Id helix–loop–helix proteins inhibit nucleoprotein complex formation by the TCF ETS-domain transcription factors

Yates, P.; Atherton, Graham T.; Deed, Richard W.; Norton, John D.; Sharrocks, Andrew D.

doi:10.1093/emboj/18.4.968

Cited by 134 publications

(118 citation statements)

References 55 publications

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“…Consistent with these findings, when Id2 is overexpressed in NMuMG cells, TGF-␤-induced E-cadherin repression and ␦EF1 induction were partially impaired ( Figure 7E and Kondo et al, 2004). Previous studies reported that Id proteins bind directly to Ets1 through the conserved HLH domain in vitro (Yates et al, 1999), and we have shown here that Ets1-induced activation of the ␦EF1 promoter was partially suppressed by overexpression of Id2 ( Figure 7C). These findings suggest inhibitory effects of Id proteins on Ets1 in TGF-␤-induced EMT.…”

Section: Ets1 and Id Proteins Act As Upstream Factors For Sip1 And ␦Ef1supporting

confidence: 90%

Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

Shirakihara

Saitoh

Miyazono

2007

MBoC

294

298

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Epithelial-mesenchymal transition (EMT), a crucial event in cancer progression and embryonic development, is induced by transforming growth factor (TGF)-␤ in mouse mammary NMuMG epithelial cells. Id proteins have previously been reported to inhibit major features of TGF-␤-induced EMT.In this study, we show that expression of the ␦EF1 family proteins, ␦EF1 (ZEB1) and SIP1, is gradually increased by TGF-␤ with expression profiles reciprocal to that of E-cadherin. SIP1 and ␦EF1 each dramatically down-regulated the transcription of E-cadherin in NMuMG cells through direct binding to the E-cadherin promoter. Silencing of the expression of both SIP1 and ␦EF1, but not either alone, completely abolished TGF-␤-induced E-cadherin repression. However, expression of mesenchymal markers, including fibronectin, N-cadherin, and vimentin, was not affected by knockdown of SIP1 and ␦EF1. TGF-␤-induced the expression of Ets1, which in turn activated ␦EF1 promoter activity. Moreover, up-regulation of SIP1 and ␦EF1 expression by TGF-␤ was suppressed by knockdown of Ets1 expression. In addition, Id2 suppressed the TGF-␤-and Ets1-induced up-regulation of ␦EF1. Taken together, these findings suggest that the ␦EF1 family proteins, SIP1 and ␦EF1, are necessary, but not sufficient, for TGF-␤-induced EMT and that Ets1 induced by TGF-␤ may function as an upstream transcriptional regulator of SIP1 and ␦EF1. INTRODUCTIONTransforming growth factor (TGF)-␤, a prototypical member of the TGF-␤ family, regulates a broad range of cellular responses, including cell proliferation, differentiation, adhesion, migration, and apoptosis (Bierie and Moses, 2006). TGF-␤ and related factors exhibit their pleiotropic effects through binding to transmembrane serine-threonine kinase receptors type I (T␤R-I) and type II (T␤R-II). On ligand-induced heteromeric complex formation between T␤R-I and T␤R-II, T␤R-I is phosphorylated and activated by T␤R-II kinase and mediates specific intracellular signaling through phosphorylation of receptor-regulated Smads (R-Smads). Phosphorylated R-Smads interact with coSmad (Smad4) and translocate into the nucleus, where they regulate transcription of target genes in cooperation with various transcription factors and transcriptional coactivators or corepressors (Miyazawa et al., 2002;Miyazono et al., 2003;Shi and Massague, 2003).TGF-␤ has potent antiproliferative effects on a wide variety of cells, including epithelial cells, endothelial cells, and hematopoietic cells, although under certain conditions it promotes the proliferation of mesenchymal cells, including fibroblasts, chondrocytes, and osteoblasts. TGF-␤ also induces the deposition of extracellular matrix proteins. In early stages of tumorigenesis, TGF-␤ inhibits the growth of epithelial cells, and insensitivity to this growth-inhibitory effect is associated with progression of tumors Derynck et al., 2001). Transgenic mice expressing a dominant-negative T␤R-II in epidermis exhibit malignant conversion of epithelial cells and promotion of tumor formation (Gorska et al., 20...

