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Molecular and Cellular Biology, May 2000, p. 3442-3448, Vol. 20, No. 10
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Deficient Gene Expression in Protein Kinase Inhibitor alpha  Null Mutant Mice

Esha A. Gangolli,1,2 Mouna Belyamani,1,2 Sara Muchinsky,3 Anita Narula,1 Kimberly A. Burton,3 G. Stanley McKnight,3 Michael D. Uhler,4 and Rejean L. Idzerda1,2,3,*

Department of Medicine, Division of Metabolism, Endocrinology and Nutrition,1 and Department of Pharmacology,3 University of Washington, Seattle, Washington 98195; Mental Health Research Institute, University of Michigan, Ann Arbor, Michigan 481094; and V.A. Puget Sound Health Care System, Seattle, Washington 981082

Received 7 January 2000/Returned for modification 13 January 2000/Accepted 14 February 2000

Protein kinase inhibitor (PKI) is a potent endogenous inhibitor of the cyclic AMP (cAMP)-dependent protein kinase (PKA). It functions by binding the free catalytic (C) subunit with a high affinity and is also known to export nuclear C subunit to the cytoplasm. The significance of these actions with respect to PKI's physiological role is not well understood. To address this, we have generated by homologous recombination mutant mice that are deficient in PKIalpha , one of the three isoforms of PKI. The mice completely lack PKI activity in skeletal muscle and, surprisingly, show decreased basal and isoproterenol-induced gene expression in muscle. Further examination revealed reduced levels of the phosphorylated (active) form of the transcription factor CREB (cAMP response element binding protein) in the knockouts. This phenomenon stems, at least in part, from lower basal PKA activity levels in the mutants, arising from a compensatory increase in the level of the RIalpha subunit of PKA. The deficit in gene induction, however, is not easily explained by current models of PKI function and suggests that PKI may play an as yet undescribed role in PKA signaling.

* Corresponding author. Mailing address: V.A. Puget Sound Health Care System, 1660 S. Columbian Way, Seattle, WA 98108. Phone: (206) 768-5490. Fax: (206) 764-2598. E-mail: idzerda{at}u.washington.edu.

Molecular and Cellular Biology, May 2000, p. 3442-3448, Vol. 20, No. 10
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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