Functional analysis of Hes-1 in preadipocytes

David A. Ross, Sridhar Hannenhalli, John W. Tobias, Neil Cooch, Ramin Shiekhattar, Tom Kadesch

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Notch signaling blocks differentiation of 3T3-L1 preadipocytes, and this can be mimicked by constitutive expression of the Notch target gene Hes-1. Although considered initially to function only as a repressor, recent evidence indicates that Hes-1 can also activate transcription. We show here that the domains of Hes-1 needed to block adipogenesis coincide with those necessary for transcriptional repression. HRT1, another basic-helix-loop-helix protein and potential Hes-1 partner, was also induced by Notch in 3T3-L1 cells but did not block adipogenesis, suggesting that Hes-1 functions primarily as a homodimer or possibly as a heterodimer with an unknown partner. Purification of Hes-1 identified the Groucho/transducin-like enhancer of split family of corepressors as the only significant Hes-1 interacting proteins in vivo. An evaluation of global gene expression in preadipocytes identified approximately 200 Hes-1-responsive genes comprising roughly equal numbers of up-regulated and down-regulated genes. However, promoter analyses indicated that the down-regulated genes were significantly more likely to contain Hes-1 binding sites, indicating that Hes-1 is more likely to repress transcription of its direct targets. We conclude that Notch most likely blocks adipogenesis through the induction of Hes-1 homodimers, which repress transcription of key target genes.

Original languageEnglish (US)
Pages (from-to)698-705
Number of pages8
JournalMolecular Endocrinology
Volume20
Issue number3
DOIs
StatePublished - Mar 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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    Ross, D. A., Hannenhalli, S., Tobias, J. W., Cooch, N., Shiekhattar, R., & Kadesch, T. (2006). Functional analysis of Hes-1 in preadipocytes. Molecular Endocrinology, 20(3), 698-705. https://doi.org/10.1210/me.2005-0325