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Molecular and Cellular Biology, August 2000, p. 6170-6183, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

HES-1 Repression of Differentiation and Proliferation in PC12 Cells: Role for the Helix 3-Helix 4 Domain in Transcription Repression

Paul Castella,1,2 Shoji Sawai,2 Keiko Nakao,2 John A. Wagner,2,3 and Michael Caudy2,3,*

Cell Biology and Genetics Graduate Program,1 Department of Cell Biology and Anatomy,2 and Department of Neurology and Neuroscience,3 Weill Medical College of Cornell University, New York, New York 10021

Received 13 April 1999/Returned for modification 20 September 1999/Accepted 17 December 1999

HES-1 is a Hairy-related basic helix-loop-helix protein with three evolutionarily conserved regions known to define its function as a transcription repressor. The basic region, helix-loop-helix domain, and WRPW motif have been characterized for their molecular function in DNA binding, dimer formation, and corepressor recruitment, respectively. In contrast, the function conferred by a fourth conserved region, the helix 3-helix 4 (H-3/4) domain, is not known. To better understand H-3/4 domain function, we expressed HES-1 variants under tetracycline-inducible control in PC12 cells. As expected, the induced expression of moderate levels of wild-type HES-1 in PC12 cells strongly inhibited nerve growth factor-induced differentiation. This repression was dependent on the H-3/4 domain. Unexpectedly, expression of HES-1 also arrested cell growth, an effect that could be reversed upon down regulation of HES-1. Concomitant with growth arrest, there was a strong reduction in bromodeoxyuridine incorporation and PCNA protein levels, although not in cyclin D1 expression. Expression of a HES-1 protein carrying the H-3/4 domain, but not the WRPW domain, still partially inhibited both proliferation and differentiation. Transcription assays in PC12 cells directly demonstrated that the H-3/4 domain can mediate DNA-binding-dependent transcription repression, even in the absence of corepressor recruitment by the WRPW motif. HES-1 expression strongly repressed transcription of the p21cip1 promoter, a cyclin-cyclin-dependent kinase inhibitor up regulated during NGF-induced differentiation, and the H-3/4 domain is necessary for this repression. Thus, the H-3/4 domain of HES-1 contributes to transcription repression independently of WRPW function, inhibits neurite formation, and facilitates two distinct and previously uncharacterized roles for HES-1: the inhibition of cell proliferation and the direct transcriptional repression of the NGF-induced gene, p21.

* Corresponding author. Mailing address: Department of Neurology and Neurosciences, Burke Medical Research Institute, Weill Medical College of Cornell University, 785 Mamaroneck Ave., White Plains, NY 10605. Phone: (914) 597-2289. Fax: (914) 597-2757. E-mail: mcaudy{at}mail.med.cornell.edu.

Molecular and Cellular Biology, August 2000, p. 6170-6183, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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