A direct role for protein kinase C and the transcription factor Jun/AP-1 in the regulation of the Alzheimer's beta-amyloid precursor protein gene.
Overexpression of the beta-amyloid precursor protein gene (beta-APP) may contribute to the abnormal generation of beta-amyloid protein in Alzheimer's disease. We demonstrate using a human glial cell line (1321N1) that activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate (PMA) increases beta-APP mRNA levels, induces known components of the transcription factor activator protein-1 (AP-1), and increases protein-DNA binding activity to AP-1 sequences within the beta-APP promoter. A beta-APP promoter-luciferase reporter gene is transcriptionally activated by PMA, as well as by expression of constitutively activated PKC or by expression of c-Jun. Further characterization suggests that the distal but not the proximal AP-1 recognition site binds nuclear proteins regulated by PKC, and that the AP-1 binding activity is likely to be composed of Jun-Jun homodimers rather than Jun-Fos heterodimers. Additional studies demonstrate that a single copy of the distal AP-1 site fused to a heterologous promoter is sufficient to confer a response to PMA. Mutagenesis of this site in the beta-APP promoter renders it unresponsive to c-Jun and attenuates transcriptional activation by PMA. We suggest that cellular mediators that activate PKC, particularly those that induce significant increases in c-Jun, may up-regulate expression of the beta-APP gene and consequently affect production and processing of this protein.
Trejo
J
J
Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla 92093.
Massamiri
T
T
Deng
T
T
Dewji
N N
NN
Bayney
R M
RM
Brown
J H
JH
D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D001253:Astrocytes / Q000166:cytology; D001483:Base Sequence; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D007527:Isoenzymes; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D008156:Luciferases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate