Mediation of NGF signaling by post-translational inhibition of HES-1, a basic helix–loop–helix repressor of neuronal differentiation
- Anders Ström1,3,
- Paul Castella1,3,
- Julia Rockwood1,2,4,
- John Wagner1,2, and
- Michael Caudy1,2,5
Abstract
The induction of neurite outgrowth by NGF is a transcription-dependent process in PC12 cells, but the transcription factors that mediate this process are not known. Here we show that the bHLH transcriptional repressor HES-1 is a mediator of this process. Inactivation of endogenous HES-1 by forced expression of a dominant-negative protein induces neurite outgrowth in the absence of NGF and increases response to NGF. In contrast, expression of additional wild-type HES-1 protein represses and delays response to NGF. Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro. Mutation of these sites generates a constitutively active protein that strongly and persistently blocks response to NGF. These results suggest that post-translational inhibition of HES-1 is both essential for and partially mediates the induction of neurite outgrowth by NGF signaling.
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Footnotes
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↵3 These authors made major, independent contributions to this work.
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↵4 Present address: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461 USA.
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↵5 Corresponding author.
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E-MAIL mcaudy{at}mail.med.cornell.edu; FAX (212) 746-8175.
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- Received August 4, 1997.
- Accepted September 23, 1997.
- Cold Spring Harbor Laboratory Press
