Specific inhibition of CBP/beta-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation.
Wnt/beta-catenin signaling has been shown to promote self-renewal in a variety of tissue stem cells, including neuronal stem cells and hematopoietic stem cells. However, activation of the Wnt/beta-catenin pathway promoted and inhibition of the pathway prevented differentiation of neuronal precursor cells. A clear explanation for the differential effects of Wnt/beta-catenin activation on neuronal precursors is not available at present. Presenilin-1 (PS-1) is a polytopic protein comprised of six to eight transmembrane domains. PS-1, as part of the gamma-secretase complex, is required for the intramembrane proteolysis of both amyloid precursor protein (APP) and Notch. Additionally, through interactions with beta-catenin, PS-1 is associated with modulation of Wnt/beta-catenin signaling. A familial Alzheimer's disease-associated PS-1 mutant, PS-1(L286V), causes a dramatic increase in T cell factor (TCF)/beta-catenin transcription in PC-12 cells, which prevents normal nerve growth factor (NGF)-induced neuronal differentiation and neurite outgrowth. Selective inhibition of TCF/beta-catenin/cAMP-response element-binding protein (CREB)-binding protein (CBP)-mediated transcription, but not TCF/beta-catenin/p300, with the recently described small molecule antagonist ICG-001 corrects these defects in neuronal differentiation, highlighting the importance of Wnt/beta-catenin signaling in this process. We propose that increased TCF/beta-catenin/CBP-mediated transcription, as well as a failure to switch to TCF/beta-catenin/p300-mediated transcription, play an important role in decreasing neuronal differentiation.
Teo
Jia-Ling
JL
Institute for Chemical Genomics, 600 Broadway, Suite 580, Seattle, WA 98122, USA.
Ma
Hong
H
Nguyen
Cu
C
Lam
Crystal
C
Kahn
Michael
M
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D008156:Luciferases; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D053764:Presenilin-1; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014162:Transfection; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D019086:Bridged Bicyclo Compounds, Heterocyclic; C495268:Ctnnb1 protein, rat; D017931:DNA Primers; C492448:ICG 001; D008565:Membrane Proteins; D053764:Presenilin-1; D011744:Pyrimidinones; D051820:TCF Transcription Factors; D051176:beta Catenin; D008156:Luciferases; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat