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MBC in Press, published online ahead of print January 12, 2005
Mol. Biol. Cell 10.1091/mbc.E04-06-0501

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Submitted on June 21, 2004
Accepted on December 22, 2004

cAMP-mediated Inhibition of DNA Replication and S-phase Progression: Involvement of Rb, p21Cip1, and PCNA

Soheil Naderi,*{dagger} Jean Y.J. Wang,{ddagger} Tung-Ti Chen,{sect} Kristine B. Gutzkow,* and Heidi K. Blomhoff*

*Institute of Basic Medical Sciences, Department of Biochemistry, University of Oslo, Oslo N-0317, Norway; {ddagger}Division of Biology and Cancer Center, University of California, San Diego, La Jolla, CA 92090-0322; {sect}AmProx Incorporated, Carlsbad, CA 92009

Monitoring Editor: Tony Hunter

cAMP exerts an antiproliferative effect on a number of cell types including lymphocytes. This effect of cAMP is proposed to be mediated by its ability to inhibit G1/S transition. In this report, we provide evidence for a new mechanism whereby cAMP might inhibit cellular proliferation. We show that elevation of intracellular levels of cAMP inhibits DNA replication and arrests the cells in S phase. The cAMP-induced inhibition of DNA synthesis was associated with the increased binding of p21Cip1 to Cdk2-cyclin complexes, inhibition of Cdk2 kinase activity, dephosphorylation of Rb and dissociation of PCNA from chromatin in S-phase cells. The ability of cAMP to inhibit DNA replication and trigger release of PCNA from chromatin required Rb and p21Cip1 proteins, since both processes were only marginally affected by increased levels of cAMP in Rb-/- and p21Cip1-/- 3T3 fibroblasts. Importantly, the implications of cAMP-induced inhibition of DNA synthesis in cancer treatment was demonstrated by the ability of cAMP to reduce apoptosis induced by S phase-specific cytotoxic drugs. Taken together, these results demonstrate a novel role for cAMP in regulation of DNA synthesis, and support a model in which activation of cAMP-dependent signaling protects cells from the effect of S-phase specific antitumor agents.

{dagger}Corresponding author. E-mail: soheil.naderi{at}basalmed.uio.no






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