title: Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis.
abstract: Pbx-regulating protein-1 (Prep1) is a tumor suppressor, whereas myeloid ecotropic viral integration site-1 (Meis1) is an oncogene. We show that, to perform these activities in mouse embryonic fibroblasts, both proteins competitively heterodimerize with pre-B-cell leukemia homeobox-1 (Pbx1). Meis1 alone transforms Prep1-deficient fibroblasts, whereas Prep1 overexpression inhibits Meis1 tumorigenicity. Pbx1 can, therefore, alternatively act as an oncogene or tumor suppressor. Prep1 posttranslationally controls the level of Meis1, decreasing its stability by sequestering Pbx1. The different levels of Meis1 and the presence of Prep1 are followed at the transcriptional level by the induction of specific transcriptional signatures. The decrease of Meis1 prevents Meis1 interaction with Ddx3x and Ddx5, which are essential for Meis1 tumorigenesis, and modifies the growth-promoting DNA binding landscape of Meis1 to the growth-controlling landscape of Prep1. Hence, the key feature of Prep1 tumor-inhibiting activity is the control of Meis1 stability.
authors.affiliation: Istituto Fondazione Italiana Ricerca sul Cancro (FIRC) di Oncologia Molecolare (IFOM), 20139 Milan, Italy.
authors.forename: Leila
authors.initials: L
authors.lastname: Dardaei
authors.forename: Elena
authors.initials: E
authors.lastname: Longobardi
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000502:physiology*; D063646:Carcinogenesis / Q000378:metabolism*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism*; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D055550:Protein Stability; D020365:RNA Helicases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D018398:Homeodomain Proteins; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C481797:Pbx1 protein, mouse; C491412:Pknox1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D034741:RNA, Small Interfering; D014157:Transcription Factors; C506751:Ddx5 protein, mouse; D053487:DEAD-box RNA Helicases; C514697:Ddx3x protein, mouse; D020365:RNA Helicases