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	Leila Dardaei, Elena Longobardi, Francesco Blasi
Journal	Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 10 Pg. E896-905 (Mar 11 2014) ISSN: 1091-6490 [Electronic] United States
PMID	24578510 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	DNA Primers Homeodomain Proteins Meis1 protein, mouse Myeloid Ecotropic Viral Integration Site 1 Protein Neoplasm Proteins Pbx1 protein, mouse Pknox1 protein, mouse Pre-B-Cell Leukemia Transcription Factor 1 RNA, Small Interfering Transcription Factors Ddx5 protein, mouse DEAD-box RNA Helicases Ddx3x protein, mouse RNA Helicases
Topics	Animals Binding, Competitive (physiology) Carcinogenesis (metabolism) Cell Line Chromatin Immunoprecipitation DEAD-box RNA Helicases (metabolism) DNA Primers (genetics) Homeodomain Proteins (metabolism) Immunoprecipitation Mass Spectrometry Mice Mice, Nude Myeloid Ecotropic Viral Integration Site 1 Protein Neoplasm Proteins (metabolism) Pre-B-Cell Leukemia Transcription Factor 1 Protein Stability RNA Helicases (metabolism) RNA, Small Interfering (genetics) Real-Time Polymerase Chain Reaction Transcription Factors (metabolism)

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