Egr-1 upregulates the Alzheimer's disease presenilin-2 gene in neuronal cells.
Regulation of the Alzheimer's disease (AD)-related gene, presenilin-2 (PSEN2), was analyzed in neuronal (SK-N-SH) and non-neuronal (human embryonic kidney 293, HEK293) cells. We show that the PSEN2 regulatory region includes two separate promoter elements, each located upstream of multiple transcription start sites in the first and second exons. The stronger upstream promoter, P1, has housekeeping characteristics: it resides in a CpG island, is TATA-less, and up to 83% of PSEN2-P1 activity depends on a stimulating protein 1 (Sp1) site at the most 5' initiation site. However, the downstream promoter P2 includes neuronal-specific elements and two sites for early growth response gene-1 (Egr-1), a transcription factor upregulated in learning paradigms and implicated in neuronal plasticity, in response to injury. We show that Egr-1 binds to PSEN-P2, and that PSEN-P2 activity is increased threefold by overexpression of Egr-1, and by 12-O-tetradecanoylphorbol-13-acetate (TPA), which induces physiological Egr-1 levels. Egr-1 represses PSEN2-P1 activity by 50% in neuronal cells, suggesting it partially shifts promoter usage from PSEN2-P1 to PSEN2-P2. This could lead to a relative increase in shorter exon 2 transcripts, which may be more efficiently translated than exon 1 transcripts. Identification of PSEN2 as an Egr-1 target suggests a link between PSEN2 expression and Egr-1-related processes, which may impact on understanding PSEN-2's physiological function and its role in Alzheimer's disease.
Medical Genetics Unit, Shaare Zedek Medical Center, PO Box 3235, Jerusalem 91031, Israel.
Paul
P
Renbaum
Rachel
R
Beeri
Efrat
E
Gabai
Merav
M
Amiel
Moran
M
Gal
Markus U
MU
Ehrengruber
Ephrat
E
Levy-Lahad
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051766:Early Growth Response Protein 1; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins; D008156:Luciferases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D053766:Presenilin-2; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D024363:Transcription Initiation Site; D014158:Transcription, Genetic / Q000187:drug effects
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D011993:Recombinant Fusion Proteins; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D004247:DNA; D008156:Luciferases; D013755:Tetradecanoylphorbol Acetate