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Null mutation of DNA strand break-binding molecule poly(ADP-ribose) polymerase causes medulloblastomas in p53(-/-) mice.

Abstract
Medulloblastoma is an invasive embryonal tumor of the cerebellum with predominant neuronal differentiation. Although several genes have been implicated in medulloblasoma formation, such as Patched (Ptc1) and the adenomatous polyposis coli gene (Apc), the majority of these tumors cannot be explained by mutations in these genes. The cellular origin as well as the genetic and molecular changes involved in the genesis and progression of human medulloblastomas remain largely unknown. Here we show that disruption of poly(ADP-ribose) polymerase (PARP-1) causes a high incidence (49%) of aggressive brain tumors in p53 null mice, with typical features of human cerebellar medulloblastomas. At as early as 8 weeks of age, lesions started on the outer surface of the cerebellum from remnant granule cell precursors of the developmental external germinal layer. Progression of these tumors is associated with the re-activation of the neuronal specific transcription factor Math1, dysregulation of Shh/Ptc1 signaling pathway, and chromosomal aberrations, including triradial and quadriradial chromosomes. The present study indicates that the loss of function of DNA double-strand break-sensing and repair molecules is an etiological factor in the evolution of the cerebellar medulloblastomas. These PARP-1/p53 double null mice represent a novel model for the pathogenesis of human medulloblastomas.
AuthorsWei-Min Tong, Hiroko Ohgaki, Huatao Huang, Christelle Granier, Paul Kleihues, Zhao-Qi Wang
JournalThe American journal of pathology (Am J Pathol) Vol. 162 Issue 1 Pg. 343-52 (Jan 2003) ISSN: 0002-9440 [Print] United States
PMID12507917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Atoh1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Hedgehog Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Oncogene Proteins
  • Proteins
  • Receptors, Cell Surface
  • Shh protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • patched receptors
  • DNA
  • Poly(ADP-ribose) Polymerases
Topics
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Brain Neoplasms (genetics, metabolism, pathology)
  • Cerebellum (growth & development, pathology)
  • Chromosome Aberrations
  • DNA (metabolism)
  • DNA Repair
  • Disease Models, Animal
  • Disease Progression
  • Embryonal Carcinoma Stem Cells
  • Hedgehog Proteins
  • Intracellular Signaling Peptides and Proteins
  • Medulloblastoma (genetics, metabolism, pathology)
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mitosis (genetics)
  • Neoplastic Stem Cells (metabolism, pathology)
  • Oncogene Proteins (metabolism)
  • Poly(ADP-ribose) Polymerases (deficiency, genetics)
  • Proteins
  • Receptors, Cell Surface
  • Signal Transduction (genetics)
  • Trans-Activators (metabolism)
  • Transcription Factors (biosynthesis)
  • Tumor Suppressor Protein p53 (deficiency, genetics)

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