title: MAPK and PI3K/AKT mediated YB-1 activation promotes melanoma cell proliferation which is counteracted by an autoregulatory loop.
abstract: Y-box binding protein 1 (YB-1) is an oncogenic transcription and translation factor and is overexpressed in several types of cancer. Our previous data showed that YB-1 is upregulated and translocated to the nucleus during melanoma progression and that YB-1 is an important transcription factor regulating proliferation, survival, migration, invasion and chemosensitivity of melanoma cells. It has been suggested that YB-1 is activated and translocated to the nucleus after S102-phosphorylation in the DNA binding domain. In this study, we show that activation of YB-1 by S102-phosphorylation and nuclear translocation is increased during melanoma progression using a human tissue microarray with 100 melanocytic lesions. Furthermore, we analysed the mechanisms governing the expression and activity of YB-1 in melanoma cells. We show that the PI3K/AKT and p53 signalling, growth factors and chemotherapeutic agents increase YB-1 promoter activity. This, however, resulted in no or only modest increase in YB-1 protein expression. We show that the MAPK and PI3K/AKT signalling pathways, both activated in melanoma cells, as well as p53 overexpression increase YB-1 S102-phosphorylation, whereas NFκB signalling inhibits phosphorylation. Overexpression of YB-1 in melanoma cells inhibits translation efficiency and by this proliferation and survival of melanoma cells indicating that there is an autoregulatory loop restricting YB-1 protein expression. These data suggest that there is a tightly regulated feedback mechanism regulating YB-1 expression and activation, necessary for proper cell cycle progression of melanoma cells.
authors.affiliation: Department of Dermatology, Division of Dermatooncology, Eberhard-Karls-University, Tübingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Sinnberg
authors.forename: Birgit
authors.initials: B
authors.lastname: Sauer
authors.forename: Per
authors.initials: P
authors.lastname: Holm
authors.forename: Barbara
authors.initials: B
authors.lastname: Spangler
authors.forename: Silke
authors.initials: S
authors.lastname: Kuphal
authors.forename: Anja
authors.initials: A
authors.lastname: Bosserhoff
authors.forename: Birgit
authors.initials: B
authors.lastname: Schittek
mesh_terms: D021581:Active Transport, Cell Nucleus; D049109:Cell Proliferation; D002470:Cell Survival; D006706:Homeostasis; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt