Compensatory regulation of RIalpha protein levels in protein kinase A mutant mice.

J Biol Chem 1997 Feb;272(7):3993-8

Department of Pharmacology, University of Washington, Seattle, Washington 98195-7750, USA.

The cAMP-dependent protein kinase holoenzyme is assembled from regulatory (R) and catalytic (C) subunits that are expressed in tissue-specific patterns. Despite the dispersion of the R and C subunit genes to different chromosomal loci, mechanisms exist that coordinately regulate the intracellular levels of R and C protein such that cAMP-dependent regulation is preserved. We have created null mutations in the RIbeta and RIIbeta regulatory subunit genes in mice, and find that both result in an increase in the level of RIalpha protein in tissues that normally express the beta isoforms. Examination of RIalpha mRNA levels and the rates of RIalpha protein synthesis in wild type and RIIbeta mutant mice reveals that the mechanism of this biochemical compensation by RIalpha does not involve transcriptional or translational control. These in vivo findings are consistent with observations made in cell culture, where we demonstrate that the overexpression of Calpha in NIH 3T3 cells results in increased RIalpha protein without increases in the rate of RIalpha synthesis or the level of RIalpha mRNA. Pulse-chase experiments reveal a 4-5-fold increase in the half-life of RIalpha protein as it becomes incorporated into the holoenzyme. Compensation by RIalpha stabilization may represent an important biological mechanism that safeguards cells from unregulated catalytic subunit activity.

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.272.7.3993DOI Listing
February 1997

Publication Analysis

Top Keywords

rialpha protein
20
rialpha
10
protein kinase
8
subunit genes
8
mutant mice
8
rialpha mrna
8
levels protein
8
level rialpha
8
compensation rialpha
8
protein
8
culture demonstrate
4
calpha nih
4
find result
4
nih 3t3
4
result increase
4
mice find
4
increase level
4
overexpression calpha
4
demonstrate overexpression
4
protein tissues
4

Altmetric Statistics

References

(Supplied by CrossRef)

Krebs et al.
Curr. Top. Cell. Regul. 1972

Uhler et al.
J. Biol. Chem. 1986

Corbin et al.
J. Biol. Chem. 1975

Corbin et al.
J. Biol. Chem. 1977

Similar Publications