Transcriptional regulation of the transforming growth factor beta 1 promoter by v-src gene products is mediated through the AP-1 complex.

Birchenall-Roberts, Maria C.; Ruscetti, Francis W.; Kasper, J; Lee, H D; Friedman, R; Geiser, Andrew G.; Sporn, Michael B.; Roberts, Anita B.; Kim, S J

doi:10.1128/mcb.10.9.4978

Cited by 108 publications

(73 citation statements)

References 9 publications

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“…A wide range of genes have been shown to be up-regulated (41)(42)(43)(44)(45) or down-regulated (1, 46 -51) in cells oncogenically transformed by v-Src. Some of these v-Src down-regulated 24 h), chromatin was cross-linked by formaldehyde and then subjected to immunoprecipitation with antibodies specific for Ac-H3 or Ac-H4 as described under "Experimental Procedures."…”

Section: Discussionmentioning

confidence: 99%

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

Gelman

2007

Journal of Biological Chemistry

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SSeCKS (Src-suppressed C kinase substrate), also called gravin/AKAP12, is a large scaffolding protein with metastasis suppressor activity. Two major isoforms of SSeCKS are expressed in most cell and tissue types under the control of two independent promoters, designated ␣ and ␤, separated by 68 kb. SSeCKS transcript and protein levels are severely decreased in Src-and Ras-transformed fibroblasts and in many epithelial tumors. By dissecting its promoters with progressive deletion analysis, we identified the sequence between ؊106 and ؊49 in the ␣ proximal promoter as the minimal v-Src-responsive element, which contains E-and GC-boxes bound by USF1 and Sp1/ Sp3, respectively. Both E-and GC-boxes are crucial for v-Srcresponsive and basal promoter activities. v-Src does not alter USF1 binding levels at the E-box, but it increases Sp1/Sp3 binding to the GC-box despite no change in their cellular protein abundance. SSeCKS ␣ and ␤ transcript levels in v-Src/3T3 cells can be restored by treatment with the histone deacetylase inhibitor, trichostatin A, but not with the DNA demethylation agent, 5-azacytidine. Chromatin changes are found only on the ␣ promoter even though the ␤ proximal promoter contains a similar E-and GC-box arrangement. Recruitment of HDAC1 is necessary and sufficient to cause repression of ␣ proximal promoter activity, and the addition of Sp1 and/or Sp3 potentiates the repression. Our data suggest that suppression of the ␤ promoter is facilitated by Src-induced changes in the ␣ promoter chromatinization mediated by a USF1-Sp1-Sp3 complex.

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Section: Discussionmentioning

confidence: 99%

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

Gelman

2007

Journal of Biological Chemistry

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“…A mechanism common to several cell types may be responsible for altering cell growth and would involve the induction of immediate-early genes by targeting ubiquitously expressed transcription factors (5,9,20,23,35,37,67,70,82). A second pathway would negatively regulate differentiationspecific genes by targeting developmentally controlled transcription factors.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, several studies have investigated the mechanisms that lead to transcriptional stimulation of genes by the v-Src protein (5,9,20,23,35,37,67,70,82). In several cases, positive regulation of transcription involves TRE or CRE elements and their cognate transcription factors of the leucine zipper family.…”

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confidence: 99%

Transcriptional Stimulation of the Retina-Specific QR1 Gene upon Growth Arrest Involves a Maf-Related Protein

