cAMP is a potent inhibitor of cell proliferation in a
variety of cell lines. Downregulation of cyclin D1 and
upregulation of the cell cycle inhibitor p27Kip1 are two
mechanisms by which cAMP may induce a G1-arrest.
Here we show that cAMP inhibits proliferation of cells
that constitutively express cyclin D1 or are deficient for
Rb, demonstrating that changes in these cell cycle
regulators do not account for the cAMP-induced growth
effects in mouse embryo fibroblasts (MEFs). Interestingly,
the antiproliferative effect of cAMP mimics the
effect previously observed for FoxO transcription factors.
These transcription factors are under negative control of
protein kinase B (PKB). We show that in MEFs cAMP
strongly induces transcriptional activation of FoxO4
through the inhibition of PKB. Accordingly, not only
p27Kip1 but also the FoxO target MnSOD is upregulated
by cAMP. Importantly, introduction of dominant-negative
FoxO partially rescues cAMP-induced inhibition of
proliferation. From these results we conclude that
inhibition of PKB and subsequent activation of FoxO
transcription factors mediates an antiproliferative effect
of cAMP