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Molecular and Cellular Biology, December 1998, p. 6921-6929, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Protein Kinase A-Dependent Derepression of the Human Prodynorphin Gene via Differential Binding to an Intragenic Silencer Element

Angel M. Carrión, Britt Mellström, and Jose R. Naranjo*

Instituto de Neurobiología, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain

Received 5 June 1998/Returned for modification 30 July 1998/Accepted 19 August 1998

Induction of the prodynorphin gene has been implicated in medium and long-term adaptation during memory acquisition and pain. By 5' deletion mapping and site-directed mutagenesis of the human prodynorphin promoter, we demonstrate that both basal transcription and protein kinase A (PKA)-induced transcription in NB69 and SK-N-MC human neuroblastoma cells are regulated by the GAGTCAAGG sequence centered at position +40 in the 5' untranslated region of the gene (named the DRE, for downstream regulatory element). The DRE repressed basal transcription in an orientation-independent and cell-specific manner when placed downstream from the heterologous thymidine kinase promoter. Southwestern blotting and UV cross-linking experiments with nuclear extracts from human neuroblastoma cells or human brain revealed a protein complex of approximately 110 kDa that specifically bound to the DRE. Forskolin treatment reduced binding to the DRE, and the time course paralleled that for an increase in prodynorphin gene expression. Our results suggest that under basal conditions, expression of the prodynorphin gene is repressed by occupancy of the DRE site. Upon PKA stimulation, binding to the DRE is reduced and transcription increases. We propose a model for human prodynorphin activation through PKA-dependent derepression at the DRE site.

* Corresponding author. Mailing address: Instituto de Neurobiología, C.S.I.C., Av. Dr. Arce 37, 28002 Madrid, Spain. Phone: 34 1 585 4726. Fax: 34 1 585 4754. E-mail: JRNARANJO{at}SAMBA.CNB.UAM.ES.

Molecular and Cellular Biology, December 1998, p. 6921-6929, Vol. 18, No. 12
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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