Promoter activity of the gene encoding the beta-amyloid precursor protein is up-regulated by growth factors, phorbol ester, retinoic acid and interleukin-1.
Abnormalities in gene regulation of the beta-amyloid precursor protein (beta APP) might be an important factor in the neuropathology of Alzheimer's disease. We analyzed the effects of nerve growth factor (NGF), basic fibroblast growth factor (bFGF), phorbol 12-myristate 13-acetate (PMA), interleukin-1 (IL-1) and retinoic acid (RA) on promoter activity of the beta APP gene. To investigate the effect of these factors on promoter activity, we used two fusion plasmids which contain sequences of -489 and -415 base pairs (bp), respectively, from the transcription start site of the beta APP gene. The truncated regions of the promoter wer linked upstream to a reporter gene, chloramphenicol acetyl transferase (CAT). Promoter activity was tested by transient transfection of fusion plasmids in PC12 cells using the electroporation method (960 microF at 350 V). We report that the treatment of PC12 cells with either NGF, bFGF, PMA, IL-1 or RA stimulated the activity of the beta APP promoter. The treatment of cells with either NGF or bFGF resulted in a higher degree of stimulation in the basal level of promoter activity than when cells were treated with either PMA, IL-1 or RA. The deletion of sequences between -489 to -416 bp had no significant effect on promoter activity. The treatment of cells with these factors for a duration of 4 days prior to transfection with the plasmids is necessary for the stimulatory effect. The cells that were only treated with any of these factors after transfection showed no significant change in the basal level of promoter activity. We conclude that certain growth factors and a cytokine could enhance the basal level of promoter activity of the beta APP gene, suggesting a possible participation of a growth-factor(s)-mediated transcription element in the control of gene expression of beta APP.
Lahiri
D K
DK
Department of Psychiatry, Indiana University School of Medicine, Indianapolis 46202, USA.
Nall
C
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D000544:Alzheimer Disease; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D005786:Gene Expression Regulation; D007375:Interleukin-1 / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016716:PC12 Cells; D010703:Phorbol Esters / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051381:Rats; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation
D016564:Amyloid beta-Protein Precursor; D007375:Interleukin-1; D009414:Nerve Growth Factors; D010703:Phorbol Esters; D014212:Tretinoin