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Nucleic Acids Research, 2003, Vol. 31, No. 12 3063-3070
© 2003 Oxford University Press

Specific interaction of heterogeneous nuclear ribonucleoprotein A1 with the –219T allelic form modulates APOE promoter activity

Mónica Campillos, José Ramón Lamas, Miguel Angel García, María Jesús Bullido, Fernando Valdivieso and Jesús Vázquez

Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Universidad Autónoma de Madrid, 28049 Cantoblanco, Madrid, Spain

*To whom correspondence should be addressed. Tel: +34 91 397 8364; Fax: +34 91 397 8087; Email: jvazquez{at}cbm.uam.es

The polymorphic –219T/G variant in the APOE promoter has been associated with variations in basal transcriptional activity as well as with the risk of developing Alzheimer’s disease, myocardial infarction and early-onset coronary heart disease. The molecular mechanisms underlying these effects are presently unknown. In this report, we show that nuclear extracts from Jurkat cells form a T-specific complex with a motif including the –219 site within the APOE promoter. By DNA-affinity chromatography and mass spectrometry, the human heterogeneous nuclear ribonucleoprotein hnRNPA1(A1) was identified as one component of the complex. In vitro binding analysis indicated that a fragment of A1 had a marked binding specificity for the T form. Interaction of A1 with this region is driven by an adjacent telomeric-like sequence; however, the presence of G, but not T, at –219 position inhibited this interaction. The differences in transcriptional activity between the –219T and –219G promoter allelic forms correlated with the expression levels of A1 in several cell lines; also, over-expression of A1 increased the activity of the T form relative to that of the G form. These results indicate that A1 transactivates APOE promoter activity by direct and specific interaction with the –219T site.


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