title: Lack of Rb and p53 delays cerebellar development and predisposes to large cell anaplastic medulloblastoma through amplification of N-Myc and Ptch2.
abstract: Medulloblastomas are among the most common malignant brain tumors in childhood. They typically arise from neoplastic transformation of granule cell precursors in the cerebellum via deregulation of molecular pathways involved in normal cerebellar development. In a mouse model, we show here that impairment of the balance between proliferation and differentiation of granule cell precursors in the external granular layer of the developing cerebellum predisposes but is not sufficient to induce neoplastic transformation of these progenitor cells. Using array-based chromosomal comparative genomic hybridization, we show that genetic instability resulting from inactivation of the p53 pathway together with deregulation of proliferation induced by Rb loss eventually leads to neoplastic transformation of these cells by acquiring additional genetic mutations, mainly affecting N-Myc and Ptch2 genes. Moreover, we show that p53 loss influences molecular mechanisms that cannot be mimicked by the loss of either p19(ARF), p21, or ATM.
authors.affiliation: Institute of Clinical Pathology, University Hospital, Zurich, Switzerland.
authors.forename: Olga
authors.initials: O
authors.lastname: Shakhova
authors.forename: Carly
authors.initials: C
authors.lastname: Leung
authors.forename: Erwin
authors.initials: E
authors.lastname: van Montfort
authors.forename: Anton
authors.initials: A
authors.lastname: Berns
authors.forename: Silvia
authors.initials: S
authors.lastname: Marino
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D016259:Genes, myc; D020022:Genetic Predisposition to Disease; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D000072079:Patched Receptors; D000072082:Patched-2 Receptor; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D000072079:Patched Receptors; D000072082:Patched-2 Receptor; C000606241:Ptch2 protein, mouse; D011956:Receptors, Cell Surface; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases