionally, the CBS 5Ј-flanking sequence contains numerous binding sites for delta EF1 and HNF-3 beta, which have previously been shown to regulate gene expression in a tissue-specific manner (35,36). Although our investigation of the Ϫ1b basal promoter indicated that the proximal 5 kbp of 5Ј-flanking sequence neither significantly enhances nor represses CBS Ϫ1b promoter activity in HepG2 cells, it is possible that this region contains sequence elements that act to repress promoter activity in CBS-deficient tissues.…”

Section: Figmentioning

confidence: 99%

The Dominant Role of Sp1 in Regulating the Cystathionine β-Synthase –1a and –1b Promoters Facilitates Potential Tissue-specific Regulation by Kruppel-like Factors

Maclean

Kraus

2004

Journal of Biological Chemistry

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Cystathionine ␤-synthase (CBS) catalyzes the condensation of serine with homocysteine to form cystathionine and occupies a crucial regulatory position between the methionine cycle and transsulfuration. The human cystathionine ␤-synthase gene promoters ؊1a and ؊1b are expressed in a limited number of tissues and are coordinately regulated with proliferation through a redox-sensitive mechanism. Site-directed mutagenesis, DNase I footprinting and deletion analysis of 5276 bp of 5 proximal ؊1b flanking sequence revealed that this region does not confer tissue-specific expression and that 210 bp of proximal sequence is sufficient for maximal promoter activity. As little as 32 bp of the ؊1b proximal promoter region is capable of driving transcription in HepG2 cells, and this activity is entirely dependent upon the presence of a single overlapping Sp1/Egr1 binding site. Co-transfection studies in Drosophila SL2 cells indicated that both promoters are transactivated by Sp1 and Sp3 but only the ؊1b promoter is subject to a site-specific synergistic regulatory interaction between Sp1 and Sp3. Sp1-deficient fibroblasts expressing both Sp3 and NF-Y were negative for CBS activity. Transfection of these cells with a mammalian Sp1 expression construct induced high levels of CBS activity indicating that Sp1 has a critical and indispensable role in the regulation of cystathionine ␤-synthase. Sp1 binding to both CBS promoters is sensitive to proliferation status and is negatively regulated by Kruppel-like factors in co-transfection experiments suggesting a possible mechanism for the tissue specific regulation of cystathionine ␤-synthase.

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“…For instance in developing mesodermal and neural tissues, ZEB1 levels change dynamically during differentiation. 4,5 It is involved in lymphopoiesis, 6 skeletal patterning, 7 chondrogenesis, 8,9 neurogenesis, and neural crest cell development. 10 More recently, a role for ZEB1 in tumor progression, particularly in epithelial to mesenchymal transition (EMT), has been reported, as reviewed by Peinado et al…”

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confidence: 99%

ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease

et al. 2008

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Zinc-finger E-box-binding homeobox 1 (ZEB1) is a transcription factor containing two clusters of Kruppel-type zinc-fingers, by which it binds E-box-like sequences on target DNAs. A role for ZEB1 in tumor progression, specifically, epithelial to mesenchymal transitions, has recently been revealed. ZEB1 acts as a master repressor of E-cadherin and other epithelial markers. We previously demonstrated that ZEB1 is confined to the stromal compartment in normal endometrium and low-grade endometrial cancers. Here, we quantify ZEB1 protein expression in endometrial samples from 88 patients and confirm that it is expressed at significantly higher levels in the tumor-associated stroma of low-grade endometrioid adenocarcinomas (type I endometrial cancers) compared to hyperplastic or normal endometrium. In addition, as we previously reported, ZEB1 is aberrantly expressed in the epithelial-derived tumor cells of highly aggressive endometrial cancers, such as FIGO grade 3 endometrioid adenocarcinomas, uterine serous carcinomas, and malignant mixed Mü llerian tumors (classified as type II endometrial cancers). We now demonstrate, in both human endometrial cancer specimens and cell lines, that when ZEB1 is inappropriately expressed in epithelial-derived tumor cells, E-cadherin expression is repressed, and that this inverse relationship correlates with increased migratory and invasive potential. Forced expression of ZEB1 in the nonmigratory, low-grade, relatively differentiated Ishikawa cell line renders them migratory. Conversely, reduction of ZEB1 in a highly migratory and aggressive type II cell line, Hec50co, results in reduced migratory capacity. Thus, ZEB1 may be a biomarker of aggressive endometrial cancers at high risk of recurrence. It may help identify women who would most benefit from chemotherapy. Furthermore, if expression of ZEB1 in type II endometrial cancers could be reversed, it might be exploited as therapy for these highly aggressive tumors.

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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

Cited by 52 publications

References 37 publications

The Transcription Factor ZEB1 Is Aberrantly Expressed in Aggressive Uterine Cancers

The Transcription Factor ZEB1 Is Aberrantly Expressed in Aggressive Uterine Cancers

The Dominant Role of Sp1 in Regulating the Cystathionine β-Synthase –1a and –1b Promoters Facilitates Potential Tissue-specific Regulation by Kruppel-like Factors

ZEB1 expression in type I vs type II endometrial cancers: a marker of aggressive disease

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