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Carcinogenesis Advance Access published online on July 27, 2008
Carcinogenesis, doi:10.1093/carcin/bgn174
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

M Tanori1, M Mancuso1, E Pasquali2, S Leonardi1, S Rebessi1, V Di Majo1, Marie-Noëlle Guilly3, F Giangaspero4,5, V Covelli6, S Pazzaglia1 and A Saran1

1 Biotechnology Unit, ENEA CR-Casaccia, Rome, Italy
2 Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy
3 CEA, DSV, DRR, Laboratoire de Cancérologie Expérimentale, Fontenay-aux-Roses, France
4 Experimental Medicine and Pathology, University of Rome "La Sapienza," Rome, Italy
5 Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy
6 Radiation Protection Unit, ENEA CR-Casaccia, Rome, Italy

To whom correspondence should be addressed: Simonetta Pazzaglia, Biotechnology Unit, ENEA CR-Casaccia, Via Anguillarese 301, 00123 Rome, Italy., E-mail: pazzaglia{at}casaccia.enea.it.

The Patched (Ptc1) protein is a negative regulator of Sonic Hedgehog (Shh) 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 Shh 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 {gamma}-H2AX foci, we observed increased apoptosis in PARP-1-deficient granule cell progenitors (GCPs) after irradiation. Double mutant mice were also strikingly more susceptible to BCC, with over 50% of animals developing multiple, large, infiltrative tumors within 30 weeks of age. The results provide genetic evidence that PARP-1 function suppresses Shh pathway-associated tumors arising in response to environmental stress.

Key Words: Patched • Sonic Hedgehog • medulloblastoma • BCC • DNA repair

Received April 10, 2008; revised June 26, 2008; accepted July 19, 2008.


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