title: The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins.
abstract: Members of the Msi family of RNA-binding proteins have recently emerged as potent oncoproteins in a range of malignancies. MSI2 is highly expressed in hematopoietic cancers, where it is required for disease maintenance. In contrast to the hematopoietic system, colorectal cancers can express both Msi family members, MSI1 and MSI2. Here, we demonstrate that, in the intestinal epithelium, Msi1 and Msi2 have analogous oncogenic effects. Further, comparison of Msi1/2-induced gene expression programs and transcriptome-wide analyses of Msi1/2-RNA-binding targets reveal significant functional overlap, including induction of the PDK-Akt-mTORC1 axis. Ultimately, we demonstrate that concomitant loss of function of both MSI family members is sufficient to abrogate the growth of human colorectal cancer cells, and Msi gene deletion inhibits tumorigenesis in several mouse models of intestinal cancer. Our findings demonstrate that MSI1 and MSI2 act as functionally redundant oncoproteins required for the ontogeny of intestinal cancers.
authors.affiliation: State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100194, China; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Yousefi
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Nakauka-Ddamba
authors.affiliation: Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Genomics and Computational Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Vandivier
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Parada
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Dong-Hun
authors.initials: DH
authors.lastname: Woo
authors.affiliation: State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100194, China; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ammar S
authors.initials: AS
authors.lastname: Naqvi
authors.affiliation: PENN Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Rao
authors.affiliation: PENN Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: John
authors.initials: J
authors.lastname: Tobias
authors.affiliation: Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Cedeno
authors.affiliation: Molecular Pharmacology and Chemistry Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Minuesa
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Katz
authors.initials: K
authors.lastname: Y
authors.affiliation: Molecular Pharmacology and Chemistry Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Trevor S
authors.initials: TS
authors.lastname: Barlowe
authors.affiliation: Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Valvezan
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sheila
authors.initials: S
authors.lastname: Shankar
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Raquel P
authors.initials: RP
authors.lastname: Deering
authors.affiliation: Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Klein
authors.affiliation: Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Shane T
authors.initials: ST
authors.lastname: Jensen
authors.affiliation: Molecular Pharmacology and Chemistry Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kharas
authors.affiliation: Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Genomics and Computational Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Gregory
authors.affiliation: State Key Laboratories for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100194, China. Electronic address: zyu@cau.edu.cn.
authors.forename: Zhengquan
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Center for Molecular Studies in Digestive and Liver Diseases, University of Pennsylvania, Philadelphia, PA 19104, USA; Cell and Molecular Biology Graduate Program, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: lengner@vet.upenn.edu.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lengner
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D017930:Genes, Reporter; D045325:HCT116 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C104786:Msi1h protein, mouse; C499059:Msi2h protein, mouse; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D016601:RNA-Binding Proteins; D051176:beta Catenin; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase