Members of the HRT family of basic helix-loop-helix proteins act as transcriptional downstream of Notch signaling

Osamu Nakagawa, David G. McFadden, Masayo Nakagawa, Hiromi Yanagisawa, Tonghuan Hu, Deepak Srivastava, Eric N. Olson

Research output: Contribution to journalArticlepeer-review

197 Scopus citations

Abstract

The Hairy-related transcription-factor (HRT) genes encode three related basic helix-loop-helix transcription factors that show sequence similarity to the Hairy and Enhancer of split family of transcriptional repressors. HRT proteins are expressed in specific regions of the developing heart, vasculature, pharyngeal arches and somites, and the periodicity of their expression in somitic precursors mirrors that of Notch signaling-related molecules. In the present study, we show that the intracellular domain of the Notch1 receptor (Notch1 IC), which is constitutively active, up-regulates HRT2 expression in 10T 1/2 fibroblasts. Luciferase reporter assays using the regulatory regions of the mouse HRT genes revealed that transcription of all three genes is stimulated by Notch1 IC. The promoters of the HRT genes share homology in a binding site for Suppressor of Hairless [Su(H)], a transcriptional mediator of Notch signaling. A dominant-negative Su(H) mutant abolished Notch-activated HRT2 expression, and mutation of the conserved Su(H) consensus site in the HRT2 promoter attenuated transcriptional activation by Notch. Ectopic expression of HRT proteins also blocked activation of HRT2 expression by Notch1 IC through a mechanism requiring the basic region, but not the conserved carboxyl-terminal YQPW-TEVGAF motif of HRT2. These findings identify HRT genes as downstream targets for Notch signaling and reveal a negative autoregulatory loop whereby HRT proteins repress their own expression through interference with Notch signaling.

Original languageEnglish (US)
Pages (from-to)13655-13660
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number25
DOIs
StatePublished - Dec 5 2000

ASJC Scopus subject areas

  • General

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