title: The MHC class II transactivator (CIITA) mRNA stability is critical for the HLA class II gene expression in myelomonocytic cells.
abstract: The human promyelocytic U937 cells express detectable levels of MHC class II (MHC-II) molecules. Treatment with 12-o--tetradecanoyl phorbol 13-acetate (TPA), inducing macrophage-like differentiation, produces a dramatic decrease of MHC-II expression as result of down-modulation of the activation of immune response gene 1 (AIR-1)-encoded MHC-II transactivator (CIITA). This event is specific, as MHC class I remains unaffected. Similar results are observed with U937 cells expressing an exogenous full-length CIITA. Molecular studies demonstrate that TPA treatment affects the stability of CIITA mRNA rather than CIITA transcription. Importantly, cis-acting elements within the distal 650 bp of the 1035-bp 3' untranslated region (3'UTR, nucleotides 3509-4543) are associated to transcript instability. Transcription inhibitors actinomycin D and 5,6-dichlororibofuranosyl benzimidazole, and the translation inhibitor cycloheximide significantly rescue the accumulation of CIITA mRNA in TPA-treated cells. A similar effect is also observed after treatment with staurosporine and the PKC-specific inhibitor GF109203X. The instability of CIITA mRNA produced by TPA in U937 cells is not seen in B cells. These results demonstrate the presence of an additional level of control of MHC-II expression in the macrophage cell lineage depending upon the control of CIITA mRNA stability, most likely mediated by differentiation-induced, 3'UTR-interacting factors which require kinase activity for their destabilizing function.
authors.affiliation: Department of Clinical and Biological Sciences, School of Medicine, University of Insubria, Varese, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: De Lerma Barbaro
authors.forename: Francesco A
authors.initials: FA
authors.lastname: Procopio
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Mortara
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosi
authors.forename: Roberto S
authors.initials: RS
authors.lastname: Accolla
mesh_terms: D020413:3' Untranslated Regions; D015870:Gene Expression / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism; D020871:RNA Stability / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D020298:U937 Cells
chemical_list: D020413:3' Untranslated Regions; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D010770:Phosphotransferases; D013755:Tetradecanoylphorbol Acetate