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Nuclear diacylglycerol kinase- is a negative regulator of cell cycle progression in C2C12 mouse myoblasts

Camilla Evangelisti^*, Pier Luigi Tazzari, Massimo Riccio, Roberta Fiume^*, Yasukazu Hozumi, Federica Falà^*, Kaoru Goto, Lucia Manzoli^*, Lucio Cocco^* and Alberto M. Martelli^*,||,1

^* Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell’Apparato Locomotore, Sezione di Anatomia, Università di Bologna, Bologna, Italy;

Servizio di Immunoematologia e Trasfusionale, Policlinico S. Orsola-Malpighi, Bologna, Italy;

Dipartimento di Anatomia e Istologia, Università di Modena e Reggio Emilia, Modena, Italy;

Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata, Japan; and

^|| IGM-CNR, IOR, Bologna, Italy

¹Correspondence: Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell’Apparato Locomotore, Cell Signalling Laboratory, Università di Bologna, via Irnerio 48, 40126 Bologna, Italy. E-mail: alberto.martelli{at}unibo.it

The nucleus contains diacylglycerol kinases (DGKs), i.e., the enzymes that, by converting diacylglycerol (DG) into phosphatidic acid, terminate DG-dependent events. It has been demonstrated that nuclear DGK- interferes with cell cycle progression. We previously reported that nuclear DGK- expression increased during myogenic differentiation, whereas its down-regulation impaired differentiation. Here, we evaluated the possible involvement of nuclear DGK- in cell cycle progression of C2C12 myoblasts. Overexpression of a wild-type DGK-, which mainly localized to the nucleus (but not of a kinase dead mutant or of a mutant that did not enter the nucleus), blocked the cells in the G₁ phase of the cell cycle, as demonstrated by in situ analysis of biotinylated-16-dUTP incorporated into newly synthesized DNA and by flow cytometry. In contrast, down-regulation of endogenous DGK- by short interfering RNA (siRNA) increased the number of cells in both the S and G₂/M phases of the cell cycle. Cell cycle arrest of cells overexpressing wild-type DGK- was accompanied by decreased levels of retinoblastoma protein phosphorylated on Ser-807/811. Down-regulation of endogenous DGK-, using siRNA, prevented the cell cycle block characterizing C2C12 cell myogenic differentiation. Overall, our results identify nuclear DGK- as a key determinant of cell cycle progression and differentiation of C2C12 cells. —Evangelisti, C., Tazzari, P. L., Riccio, M., Fiume, R., Hozumi, Y., Falà, F., Goto, K., Manzoli, L., Cocco, L., Martelli, A. M. Nuclear diacylglycerol kinase- is a negative regulator of cell cycle progression in C2C12 mouse myoblasts.

Key Words: nucleus • lipid-dependent signaling pathways • siRNA • phosphorylated pRB

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