TY - JOUR
T1 - Endogenous protein kinase inhibitor γ terminates immediate-early gene expression induced by cAMP-dependent protein kinase (PKA) signaling
T2 - Termination depends on PKA inactivation rather than PKA export from the nucleus
AU - Chen, Xin
AU - Dai, Jia Chun
AU - Orellana, Stephanie A.
AU - Greenfield, Edward M.
PY - 2005/1/28
Y1 - 2005/1/28
N2 - 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 β-adrenergic agonist, isoproterenol. We found that endogenous PKIγ is required for efficient termination of nuclear PKA activity, transcription factor phosphorylation, and immediate-early genes. Moreover, PKIγ 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 PKIγ 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.
AB - 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 β-adrenergic agonist, isoproterenol. We found that endogenous PKIγ is required for efficient termination of nuclear PKA activity, transcription factor phosphorylation, and immediate-early genes. Moreover, PKIγ 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 PKIγ 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.
UR - http://www.scopus.com/inward/record.url?scp=13244259434&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=13244259434&partnerID=8YFLogxK
U2 - 10.1074/jbc.M412558200
DO - 10.1074/jbc.M412558200
M3 - Article
C2 - 15557275
AN - SCOPUS:13244259434
SN - 0021-9258
VL - 280
SP - 2700
EP - 2707
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 4
ER -