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Vol. 11, Issue 3, 1061-1076, March 2000

Transforming Growth Factor ₁ Selectively Inhibits the Cyclic AMP-dependent Proliferation of Primary Thyroid Epithelial Cells by Preventing the Association of Cyclin D3-cdk4 with Nuclear p27^kip1

Fabienne Depoortere,^* Isabelle Pirson,^* Jiri Bartek, Jacques E. Dumont,^* and Pierre P. Roger^*

 ^*Institute of Interdisciplinary Research, Université Libre de Bruxelles, Campus Erasme, B-1070 Brussels, Belgium; and  Division of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen, Denmark

Dog thyroid epithelial cells in primary culture constitute a physiologically relevant model of positive control of DNA synthesis initiation and G0-S prereplicative phase progression by cAMP as a second messenger for thyrotropin (thyroid-stimulating hormone [TSH]). As previously shown in this system, the cAMP-dependent mitogenic pathway differs from growth factor cascades as it stimulates the accumulation of p27^kip1 but not cyclins D. Nevertheless, TSH induces the nuclear translocations and assembly of cyclin D3 and cdk4, which are essential in cAMP-dependent mitogenesis. Here we demonstrate that transforming growth factor ₁ (TGF₁) selectively inhibits the cAMP-dependent cell cycle in mid-G1 and various cell cycle regulatory events, but it weakly affects the stimulation of DNA synthesis by epidermal growth factor (EGF), hepatocyte growth factor, serum, and phorbol esters. EGF+serum and TSH did not interfere importantly with TGF receptor signaling, because they did not affect the TGF-induced nuclear translocation of Smad 2 and 3. TGF inhibited the phosphorylation of Rb, p107, and p130 induced by TSH, but it weakly affected the phosphorylation state of Rb-related proteins in EGF+serum-treated cells. TGF did not inhibit c-myc expression. In TSH-stimulated cells, TGF did not affect the expression of cyclin D3, cdk4, and p27^kip1, nor the induced formation of cyclin D3-cdk4 complexes, but it prevented the TSH-induced relocalization of p27^kip1 from cdk2 to cyclin D3-cdk4. It prevented the nuclear translocations of cdk4 and cyclin D3 without altering the assembly of cyclin D3-cdk4 complexes probably formed in the cytoplasm, where they were prevented from sequestering nuclear p27^kip1 away from cdk2. This study dissociates the assembly of cyclin D3-cdk4 complexes from their nuclear localization and association with p27^kip1. It provides a new mechanism of regulation of proliferation by TGF, which points out the subcellular location of cyclin D-cdk4 complexes as a crucial factor integrating mitogenic and antimitogenic regulations in an epithelial cell in primary culture.

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Corresponding author. E-mail address: proger{at}ulb.ac.be.

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Molecular Biology of the Cell
Vol. 11, 1061-1076, March 2000
Copyright © 2000 by The American Society for Cell Biology

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