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Volume 16, Number 23, Issue of December 1, 1996 pp. 7550-7556
Copyright ©1996 Society for Neuroscience

Transcription Factor AP-2 Regulates Human Apolipoprotein E Gene Expression in Astrocytoma Cells

Received July 22, 1996; revised Sept. 13, 1996; accepted Sept. 20, 1996.

Miguel A. García, Jesús Vázquez, Cecilio Giménez, Fernando Valdivieso, and Francisco Zafra

Centro de Biología Molecular "Severo Ochoa," Facultad de Ciencias, Universidad Autónoma de Madrid, Consejo Superior de Investigaciones Científicas, E-28049 Madrid, Spain

Apolipoprotein E (apoE), one of the major plasma lipoproteins, also is expressed in a variety of cell types, including the glial cells of the nervous system. apoE is involved in processes of degeneration and regeneration after nerve lesions as well as in the pathogenesis of Alzheimer's disease (AD). Glial synthesis of apoE is activated in response to injury both in the peripheral and central nervous system. We now report that the activity of the proximal apoE promoter in astrocytes is upregulated by cAMP and retinoic acid, which act synergistically. Sequence analysis of the apoE promoter indicated the presence of several AP-2 consensus sequences that could mediate the stimulatory effect of cAMP and retinoic acid. The possible functional role of AP-2 was examined by cotransfection of AP-2-deficient HepG2 cells with an apoE promoter construct and a human AP-2 expression construct. Cotransfection with AP-2 significantly elevated apoE promoter activity. DNase I footprinting technique revealed the existence of two binding sites for recombinant AP-2 in regions from 48 to 74 and from 107 to 135 of the apoE promoter. Mutations in these regions markedly impaired the trans-stimulatory effect of AP-2. These results indicate the existence of functional AP-2 sites in the promoter region of apoE that could contribute to the complex regulation of this gene in developmental, degenerative, and regenerative processes of the nervous system.

Key words: apolipoprotein E; astrocytes; AP-2; cAMP; retinoic acid; promoter

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