HERP, a Novel Heterodimer Partner of HES/E(spl) in Notch Signaling

Iso, Tatsuya; Sartorelli, Vittorio; Poizat, Coralie; Iezzi, Simona; Wu, Hung‐Yi; Chung, Gene; Kedes, Larry; Hamamori, Yasuo

doi:10.1128/mcb.21.17.6080-6089.2001

Cited by 195 publications

(223 citation statements)

References 51 publications

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“…In addition, our results indicate that endogenous HES-1 binds to the E2F-1 promoter as a heterodimer with the related protein (Figure 3c). HES-1/HERP-1/2-heterodimers have been reported to function as even stronger repressors than HES-1 alone (Iso et al, 2001). Binding of HES-1 to a promoter has only been demonstrated in few cases, besides its binding to its own promoter (Takebayashi et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we found that purified GST-HES-1 protein was able to bind to the wild-type element, while the mutated element did not bind ( Figure 3b). In addition, using nuclear extracts from T47D cells, we found that HES-1 bound as a homodimer to the HES-1 binding site in the HES-1 promoter but binding to the HES-1 binding site in the E2F-1 promoter was only present as a faster migrating band which could be competed with a HES-1 binding oligo Reduction of E2F-1 expression by atRA is dependent on HES-1 J Hartman et al indicating that this band is a heterodimer between HES-1 and the related factor HERP-1/2 described by Iso et al (2001). Extracts from cells exposed to atRA showed an increased binding of the HERP-1/2-HES-1 heterodimer ( Figure 3c).…”

Section: Hes-1 Expression Arrests T47d Cells In the G 1 Phase Of The mentioning

confidence: 99%

“…The factor is expressed in many tissues such as CNS, lung, kidney, intestine (Sasai et al, 1992;Fisher and Caudy, 1998). The closely related factors HERP-1/HERP-2 can form a heterodimer with HES-1 which has a higher DNA binding affinity and stronger repressive function than respective homodimers (Iso et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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HES-1 inhibits 17β-estradiol and heregulin-β1-mediated upregulation of E2F-1

et al. 2004

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We have previously shown that expression of the transcription factor HES-1 is required for the growthinhibitory effect of all-trans retinoic acid on MCF-7 cells. In this study, we have used T47D cells with tetracyclinregulated expression of wild-type or a dominant-negative form of HES-1. Expression of HES-1 in T47D cells inhibited G 1 /S-phase transition and activation of Cdk2 elicited by estrogen. Estrogen treatment of T47D cells caused increased expression of E2F-1, and this expression was inhibited by cotreatment with all-trans retinoic acid. We show that the effect is mediated through HES-1, which directly downregulates E2F-1 expression through a CACGAG-site within the E2F-1 promoter. Furthermore, proliferation caused by heregulin-b1 treatment of T47D cells was inhibited by all-trans retinoic acid and this effect was mediated by HES-1. Interestingly, heregulin-b1-mediated upregulation of E2F-1 expression was directly inhibited by HES-1 through the same CACGAG-site as seen with estrogen-stimulated induction. In addition, we found that two important downstream target genes of estrogen and heregulin-b1 that are regulated through E2F-1, cyclin E and NPAT, were both regulated in a similar fashion by all-trans retinoic acid, and these effects were antagonized by dominant-negative HES-1. These findings establish that HES-1 inhibits both estrogen-and heregulin-b1-stimulated growth of breast cancer cells, and further suggest that growth inhibition induced in these cells by all-trans retinoic acid occurs via HES-1-mediated downregulation of E2F-1 expression.

