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Vol. 19, Issue 11, 4814-4825, November 2008

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Cyclic AMP Inhibits the Proliferation of Thyroid Carcinoma Cell Lines through Regulation of CDK4 Phosphorylation

Ana Sofia Rocha^*,, Sabine Paternot^*, Katia Coulonval^*, Jacques E. Dumont^*, Paula Soares, and Pierre P. Roger^*

*Institute of Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles, Campus Erasme, B-1070 Brussels, Belgium; and Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-465 Porto, Portugal

Submitted June 18, 2008; Revised August 6, 2008; Accepted September 4, 2008
Monitoring Editor: Carl-Henrik Heldin

How cyclic AMP (cAMP) could positively or negatively regulate G1 phase progression in different cell types or in cancer cells versus normal differentiated counterparts has remained an intriguing question for decades. At variance with the cAMP-dependent mitogenesis of normal thyroid epithelial cells, we show here that cAMP and cAMP-dependent protein kinase activation inhibit S-phase entry in four thyroid carcinoma cell lines that harbor a permanent activation of the Raf/ERK pathway by different oncogenes. Only in Ret/PTC1-positive TPC-1 cells did cAMP markedly inhibit the Raf/ERK cascade, leading to mTOR pathway inhibition, repression of cyclin D1 and p21 and p27 accumulation. p27 knockdown did not prevent the DNA synthesis inhibition. In the other cells, cAMP little affected these signaling cascades and levels of cyclins D or CDK inhibitors. However, cAMP differentially inhibited the pRb-kinase activity and T172-phosphorylation of CDK4 complexed to cyclin D1 or cyclin D3, whereas CDK-activating kinase activity remained unaffected. At variance with current conceptions, our studies in thyroid carcinoma cell lines and previously in normal thyrocytes identify the activating phosphorylation of CDK4 as a common target of opposite cell cycle regulations by cAMP, irrespective of its impact on classical mitogenic signaling cascades and expression of CDK4 regulatory partners.

Address correspondence to: Pierre P. Roger (proger{at}ulb.ac.be)

Abbreviations used: CAK, CDK-activating kinase; CDK, cyclin-dependent kinase; FBS, fetal bovine serum; FSK, forskolin; PKA, cAMP-dependent protein kinase.

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