| First Author | Martínez-Moreno M | Year | 2012 |
| Journal | Mol Cell Biol | Volume | 32 |
| Issue | 20 | Pages | 4168-80 |
| PubMed ID | 22890845 | Mgi Jnum | J:189253 |
| Mgi Id | MGI:5444802 | Doi | 10.1128/MCB.00654-12 |
| Citation | Martinez-Moreno M, et al. (2012) FoxO-dependent regulation of diacylglycerol kinase alpha gene expression. Mol Cell Biol 32(20):4168-80 |
| abstractText | Diacylglycerol kinase alpha (DGKalpha) regulates diacylglycerol levels, catalyzing its conversion into phosphatidic acid. The alpha isoform is central to immune response regulation; it downmodulates Ras-dependent pathways and is necessary for establishment of the unresponsive state termed anergy. DGKalpha functions are regulated in part at the transcriptional level although the mechanisms involved remain poorly understood. Here, we analyzed the 5' end structure of the mouse DGKalpha gene and detected three binding sites for forkhead box O (FoxO) transcription factors, whose function was confirmed using luciferase reporter constructs. FoxO1 and FoxO3 bound to the 5' regulatory region of DGKalpha in quiescent T cells, as well as after interleukin-2 (IL-2) withdrawal in activated T cells. FoxO binding to this region was lost after complete T cell activation or IL-2 addition, events that correlated with FoxO phosphorylation and a sustained decrease in DGKalpha gene expression. These data strongly support a role for FoxO proteins in promoting high DGKalpha levels and indicate a mechanism by which DGKalpha function is downregulated during productive T cell responses. Our study establishes a basis for a causal relationship between DGKalpha downregulation, IL-2, and anergy avoidance. |
