A refractory phase in cyclic AMP-responsive transcription requires down regulation of protein kinase A.
Cyclic AMP (cAMP) stimulates the expression of numerous genes through the protein kinase A (PK-A)-mediated phosphorylation of the nuclear factor CREB at Ser-133 (G. A. Gonzalez and M. R. Montminy, Cell 59:675-680, 1989). Like other signal transduction pathways, cAMP induces gene expression with burst-attenuation kinetics; cAMP-dependent transcription and CREB phosphorylation peak within 30 min and decline steadily over the next 4 to 6 h via the protein phosphatase 1-mediated dephosphorylation of CREB (M. Hagiwara, A. Alberts, P. Brindle, J. Meinkoth, J. Feramisco, T. Deng, M. Karin, S. Shenolikar, and M. Montminy, Cell 70:105-113, 1992). Here we characterize a third phase in cAMP-responsive transcription--a refractory period during which hormone-treated cells become transcriptionally unresponsive to subsequent stimulation by cAMP. This refractory period begins 6 to 8 h after stimulation and lasts 3 to 5 days after the removal of hormone. In contrast to the earlier attenuation phase, transcription of cAMP-responsive genes during the refractory period is not restored by inhibitors of protein phosphatase 1 activity. Rather, the establishment and maintenance of this phase rely on a marked reduction in PK-A catalytic subunit expression at the translational level. As overexpression of C-subunit protein can reactive transcription of cAMP-responsive genes during the refractory period, our results suggest that hormone-responsive cells may stimulate, attenuate, and then silence signal-dependent genes through distinct regulatory mechanisms.
Armstrong
R
R
Clayton Foundation Laboratories for Peptide Biology, Salk Institute, University of California at San Diego, La Jolla 92037.
Wen
W
W
Meinkoth
J
J
Taylor
S
S
Montminy
M
M
D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D007700:Kinetics; D046911:Macromolecular Substances; D010766:Phosphorylation; D010768:Phosphoserine / Q000032:analysis; D051381:Rats; D015398:Signal Transduction; D013961:Thyroid Gland; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D001616:beta-Galactosidase / Q000096:biosynthesis
D017362:Cyclic AMP Response Element-Binding Protein; D046911:Macromolecular Substances; D010768:Phosphoserine; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D001616:beta-Galactosidase