title: BCL-6 is phosphorylated at multiple sites in its serine- and proline-clustered region by mitogen-activated protein kinase (MAPK) in vivo.
abstract: BCL-6 gene alterations have been observed in 27-45% of diffuse large B-cell lymphomas (DLBs) with chromosomal translocations at 3q27. The deregulated expression of normal BCL-6 protein caused by this chromosomal translocation is believed to be responsible for lymphomagenesis. Recently, we demonstrated that BCL-6 is expressed at high levels in germinal center B-cells as a 92-98 kDa nuclear protein in a constitutively phosphorylated form. In this study, we show that BCL-6 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro at the sites phosphorylated in vivo. These numerous phosphorylation sites were found to be located in its serine- and proline-clustered (SPC) region (amino acids-250-483). BCL-6 phosphorylation significantly increased in Ramos cells following stimulation with 12-o-tetradecanoylphorbol-13-acetate (TPA) or BCL-6- and erk1-transfected COS-7 cells stimulated with epidermal growth factor (EGF), and the increase of phosphorylation was inhibited by MEK1 inhibitor, PD98059. Furthermore, we observed that BCL-6 was associated with MAPK in vivo and its SPC region was important for this association. These results suggest that the functions of BCL-6 are regulated by phosphorylation mediated by the MAPK signaling pathway.
authors.affiliation: Department of Pathology, Institute of Medical Science, University of Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Moriyama
authors.forename: T
authors.initials: T
authors.lastname: Yamochi
authors.forename: K
authors.initials: K
authors.lastname: Semba
authors.forename: T
authors.initials: T
authors.lastname: Akiyama
authors.forename: S
authors.initials: S
authors.lastname: Mori
mesh_terms: D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases