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Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

Oncogene volume 26, pages 6630–6640 (2007)Cite this article

Abstract

Cyclin D2 plays an important role in regulation of hematopoietic cell proliferation by cytokines and is implicated in oncogenesis of various hematopoietic malignancies. However, mechanisms regulating cyclin D2 stability and its expression level have remained to be known. Here, we demonstrate that interleukin-3 signaling stabilizes cyclin D2 by inhibition of glycogen synthase kinase-3β (GSK3β) through Janus kinase2-dependent activation of phosphatidylinositol 3′-kinase (PI3K)/Akt signaling pathway in hematopoietic 32Dcl3 cells. On the other hand, osmotic stress was shown to induce a rapid proteasomal degradation of cyclin D2, which was mediated by activation of p38. GSK3β and p38 was demonstrated to phosphorylate cyclin D2 on Thr280 in vitro, while a cyclin D2 mutant with this residue substituted with Ala was found to be resistant to ubiquitination and proteasome-dependent degradation in 32Dcl3 cells. Inhibition of the PI3K pathway or induction of osmotic stress also caused a rapid proteasomal degradation of cyclin D2 in primary leukemic or myeloma cells. These results indicate that cyclin D2 expression in normal and malignant hematopoietic cells is regulated by ubiquitin/proteasome-dependent degradation that is triggered by Thr280 phosphorylation by GSK3β or p38, which is induced by inhibition of the PI3K pathway or by osmotic stress, respectively.

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Acknowledgements

We thank Drs Roger J Davis and Masakazu Hattori for the generous gifts of experimental materials. This study was supported in part by grants from Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Hematology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    A Kida, K Kakihana, S Kotani, T Kurosu & O Miura

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  1. A Kida
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Correspondence to O Miura.

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Kida, A., Kakihana, K., Kotani, S. et al. Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells. Oncogene 26, 6630–6640 (2007). https://doi.org/10.1038/sj.onc.1210490

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