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Molecular and Cellular Biology, September 2001, p. 6080-6089, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.6080-6089.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Tatsuya Iso,1,2 Vittorio Sartorelli,3 Coralie Poizat,1,2 Simona Iezzi,3 Hung-Yi Wu,1,2 Gene Chung,1 Larry Kedes,1,2,4,* and Yasuo Hamamori1,2,*

Institute for Genetic Medicine,1 Department of Biochemistry and Molecular Biology,2 and Department of Medicine,4 Keck School of Medicine of the University of Southern California, Los Angeles, California 90089-9075, and Laboratory of Muscle Biology, Muscle Gene Expression Group, NIAMS-IRP, National Institutes of Health, Bethesda, Maryland 208923

Received 31 January 2001/Returned for modification 19 March 2001/Accepted 21 May 2001

HERP1 and -2 are members of a new basic helix-loop-helix (bHLH) protein family closely related to HES/E(spl), the only previously known Notch effector. Like that of HES, HERP mRNA expression is directly up-regulated by Notch ligand binding without de novo protein synthesis. HES and HERP are individually expressed in certain cells, but they are also coexpressed within single cells after Notch stimulation. Here, we show that HERP has intrinsic transcriptional repression activity. Transcriptional repression by HES/E(spl) entails the recruitment of the corepressor TLE/Groucho via a conserved WRPW motif, whereas unexpectedly the corresponding---but modified---tetrapeptide motif in HERP confers marginal repression. Rather, HERP uses its bHLH domain to recruit the mSin3 complex containing histone deacetylase HDAC1 and an additional corepressor, N-CoR, to mediate repression. HES and HERP homodimers bind similar DNA sequences, but with distinct sequence preferences, and they repress transcription from specific DNA binding sites. Importantly, HES and HERP associate with each other in solution and form a stable HES-HERP heterodimer upon DNA binding. HES-HERP heterodimers have both a greater DNA binding activity and a stronger repression activity than do the respective homodimers. Thus, Notch signaling relies on cooperation between HES and HERP, two transcriptional repressors with distinctive repression mechanisms which, either as homo- or as heterodimers, regulate target gene expression.

* Corresponding author. Mailing address for Larry Kedes: 2250 Alcazar St., Los Angeles, CA 90089. Phone: (323) 442-1144. Fax: (323) 442-2764. E-mail: kedes{at}hsc.usc.edu. Present address for Yasuo Hamamori: One Baylor Plaza, 506C, Houston, TX 77030. Phone: (713) 798-3088. Fax: (713) 798-7437. E-mail: hamamori{at}bcm.tmc.edu.

Molecular and Cellular Biology, September 2001, p. 6080-6089, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.6080-6089.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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