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Nucleic Acids Research, 1994, Vol. 22, No. 4 569-575
© 1994

MOLECULAR BIOLOGY

Activation of cAMP-dependent protein kinase alters the chromatin structure of the urokinase-type plasminogen activator gene promoter

Janet S. Lee+, Luigi Catanzariti, Brian A. Hemmings, Birgitta Kiefer and Yoshikuni Nagamine*

Friedrich Miescher-lnstitut Postfach 2543, CH-4002, Basel, Switzerland

*To whom correspondence should be addressed

Received November 26, 1993. Accepted January 24, 1994.

In LLC-PK, cells, the uroklnase-type plasminogen activator (uPA) gene Is induced by two of the major signal transductlon pathways, the protein kinase C (PKC) and the cAMP-dependent protein kinase (PKA) pathways. We have analyzed the chromatin structure of 26 kb of the uPA gene locus and have shown that PKA activation but not PKC activation Induces major chromatin structural alterations in the uPA gene promoter. In uninduced cells, several DNase I hypersensitive (HS) sites were detected In the 5' and 3' flanking regions but not In the transcribed region. Two of the sites correspond to previously characterized regulatory sites: a cAMP responsive site at nucleotide position -3500 with respect to the Initiation site, and the PEA3/AP1 site at -2100 that mediates PKC activation. After the activation of PKA but not PKC, a strong HS site was induced at -2600. Functional analysis of this region revealed cAMP responsive activity. Chromatin structural alterations again brought about specifically by PKA but not by PKC were were also detected In the upstream of the promoter by topoisomerase I cleavage site analysis, with two prominent sites appearing at - 2800 and - 3300. These results suggest that the strong cAMP induction of the uPA gene requires structural alterations that permit cooperative interactions between the multiple cAMP responsive sites.

+Present address: Laboratoire de Génétique Moleculaire des Eucaryotes de CNRS, Unité 184 de 1'INSERM, Faculté de Méclecine, 11 rue Humann, 67085 Strasbourg, France


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