Egr-1 and Hipk2 are required for the TrkA to p75^NTR switch that occurs downstream of IGF1-R

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• 作者：Hui Li ; Claudio Costantini ; Heidi Scrable ; Richard Weindruch ; Luigi Puglielli
• 关键词：Aging ; Alzheimer's disease ; Egr-1 ; Hipk2 ; IGF1-R ; p75^NTR ; TrkA
• 刊名：Neurobiology of Aging
• 出版年：2009
• 出版时间：December 2009
• 年：2009
• 卷：30
• 期：12
• 页码：2010-2020
• 全文大小：1109 K

文摘

The aging program mediated by IGF1-R is responsible for a naturally occurring TrkA to p75^NTR 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, 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 Hipk2 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 p44 transgene in p44^+/+ animals, a model of accelerated aging.