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Section: Discussionmentioning

confidence: 99%

Section: Hes-1 Expression Arrests T47d Cells In the G 1 Phase Of The mentioning

confidence: 99%

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HES-1 inhibits 17β-estradiol and heregulin-β1-mediated upregulation of E2F-1

et al. 2004

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“…These genes code for transcriptional repressors of the ''basic helix-loop-helix'' (bHLH) type acting as Notch effectors, downregulating expression of other target genes, such as specific tissue transcription factors. A new family of bHLH type transcription repressors, targets of Notch signalling, indicated as HERP, was recently identified (Kokubo et al, 1999;Iso et al, 2001Iso et al, , 2003a. Although very similar, HES and HERP families have been found to use distinct domains and corepressors for their transcription repressor function.…”

Section: Target Genes Of Notch Signallingmentioning

confidence: 99%

“…The main targets of Notch signalling are HES genes in mammals and enhancer of split E(spl) genes in Drosophila, often indicated as HES/E(spl) gene family (Egan et al, 1998;Artavanis-Tsakonas et al, 1999;Iso et al, 2001Iso et al, , 2002. These genes code for transcriptional repressors of the ''basic helix-loop-helix'' (bHLH) type acting as Notch effectors, downregulating expression of other target genes, such as specific tissue transcription factors.…”

Section: Target Genes Of Notch Signallingmentioning

confidence: 99%

Physiology and pathology of notch signalling system

Bianchi

Dotti

Federico

2005

Journal Cellular Physiology

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Notch proteins encode a family of transmembrane receptors that are part of a signalling transduction system known as Notch signalling, an extremely conserved and widely used mechanism regulating programs governing growth, apoptosis and differentiation in metazoans. Notch signalling begins when the Notch receptor binds ligands and ends when the Notch intracellular domain enters the nucleus and activates transcription of target genes. This core pathway is subjected to a wide array of regulatory influences and protein-protein interactions and is correlated with other signalling pathway. This review will sumarize recent findings concerning the physiology and pathology of Notch signalling in vascular development and homeostasis. Moreover, the clinical phenotypes of Notch3 signalling system pathology will be described, with particular regard to CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) for which the most recent pathogenetic hypotheses are reported.

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Repression of chondrogenesis through binding of notch signaling proteins HES‐1 and HEY‐1 to N‐box domains in the COL2A1 enhancer site

Grogan¹,

Olee²,

Hiraoka³

et al. 2008

Arthritis & Rheumatism

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Objective. Notch signaling is implicated in the repression of mesenchymal stem cell (MSC) chondrogenic differentiation. The purpose of this study was to examine the mechanism of this repression and how it is modulated to permit chondrogenesis.Methods. Notch intracellular domain (NICD) protein levels were monitored via Western blotting throughout chondrogenic differentiation of human MSCs in pellet cultures. Overexpression of Notch signaling components and their effect on chondrogenesis was achieved by transfecting plasmids coding for NICD, HES-1, and HERP-2/HEY-1. COL2A1 and AGGRECAN expression was monitored via quantitative polymerase chain reaction analysis. Chromatin immunoprecipitation (ChIP) was used to test whether HES-1 and HEY-1 bind putative N-box domains in intron 1 of COL2A1.Results. High levels of NICD proteins were reduced during chondrogenesis of human MSCs, and this was mediated by transforming growth factor ␤3 (TGF␤3). COL2A1 gene expression was repressed following overexpression of NICD (2-fold) and HES-1 (3-fold) and was markedly repressed by overexpression of HEY-1 (80-fold). HEY-1 repressed AGGRECAN expression 10-fold, while NICD and HES-1 had no effect. We identified 2 putative N-box domains adjacent to, and part of, the SOX9 enhancer binding site located in intron 1 of COL2A1. ChIP studies showed that endogenous HES-1 and HEY-1 bound to these sites.Transducin-like enhancer, the HES-1 corepressor protein, was displaced during chondrogenic differentiation and following TGF␤3 treatment.Conclusion. These results reveal novel mechanisms by which Notch signaling represses gene expression. Notch signaling proteins act on the SOX9 binding site in the COL2A1 enhancer and prevent SOX9-mediated transcriptional activation of COL2A1 and, thus, chondrogenic differentiation.

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HERP, a Novel Heterodimer Partner of HES/E(spl) in Notch Signaling

Cited by 195 publications

References 51 publications

HES-1 inhibits 17β-estradiol and heregulin-β1-mediated upregulation of E2F-1

HES-1 inhibits 17β-estradiol and heregulin-β1-mediated upregulation of E2F-1

Physiology and pathology of notch signalling system

Repression of chondrogenesis through binding of notch signaling proteins HES‐1 and HEY‐1 to N‐box domains in the COL2A1 enhancer site

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