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Degradation of cyclin D3 independent of Thr-283 phosphorylation

Abstract

Cyclin D3 has been shown to play a major role in the regulation of cell cycle progression in lymphocytes. It is therefore important to understand the mechanisms involved in the regulation of this protein. We have previously shown that both basal and cAMP-induced degradation of cyclin D3 in Reh cells is dependent on Thr-283 phosphorylation by glycogen synthase kinase-3β (GSK-3β). We now provide evidence of an alternative mechanism being involved in the regulation of cyclin D3 degradation. Treatment of lymphoid cells with okadaic acid (OA), an inhibitor of protein phosphatases 1 and 2A (PP1 and PP2A), induces rapid phosphorylation and proteasomal degradation of cyclin D3. This degradation is not inhibited by the GSK-3β inhibitors lithium or Kenpaullone, or by substitution of Thr-283 with Ala on cyclin D3, indicating that cyclin D3 can be degraded independently of Thr-283 phosphorylation and GSK-3β activity. Interestingly, in vitro experiments revealed that PP1, but not PP2A, was able to dephosphorylate cyclin D3 efficiently, and PP1 was found to associate with His-tagged cyclin D3. These results support the hypothesis that PP1 constitutively keeps cyclin D3 in a stable, dephosphorylated state, and that treatment of cells with OA leads to phosphorylation and degradation of cyclin D3 through inhibition of PP1.

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Acknowledgements

We are grateful to Dr David Beach and Dr Mathieu Bollen for providing the pD3-H347 plasmid and the purified PP1, respectively. We thank Camilla Solberg and Hilde R Haug for excellent technical assistance. This work was supported by grants from the Norwegian Cancer Society, the Norwegian Research Council, the Jahre Foundation, the Blix Family Foundation, Rachel and Otto Kr Bruun's legacy and the Nansen Foundation.

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Correspondence to S Naderi.

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Låhne, H., Kloster, M., Lefdal, S. et al. Degradation of cyclin D3 independent of Thr-283 phosphorylation. Oncogene 25, 2468–2476 (2006). https://doi.org/10.1038/sj.onc.1209278

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