Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1964023 | Cellular Signalling | 2009 | 9 Pages |
Abstract
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.
Keywords
PI3Kphosphoinositide dependent kinase-1phosphate buffered saline, pH 7.4PIP2PDK-1phorbol 12-myristate 13-acetateGSKDGKNLSPKCPLCp70S6KECLCDKPBSmTORPRBPMAp70S6 kinasephosphatidic acidenhanced chemiluminescenceProliferationDifferentiationdiacylglycerol kinasediacylglycerolnuclear localization signalLipid signalingPhosphatidylinositol 3-kinasePhosphatidylinositol 4,5 bisphosphatemammalian target of rapamycinNucleusretinoblastoma proteinProtein kinase CPropidium iodidecyclin dependent kinaseglycogen synthase kinase
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Authors
Camilla Evangelisti, Annalisa Astolfi, Gian Carlo Gaboardi, Pierluigi Tazzari, Andrea Pession, Kaoru Goto, Alberto M. Martelli,