title: OX40 engagement stabilizes Mxd4 and Mnt protein levels in antigen-stimulated T cells leading to an increase in cell survival.
abstract: OX40 engagement on activated T cells leads to increased proliferation, expansion and survival of Ag-specific T cells. Direct ex vivo examination of Ag-stimulated murine T cells show that the Myc antagonists, Mxd4 and Mnt, are transiently upregulated and translocated to the nucleus following OX40 engagement and may be involved in suppressing cell death. Both Mxd4 and Mnt are upregulated following OX40 stimulation through increased protein stability and we identify a critical phosphorylation site in Mxd4 that controls Mxd4 stability. The upregulation of Mxd4 and Mnt contributes to OX40-mediated T-cell survival because siRNA knockdown of Mxd4 and Mnt led to increased cell death. We hypothesize the upregulation of c-Myc following OX40 engagement drives T-cell proliferation and that upregulation of Mxd4 and Mnt suppresses Myc-dependent cell death. Thus, Mxd4 and Mnt upregulation following OX40 engagement most likely increases T-cell survival.
authors.affiliation: Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213-2933, USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Vasilevsky
authors.forename: Carl E
authors.initials: CE
authors.lastname: Ruby
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hurlin
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002470:Cell Survival; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D010768:Phosphoserine / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000276:immunology; D034741:RNA, Small Interfering; D053262:Receptors, OX40 / Q000276:immunology*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C097224:Mad4 protein, mouse; C484561:Mnt protein, mouse; D020598:Proto-Oncogene Proteins c-myb; D034741:RNA, Small Interfering; D053262:Receptors, OX40; D012097:Repressor Proteins; C505717:Tnfrsf4 protein, mouse; D010768:Phosphoserine