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Section: Ets1 and Id Proteins Act As Upstream Factors For Sip1 And ␦Ef1supporting

confidence: 90%

Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

Shirakihara

Saitoh

Miyazono

2007

MBoC

294

298

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“…These include MIDA1 (Shoji et al, 1995;Inoue et al, 1999Inoue et al, , 2000, Pax2, Pax5 and Pax8 (Roberts et al, 2001), Elk-1 (Yates et al, 1999), c-Ets-1 (Ohtani et al, 2001) and the retinoblastoma protein family (Iavarone et al, 1994;Lasorella et al, 1996Lasorella et al, , 2000. Elucidation of the detailed relationships of Id proteins with these factors would reveal novel roles for Id proteins in di erentiation and proliferation controls, and promote our understanding of how di erentiation and proliferation are regulated.…”

Section: Discussionmentioning

confidence: 99%

“…These molecules may be candidates for this positive transcription regulator. In fact, Id proteins have been reported to interact with Ets family proteins (Yates et al, 1999;Ohtani et al, 2001). Id proteins physically interact with the Ets proteins and suppress their functions (Yates et al, 1999;Ohtani et al, 2001), whereas NK cell development is impaired in the absence of either factor (Barton et al, 1998;Yokota et al, 1999).…”

Section: Nk Cellsmentioning

confidence: 99%

Id and development

2001

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During development, it is obvious that enormous multiplication and diversi®cation of cells is required to build a body plan from a single fertilized egg and that these two processes, proliferation and di erentiation, must be coordinated properly. Id proteins, negative regulators of basic helix ± loop ± helix transcription factors, possess the ability to inhibit di erentiation and to stimulate proliferation, and are useful molecules for investigating the mechanisms regulating development. In the past few years, our understanding of the roles of Id proteins has been substantially enhanced by the detailed investigation of genetically modi®ed animals. The data have indicated that the functions of Id proteins in vivo are functionally related to those revealed by earlier work in cell culture systems. However, unexpected organs and cell types have also been found to require Id proteins for their normal development. This review looks at the advances made in our understanding of the in vivo functions of Id proteins. The topics discussed include neurogenesis, natural killer cell development, lymphoid organogenesis, mammary gland development and spermatogenesis. Oncogene (2001) 20, 8290 ± 8298

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“…Our results suggested the binding of BRCA1b protein to the aminoterminal ETS domain (amino acids 1 ± 89) of Elk-1 protein ( Figure 4a). This winged-helix ± turn-helix (wHTH) ETS domain of Elk-1, which is highly conserved among all ETS proteins, mediates both DNA binding (Rao and Reddy, 1992) and protein ± protein interactions with itself (Drewett et al, 2000) or other proteins (Yates et al, 1999). If this ETS domain is su cient for interaction with BRCA1 proteins, then one should expect all the other Ets related proteins to bind to BRCA1.…”

Section: Localization Of the Brca1 Binding Domain Of Elk-1mentioning

confidence: 99%

c-Fos oncogene regulator Elk-1 interacts with BRCA1 splice variants BRCA1a/1b and enhances BRCA1a/1b-mediated growth suppression in breast cancer cells

et al. 2001

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Elk-1, a c-Fos protooncogene regulator, which belongs to the ETS-domain family of transcriptional factors, plays an important role in the induction of immediate early gene expression in response to a variety of extracellular signals. In this study, we demonstrate for the ®rst time the in vitro and in vivo interaction of Elk-1 with BRCA1 splice variants BRCA1a and BRCA1b using GST-pull down assays, co-imunoprecipitations/Western blot analysis of cell extracts from breast cancer cells and mammalian two-hybrid assays. We have localized the BRCA1 interaction domain of Elk-1 protein to the conserved ETS domain, a motif involved in DNA binding and protein ± protein interactions. We also observed binding of BRCA1 proteins to other ETS-domain transcription factors SAP1, ETS-1, ERG-2 and Fli-1 but not to Elk-1 splice variant DElk-1 and c-Fos protooncogene. Both BRCA1a and BRCA1b splice variants function as growth suppressors of human breast cancer cells. Interestingly, our studies reveal that although both Elk-1 and SAP-1 are highly homologous members of a subfamily of ETS domain proteins called ternary complex factors, it is only Elk-1 but not SAP-1 that can augment the growth suppressive function of BRCA1a/1b proteins in breast cancer cells. Thus Elk-1 could be a potential downstream target of BRCA1 in its growth control pathway. Furthermore, we have observed inhibition of c-Fos promoter activity in BRCA1a transfected stable breast cancer cells and over expression of BRCA1a/1b attenuates MEK-induced SRE activation in vivo. These results demonstrate for the ®rst time a link between the growth suppressive function of BRCA1a/1b proteins and signal transduction pathway involving Elk-1 protein. All these results taken together suggest that one of the mechanisms by which BRCA1a/1b proteins function as growth/tumor suppressors is through inhibition of the expression of Elk-1 target genes like c-Fos.

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Id helix–loop–helix proteins inhibit nucleoprotein complex formation by the TCF ETS-domain transcription factors

Cited by 134 publications

References 55 publications

Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-β

Id and development

c-Fos oncogene regulator Elk-1 interacts with BRCA1 splice variants BRCA1a/1b and enhances BRCA1a/1b-mediated growth suppression in breast cancer cells

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