title: Transformation of the intestinal epithelium by the MSI2 RNA-binding protein.
abstract: The MSI2 RNA-binding protein is a potent oncogene playing key roles in haematopoietic stem cell homeostasis and malignant haematopoiesis. Here we demonstrate that MSI2 is expressed in the intestinal stem cell compartment, that its expression is elevated in colorectal adenocarcinomas, and that MSI2 loss-of-function abrogates colorectal cancer cell growth. MSI2 gain-of-function in the intestinal epithelium in a drug-inducible mouse model is sufficient to phenocopy many of the morphological and molecular consequences of acute loss of the APC tumour suppressor in the intestinal epithelium in a Wnt-independent manner. Transcriptome-wide RNA-binding analysis indicates that MSI2 acts as a pleiotropic inhibitor of known intestinal tumour suppressors including Lrig1, Bmpr1a, Cdkn1a and Pten. Finally, we demonstrate that inhibition of the PDK-AKT-mTORC1 axis rescues oncogenic consequences of MSI2 induction. Taken together, our findings identify MSI2 as a central component in an unappreciated oncogenic pathway promoting intestinal transformation.
authors.affiliation: 1] State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100194, China [2] Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: 1] Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Yousefi
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Nakauka-Ddamba
authors.affiliation: 1] Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] PENN Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Genomics and Computational Biology Graduate Program, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Parada
authors.affiliation: PENN Molecular Profiling Facility, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Rao
authors.affiliation: Molecular Pharmacology and Chemistry Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Minuesa
authors.affiliation: The Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
authors.forename: Yarden
authors.initials: Y
authors.lastname: Katz
authors.affiliation: 1] Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] PENN Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Genomics and Computational Biology Graduate Program, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Gregory
authors.affiliation: Molecular Pharmacology and Chemistry Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kharas
authors.affiliation: State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100194, China.
authors.forename: Zhengquan
authors.initials: Z
authors.lastname: Yu
authors.affiliation: 1] Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Center for Molecular Studies in Digestive and Liver Diseases, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [4] Department of Cell and Developmental Biology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [5] Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lengner
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D004317:Doxorubicin / Q000737:chemistry; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000378:metabolism*; D007422:Intestines / Q000382:microbiology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D059467:Transcriptome; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: C438151:MSI2 protein, human; C499059:Msi2h protein, mouse; D016601:RNA-Binding Proteins; D051153:Wnt Proteins; D004317:Doxorubicin; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse