Egr-1 and Hipk2 are required for the TrkA to p75NTR switch that occurs downstream of IGF1-R

Hui Li, Claudio Costantini, Heidi Scrable, Richard Weindruch, Luigi Puglielli

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The aging program mediated by IGF1-R is responsible for a naturally occurring TrkA to p75NTR switch that leads to activation of the second messenger ceramide and increased production of the Alzheimer's disease amyloid β-peptide. Biochemical and genetic approaches that target IGF1-R signaling, p75NTR, or ceramide are able to block the above events. Here, we show that the transcription factors Egr-1 and Hipk2 are required elements for the TrkA to p75NTR switch downstream of IGF1-R signaling. Specifically, Egr-1 is required for the upregulation of p75NTR, whereas Hipk2 is required for the downregulation of TrkA. In fact, gene silencing of Egr-1 abolished the ability of IGF1 to upregulate p75NTR, whereas similar approaches directed against Hipk2 blocked the downregulation of TrkA. In addition, IGF1 treatment favored binding of Egr-1 and Hipk2 to the promoter of p75NTR and TrkA, respectively. Finally, the expression levels of both Egr-1 and Hipk2 are upregulated in an age-dependent fashion. Such an event is opposed by caloric restriction, a model of delayed aging, and favored by the p44 transgene in p44+/+ animals, a model of accelerated aging.

Original languageEnglish (US)
Pages (from-to)2010-2020
Number of pages11
JournalNeurobiology of aging
Volume30
Issue number12
DOIs
StatePublished - Dec 2009

Keywords

  • Aging
  • Alzheimer's disease
  • Egr-1
  • Hipk2
  • IGF1-R
  • TrkA
  • p75

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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