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Vol. 16, Issue 3, 1527-1542, March 2005

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cAMP-mediated Inhibition of DNA Replication and S Phase Progression: Involvement of Rb, p21^Cip1, and PCNA

Soheil Naderi ^*, Jean Y.J. Wang , Tung-Ti Chen , Kristine B. Gutzkow ^*, and Heidi K. Blomhoff ^*

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

Submitted June 21, 2004; Accepted December 22, 2004
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 p21^Cip1 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 p21^Cip1 proteins, since both processes were only marginally affected by increased levels of cAMP in Rb^-/- and p21^Cip1-/- 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.

Abbreviations used: cAMP, cyclic AMP; Rb, retinoblastoma protein; Cdk, cyclin-dependent kinase; CKI, cyclin-dependent kinase inhibitor; PCNA, proliferating cell nuclear antigen; RFC, replication factor C; pol , DNA polymerase ; CPT, camptothecin; 5-FU, 5-fluorouracil; HU, hydroxyurea; PAC, paclitaxel; VB, vinblastine; PI, propidium iodide; FITC, fluorescein isothiocyanate; BrdU, bromodeoxyuridine; MEFs, mouse embryo fibroblasts; Aph, aphidicolin; IBMX, 3-isobutyl-1-methylxantine; PGE₂, prostaglandin E₂; CTX, cholera toxin; MNase, micrococcal nuclease.

Address correspondence to: Soheil Naderi (soheil.naderi{at}basalmed.uio.no).

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