Pouponnot

Nishizawa

Calothy

et al. 1995

Molecular and Cellular Biology

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The avian neural retina (NR) is derived from proliferating neuroectodermal precursors which differentiate after terminal mitosis and become organized in cell strata. Proliferation of postmitotic NR cells can be induced by infection with Rous sarcoma virus (RSV) and requires the expression of a functional v-Src protein. QR1 is a retina-specific gene expressed exclusively at the stage of growth arrest and differentiation during retinal development. In NR cells infected with tsPA101, an RSV mutant conditionally defective in pp60 v-src mitogenic capacity, QR1 expression is downregulated in proliferating cells at 37؇C and is fully restored when the cells become quiescent as a result of pp60 v-src inactivation at 41؇C. We were able to arrest proliferation of tsPA101-infected quail NR cells expressing an active v-Src protein by serum starvation at 37؇C. This allowed us to investigate the role of cell growth in regulating QR1 transcription. We report that QR1 transcription is stimulated in growth-arrested cells at 37؇C compared with that in proliferating cells maintained at the same temperature. Growth arrest-dependent stimulation of QR1 transcription requires the integrity of the A box, a previously characterized cis-acting element responsible for QR1 transcriptional stimulation upon v-Src inactivation and during retinal differentiation. We also show that formation of the C1 complex on the A box is increased upon growth arrest by serum starvation in the presence of an active v-Src oncoprotein. Thus, the C1 complex represents an important link between cell cycle and developmental control of QR1 gene transcription during NR differentiation and RSV infection. By using antibodies directed against different Maf proteins of the leucine zipper family and competition with Maf consensus site-containing oligonucleotides in a gel shift assay, we show that the C1 complex is likely to contain a Maf-related protein. We also show that a purified bacterially expressed v-Maf protein is able to bind the A box and that the level of a 43-kDa Maf-related protein is increased upon growth arrest in infected retinal cells. Moreover, ectopic expression of c-mafI, c-mafII, and mafB cDNAs in quiescent tsPA101-infected quail NR cells is able to stimulate transcription of a QR1 reporter gene through the A box. Therefore, QR1 appears to be the first target gene for a Maf-related protein(s) in the NR.

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“…TGF-b expression tends to be increased in a wide variety of cancers (including colon cancer) relative to adjacent normal tissues (Derynck et al, 1987). Transformation of cells with dominant oncogenes (eg Ha-ras or v-src) results in transcriptional activation of the TGF-b1 gene (Birchenall-Roberts et al, 1990;Geiser et al, 1994). These observations suggest that tumor cells have lost the ability to respond to the growth-inhibitory e ects of the relatively abundant TGF-b that is expressed in tumors.…”

Section: Introductionmentioning

confidence: 99%

Transformation of intestinal epithelial cells by chronic TGF-β1 treatment results in downregulation of the type II TGF-β receptor and induction of cyclooxygenase-2

et al. 1999

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The precise role of TGF-b in colorectal carcinogenesis is not clear. The purpose of this study was to determine the phenotypic alterations caused by chronic exposure to TGF-b in non-transformed intestinal epithelial (RIE-1) cells. Growth of RIE-1 cells was inhibited by 475% following TGF-b1 treatment for 7 days, after which the cells resumed a normal growth despite the presence of TGF-b1. These`TGF-b-resistant' cells (RIE-Tr) were continuously exposed to TGF-b for 450 days. Unlike the parental RIE cells, RIE-Tr cells lost contact inhibition, formed foci in culture, grew in soft agarose. RIE-Tr cells demonstrated TGF-b-dependent invasive potential in an in vitro assay and were resistant to Matrigel and Na-butyrate-induced apoptosis. The RIETr cells were also tumorigenic in nude mice. The transformed phenotype of RIE-Tr cells was associated with a 95% decrease in the level of the type II TGF-b receptor (TbRII) protein, a 40-fold increase in cyclooxygenase-2 (COX-2) protein, and 5.9-fold increase in the production of prostacyclin. Most RIE-Tr subclones that expressed low levels of TbRII and high levels of COX-2 were tumorigenic. Those subclones that express abundant TbRII and low levels of COX-2 were not tumorigenic in nude mice. A selective COX-2 inhibitor inhibited RIE-Tr cell growth in culture and tumor growth in nude mice. The reduced expression of TbRII, increased expression of COX-2, and the ability to form colonies in Matrigel were all reversible upon withdrawal of exogenous TGFb1 for the RIE-Tr cells.

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Transcriptional regulation of the transforming growth factor beta 1 promoter by v-src gene products is mediated through the AP-1 complex.

Cited by 108 publications

References 9 publications

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

v-Src-mediated Down-regulation of SSeCKS Metastasis Suppressor Gene Promoter by the Recruitment of HDAC1 into a USF1-Sp1-Sp3 Complex

Transcriptional Stimulation of the Retina-Specific QR1 Gene upon Growth Arrest Involves a Maf-Related Protein

Transformation of intestinal epithelial cells by chronic TGF-β1 treatment results in downregulation of the type II TGF-β receptor and induction of cyclooxygenase-2

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