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J. Biol. Chem., Vol. 280, Issue 4, 2700-2707, January 28, 2005

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Endogenous Protein Kinase Inhibitor Terminates Immediate-early Gene Expression Induced by cAMP-dependent Protein Kinase (PKA) Signaling

TERMINATION DEPENDS ON PKA INACTIVATION RATHER THAN PKA EXPORT FROM THE NUCLEUS^*

Xin Chen, Jia-Chun Dai, Stephanie A. Orellana¶, and Edward M. Greenfield¶||**

From the Orthopaedics, Pediatrics, ^¶Physiology and Biophysics, and ^||Pathology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106-5000

Expression of many genes induced by cAMP-dependent protein kinase (PKA) signaling is rapidly terminated. Although many mechanisms contribute to regulation of PKA signaling, members of the endogenous protein kinase inhibitor (PKI) family may be particularly important for terminating nuclear PKA activity and gene expression. Here we used both siRNA and antisense knockdown strategies to examine PKA signaling activated by parathyroid hormone or the -adrenergic agonist, isoproterenol. We found that endogenous PKI is required for efficient termination of nuclear PKA activity, transcription factor phosphorylation, and immediate-early genes. Moreover, PKI is required for export of PKA catalytic subunits from the nucleus back to the cytoplasm following activation of PKA signaling because this is also inhibited by PKI knockdown. Leptomycin B blocks PKA nuclear export but has little or no effect on nuclear PKA activity or immediate-early gene expression. Thus, inactivation of PKA activity in the nucleus is sufficient to terminate signaling, and nuclear export is not required. These results were the first in any cell type showing that endogenous levels of PKI regulate PKA signaling.

Received for publication, November 5, 2004

^* This work was supported by National Institutes of Health Grant DK064963 (to E. M. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the DDBJ/GenBank^TM/EBI Data Bank with accession number(s) AY150308.

^** To whom correspondence should be addressed: Dept. of Orthopaedics, Case Western Reserve University, 2109 Adelbert Rd., BRB1028, Cleveland, OH 44106. Tel.: 216-368-1331; Fax: 216-368-1332; E-mail: emg3{at}po.cwru.edu.

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