Presenilin-2 (PS2) expression up-regulation in a model of retinopathy of prematurity and pathoangiogenesis.
Presenilin-2 (PS2; AD4), a regulator of intercellular signaling during CNS development and cell fate determination, appears to be involved in pathogenic processing of beta-amyloid precursor protein (betaAPP) into potentially neurotoxic beta-amyloid (Abeta) peptides. The PS2 gene promoter contains multiple DNA binding sites for the relatively rare hypoxia-inducible transcription factor HIF-1, suggesting that PS2 expression may be a sensitive indicator of decreased oxygen availability. We have used a cycled hypoxia/hyperoxia (10-50% O2) protocol followed by normoxia (20% O2) as a retinal model of retinopathy of prematurity to induce neovascularization (NV) in rat pups. Retinal cell nuclear extracts from pups undergoing hypoxia exhibited a dramatic increase in HIF-1-DNA binding, followed by a delayed (2-7 day) elevation of PS2 RNA message and protein. PS2 gene activation during hypoxia may direct cellular fate towards pathoangiogenesis and intercellular PS2-mediated signaling dysfunction.
Lukiw
W J
WJ
Neuroscience Center and Department of Ophthalmology, Louisiana State University School of Medicine, New Orleans 70112-2272, USA.
Gordon
W C
WC
Rogaev
E I
EI
Thompson
H
H
Bazan
N G
NG
D000818:Animals; D000831:Animals, Newborn; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007231:Infant, Newborn; D008565:Membrane Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011247:Pregnancy; D053766:Presenilin-2; D051381:Rats; D012160:Retina / Q000378:metabolism; D015861:Retinal Neovascularization / Q000209:etiology / Q000378:metabolism*; D012178:Retinopathy of Prematurity / Q000378:metabolism*; D014157:Transcription Factors; D015854:Up-Regulation / Q000502:physiology
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D009687:Nuclear Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D014157:Transcription Factors