Egr-1 and Hipk2 are required for the TrkA to p75(NTR) switch that occurs downstream of IGF1-R.
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 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 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.
Li
Hui
H
Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA.
Costantini
Claudio
C
Scrable
Heidi
H
Weindruch
Richard
R
Puglielli
Luigi
L
D000375:Aging / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D031204:Caloric Restriction; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000819:agonists / Q000378:metabolism*; D020917:Receptor, trkA / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D050819:Transcription Factor Brn-3A / Q000378:metabolism
D002352:Carrier Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; C494189:Pou4f1 protein, mouse; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D050819:Transcription Factor Brn-3A; D007334:Insulin-Like Growth Factor I; C115114:HIPK2 protein, human; C492003:Hipk2 protein, mouse; D017526:Receptor, IGF Type 1; D020917:Receptor, trkA; D017346:Protein Serine-Threonine Kinases