Journal Article

PARP-1 cooperates with Ptc1 to suppress medulloblastoma and basal cell carcinoma

Mirella Tanori, Mariateresa Mancuso, Emanuela Pasquali, Simona Leonardi, Simonetta Rebessi, Vincenzo Di Majo, Marie-Noëlle Guilly, Felice Giangaspero, Vincenzo Covelli, Simonetta Pazzaglia and Anna Saran

in Carcinogenesis

Volume 29, issue 10, pages 1911-1919
Published in print October 2008 | ISSN: 0143-3334
Published online July 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn174
PARP-1 cooperates with Ptc1 to suppress medulloblastoma and basal cell carcinoma

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The patched (Ptc1) protein is a negative regulator of sonic hedgehog signaling, a genetic pathway whose perturbation causes developmental defects and predisposition to specific malignant tumors. Humans and mice with mutated Ptc1 are prone to medulloblastoma and basal cell carcinoma (BCC), both tumors showing dependence on radiation damage for rapid onset and high penetrance. Poly(ADP-ribose) polymerase (PARP-1) is a nuclear enzyme that plays a multifunctional role in DNA damage signaling and repair. In healthy and fertile PARP-1-null mice, radiation exposure reveals an extreme sensitivity and a high genomic instability. To test for interactions between PARP-1 and sonic hedgehog signaling, PARP-1-null mice were crossed to Ptc1 heterozygous mice. PARP-1 deletion further accelerated medulloblastoma development in irradiated Ptc1+/− mice, showing that PARP-1 inactivation sensitizes cerebellar cells to radiation tumorigenic effects. In addition to increased formation and slowed down kinetics of disappearance of γ-H2AX foci, we observed increased apoptosis in PARP-1-deficient granule cell progenitors after irradiation. Double-mutant mice were also strikingly more susceptible to BCC, with >50% of animals developing multiple, large, infiltrative tumors within 30 weeks of age. The results provide genetic evidence that PARP-1 function suppresses sonic hedgehog pathway-associated tumors arising in response to environmental stress.

Journal Article.  6264 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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