TIS21/BTG2/PC3 and cyclin D1 are key determinants of nuclear diacylglycerol kinase-ζ-dependent cell cycle arrest

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• 作者：Camilla Evangelisti ; Annalisa Astolfi ; Gian Carlo Gaboardi ; Pierluigi Tazzari ; Andrea Pession ; Kaoru Goto ; Alberto M. Martelli
• 关键词：Nucleus ; Lipid signaling ; Diacylglycerol ; Proliferation ; Differentiation
• 刊名：Cellular Signalling
• 出版年：2009
• 出版时间：May 2009
• 年：2009
• 卷：21
• 期：5
• 页码：801-809
• 全文大小：1213 K

文摘

In addition to lipid second messengers derived from the plasma membrane, increasing evidence supports the existence of nuclear lipid-dependent signaling networks. Diacylglycerol is a key second messenger, generated at the nuclear level, which is metabolized by diacylglycerol kinases (DGKs). It has been demonstrated that nuclear DGK-ζ negatively regulates cell cycle progression. The aim of this study was to identify key determinants of nuclear DGK-ζ-dependent cell cycle arrest in C2C12 mouse myoblasts. Using DNA microarrays, Real-Time RT-PCR and western blot, we demonstrated that nuclear DGK-ζ downregulated the expression of cyclin D1 and increased the expression of TIS21/BTG2/PC3, a transcriptional regulator of cyclin D1 with a strong anti-proliferative function. Overexpression of TIS21/BTG2/PC3 blocked the cells in G1 phase of the cell cycle and decreased the levels of Ser807/811 phosphorylated retinoblastoma protein, similarly to overexpression of DGK-ζ. Moreover, during myogenic differentiation of C2C12 cells, we showed an increase of TIS21/BTG2/PC3 expression and a decrease in cyclin D1 levels. siRNA downregulation of TIS21/BTG2/PC3 impaired myogenic differentiation by opposing cell cycle arrest. In summary, these data identify TIS21/BTG2/PC3 and cyclin D1 as downstream effectors of nuclear DGK-ζ and highlight the importance of this DGK isoform in the regulation of myoblast proliferation and differentiation.