cAMP signaling regulates histone H3 phosphorylation and mitotic entry through a disruption of G2 progression.
cAMP signaling is known to have significant effects on cell growth, either inhibitory or stimulatory depending on the cell type. Study of cAMP-induced growth inhibition in mammalian somatic cells has focused mainly on the combined role of protein kinase A (PKA) and mitogen-activated protein (MAP) kinases in regulation of progression through the G1 phase of the cell cycle. Here we show that cAMP signaling regulates histone H3 phosphorylation in a cell cycle-dependent fashion, increasing it in quiescent cells but dramatically reducing it in cycling cells. The latter is due to a rapid and dramatic loss of mitotic histone H3 phosphorylation caused by a disruption in G2 progression, as evidenced by the inhibition of mitotic entry and decreased activity of the CyclinB/Cdk1 kinase. The inhibition of G2 progression induced through cAMP signaling is dependent on expression of the catalytic subunit of PKA and is highly sensitive to intracellular cAMP concentration. The mechanism by which G2 progression is inhibited is independent of both DNA damage and MAP kinase signaling. Our results suggest that cAMP signaling activates a G2 checkpoint by a unique mechanism and provide new insight into normal cellular regulation of G2 progression.
Rodriguez-Collazo
Pedro
P
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Snyder
Sara K
SK
Chiffer
Rebecca C
RC
Bressler
Erin A
EA
Voss
Ty C
TC
Anderson
Eric P
EP
Genieser
Hans-Gottfried
HG
Smith
Catharine L
CL
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D020134:Catalytic Domain / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D016195:G2 Phase / Q000235:genetics*; D018816:Genes, cdc / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008938:Mitosis / Q000235:genetics*; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics
D018797:Cell Cycle Proteins; D019926:Cyclin B; D006657:Histones; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D016203:CDC2 Protein Kinase