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

NEUROBIOLOGY OF AGING

卷:30

Article

Li, Hui^1,2  Costantini, Claudio¹  Scrable, Heidi³  Weindruch, Richard^1,4  Puglielli, Luigi^1,2,4 

[1] Univ Wisconsin Madison, Dept Med, Madison, WI 53705 USA

[2] Univ Wisconsin Madison, Neurosci Training Program, Madison, WI 53705 USA

[3] Univ Virginia, Dept Neurosci, Charlottesville, VA 22908 USA

[4] VA Med Ctr, Geriatr Res Educ Clin Ctr, Madison, WI 53705 USA

关键词: Aging;    Alzheimer's disease;    Egr-1;    Hipk2;    IGF1-R;    p75(NTR);    TrkA;   

DOI  :  10.1016/j.neurobiolaging.2008.02.015

来源: Elsevier

【 摘 要 】

The aging program mediated by IGF1-R is responsible for a naturally occumng TrkA to p75(NT)R switch that leads to activation of the second messenger ceramide and increased production of the Alzheimer's disease amyloid beta-peptide. Biochemical and genetic approaches that target IGF1-R signaling, p75(NTR), 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 p75(NTR) switch downstream of IGF1-R signaling. Specifically, Egr-1 is required for the upregulation of p75(NTR), whereas Hipk2 is required for the downregulation of TrkA. In fact, gene silencing of Egr-1 abolished the ability of IGF1 to upregulate p75(NTR), whereas similar approaches directed against Hipk-2 blocked the downregulation of TrkA. In addition, IGF1 treatment favored binding of Egr-1 and Hipk2 to the promoter of p75(NTR) 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 p,44 transgene in p44(+/+) animals, a model of accelerated aging, (C) 2008 Elsevier Inc All rights reserved.

【 授权许可】

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