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 Nölle Guilly, Felice Giangaspero, Vincenzo Covelli, Simonetta Pazzaglia, Anna Saran

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1911-1919
Number of pages9
JournalCarcinogenesis
Volume29
Issue number10
DOIs
Publication statusPublished - 2008

ASJC Scopus subject areas

  • Cancer Research

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