The chromosome 21 transcription factor ETS2 transactivates the beta-APP promoter: implications for Down syndrome.
The gene that codes for beta-amyloid precursor protein (beta-APP), a protein centrally involved in senile plaque formation in Down syndrome (DS) and Alzheimer's disease (AD), is located on chromosome 21. In DS beta-APP expression is three- to fourfold higher than what is expected from the 1.5-fold increased gene load, suggesting that other genes on chromosome 21 directly or indirectly can further up-regulate beta-APP. Here we show that the chromosome 21 transcription factor ETS2 transactivates the beta-APP gene via specific Ets binding sites in the beta-APP promoter and, in this respect, cooperates with the transcription factor complex AP1. We further show that brains and primary neuronal cultures from Ets2 transgenic mice, as well as 3T3 fibroblasts that overexpress ETS2, display molecular abnormalities also seen in DS, such as elevated expression of beta-APP protein, an increase in presenilin-1 and increased beta-amyloid production. We conclude that ETS2 is a transcriptional regulator of beta-APP and that overexpression of ETS2 in DS may play a role in the pathogenesis of the brain abnormalities in DS and possibly AD.
Wolvetang
E W
EW
Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Monash University, Monash Medical Center, 246 Clayton Road, 3168, Clayton, Australia. ernst.wolvetang@med.monash.edu.au
Bradfield
O M
OM
Tymms
M
M
Zavarsek
S
S
Hatzistavrou
T
T
Kola
I
I
Hertzog
P J
PJ
D016475:3T3 Cells; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D004268:DNA-Binding Proteins; D004314:Down Syndrome / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1; D011401:Promoter Regions, Genetic; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000502:physiology*; D012097:Repressor Proteins; D015534:Trans-Activators / Q000096:biosynthesis / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; C107465:ERF protein, human; C494069:ETS2 protein, human; C494070:Ets2 protein, mouse; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D050787:Proto-Oncogene Protein c-ets-2; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors