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Mol. Cell. Biol. 21 (17): 6071-6079

Copyright © 2001 by the American Society for Microbiology. All rights reserved.

Molecular and Cellular Biology, September 2001, p. 6071-6079, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.6071-6079.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

HERP, a New Primary Target of Notch Regulated by Ligand Binding

Tatsuya Iso,1,2 Vittorio Sartorelli,3 Gene Chung,1 Toshiaki Shichinohe,1,4 Larry Kedes,1,2,5,* and Yasuo Hamamori1,2,*

Institute for Genetic Medicine,1 Department of Biochemistry and Molecular Biology,2 Department of Pathology,4 and Department of Medicine,5 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

Notch signaling dictates cell fate and critically influences cell proliferation, differentiation, and apoptosis in metazoans. Ligand binding initiates the signal through regulated intramembrane proteolysis of a transmembrane Notch receptor which releases the signal-transducing Notch intracellular domain (NICD). The HES/E(spl) gene family is a primary target of Notch and thus far the only known Notch effector. A newly isolated HERP family, a HES-related basic helix-loop-helix protein family, has been proposed as a potential target of Notch, based on its induction following NICD overexpression. However, NICD is physiologically maintained at an extremely low level that typically escapes detection, and therefore, nonregulated overexpression of NICD---as in transient transfection---has the potential of generating cellular responses of little physiological relevance. Indeed, a constitutively active NICD indiscriminately up-regulates expression of both HERP1 and HERP2 mRNAs. However, physiological Notch stimulation through ligand binding results in the selective induction of HERP2 but not HERP1 mRNA and causes only marginal up-regulation of HES1 mRNA. Importantly, HERP2 is an immediate target gene of Notch signaling since HERP2 mRNA expression is induced even in the absence of de novo protein synthesis. HERP2 mRNA induction is accompanied by specific expression of HERP2 protein in the nucleus. Furthermore, using RBP-Jk-deficient cells, we show that an RBP-Jk protein, a transcription factor that directly activates HES/E(spl) transcription, also is essential for HERP2 mRNA expression and that expression of exogenous RBP-Jk is sufficient to rescue HERP2 mRNA expression. These data establish that HERP2 is a novel primary target gene of Notch that, together with HES, may effect diverse biological activities of Notch.

* 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} Present address for Yasuo Hamamori: One Baylor Plaza, 506C, Houston, TX 77030. Phone: (713) 798-3088. Fax: (713) 798-7437. E-mail: hamamori{at}

Molecular and Cellular Biology, September 2001, p. 6071-6079, Vol. 21, No. 17
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.17.6071-6079.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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T.-S. Yeh, Y.-M. Lin, R.-H. Hsieh, and M.-J. Tseng (2003)
J. Biol. Chem. 278, 41963-41969
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J. Biol. Chem. 278, 32227-32235
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   Abstract »    Full Text »    PDF »
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J. Med. Genet. 39, 644-655
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B. Yan, N. Raben, and P. Plotz (2002)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
Notch Signaling Induces Rapid Degradation of Achaete-Scute Homolog 1.
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   Abstract »    Full Text »    PDF »
Hey bHLH Factors in Cardiovascular Development.
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   Abstract »    PDF »
HERP, a Novel Heterodimer Partner of HES/E(spl) in Notch Signaling.
T. Iso, V. Sartorelli, C. Poizat, S. Iezzi, H.-Y. Wu, G. Chung, L. Kedes, and Y. Hamamori (2001)
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   Abstract »    Full Text »    PDF »

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