title: WIP1 modulates responsiveness to Sonic Hedgehog signaling in neuronal precursor cells and medulloblastoma.
abstract: High-level amplification of the protein phosphatase PPM1D (WIP1) is present in a subset of medulloblastomas (MBs) that have an expression profile consistent with active Sonic Hedgehog (SHH) signaling. We found that WIP1 overexpression increased expression of Shh target genes and cell proliferation in response to Shh stimulation in NIH3T3 and cerebellar granule neuron precursor cells in a p53-independent manner. Thus, we developed a mouse in which WIP1 is expressed in the developing brain under control of the Neurod2 promoter (ND2:WIP1). The external granule layer (EGL) in early postnatal ND2:WIP1 mice exhibited increased proliferation and expression of Shh downstream targets. MB incidence increased and survival decreased when ND2:WIP1 mice were crossed with an Shh-activated MB mouse model. Conversely, Wip1 knockout significantly suppressed MB formation in two independent mouse models of Shh-activated MB. Furthermore, Wip1 knockdown or treatment with a WIP1 inhibitor suppressed the effects of Shh stimulation and potentiated the growth inhibitory effects of SHH pathway-inhibiting drugs in Shh-activated MB cells in vitro. This suggests an important cross-talk between SHH and WIP1 pathways that accelerates tumorigenesis and supports WIP1 inhibition as a potential treatment strategy for MB.
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Winship Cancer Institute, and the Emory University School of Medicine, Atlanta, GA, USA.|Department of Pharmacology, Atlanta, GA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Nahta
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Arnold
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Buss
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Brown
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Maier
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA.|Winship Cancer Institute, and the Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Kenney
authors.affiliation: Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Center, and Program in Developmental and Stem Cell Biology, Toronto, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Remke
authors.affiliation: Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Ramaswamy
authors.affiliation: Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Center, and Program in Developmental and Stem Cell Biology, Toronto, Ontario, Canada.
authors.forename: M D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA.|Winship Cancer Institute, and the Emory University School of Medicine, Atlanta, GA, USA.|Children's Healthcare of Atlanta, Atlanta, GA, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Castellino
mesh_terms: D000818:Animals; D015415:Biomarkers; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D058953:Neural Stem Cells / Q000378:metabolism*; D000071636:Protein Phosphatase 2C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D015415:Biomarkers; D053823:Hedgehog Proteins; D016159:Tumor Suppressor Protein p53; C000607458:PPM1D protein, human; D000071636:Protein Phosphatase 2C