c-Abl modulates AICD dependent cellular responses: transcriptional induction and apoptosis.
APP intracellular domain (AICD) has been proposed as a transcriptional inductor that moves to the nucleus with the adaptor protein Fe65 and regulates transcription. The two proteins, APP and Fe65, can be phosphorylated by c-Abl kinase. Neprilysin has been proposed as a target gene for AICD. We found that AICD expression is decreased by treatment with STI-571, a c-Abl inhibitor, suggesting a modulation of AICD transcription by c-Abl kinase. We observed interaction between c-Abl kinase, the AICD fragment and the Fe65 adaptor protein. In addition, STI-571 reduces apoptosis in APPSw, and the apoptotic response induced by Fe65 over-expression was inhibited by with the expression of a kinase dead (KD) c-Abl and enhanced by over-expression of WT-c-Abl. However, in the APPSw cells, the ability of the KD-c-Abl to protect against Fe65 was reduced. Finally, in APPSw clone, we detected higher trans-activation of the pro-apoptotic p73 isoform, TAp73 promoter. Our results show that c-Abl modulates AICD dependent cellular responses, transcriptional induction as well as the apoptotic response, which could participate in the onset and progression of the neurodegenerative pathology, observed in Alzheimer's disease (AD).
Vázquez
Mary C
MC
Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Pontifical Catholic University of Chile, Santiago, Chile.
Vargas
Lina M
LM
Inestrosa
Nibaldo C
NC
Alvarez
Alejandra R
AR
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival; D017930:Genes, Reporter; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000068877:Imatinib Mesylate; D051379:Mice; D009154:Mutation; D015260:Neprilysin / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D058255:Protease Nexins; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C486243:Apbb1 protein, mouse; D001549:Benzamides; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016877:Oxidants; D010879:Piperazines; D058255:Protease Nexins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D000068877:Imatinib Mesylate; D006861:Hydrogen Peroxide; D016315:Proto-Oncogene Proteins c-abl; D015260:Neprilysin