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Carcinogenesis Advance Access originally published online on July 27, 2008
Carcinogenesis 2008 29(10):1911-1919; 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

Mirella Tanori, Mariateresa Mancuso, Emanuela Pasquali1, Simona Leonardi, Simonetta Rebessi, Vincenzo Di Majo, Marie-Noëlle Guilly2, Felice Giangaspero3,4, Vincenzo Covelli5, Simonetta Pazzaglia* and Anna Saran

Section of Toxicology and Biomedical Sciences, Biotechnologies, Agro-Industry and Health Protection Department, Ente per le Nuove Tecnologie, l'Energia e l'Ambiente (ENEA), Centro Ricerche Casaccia, 00123 Rome, Italy
1 Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy
2 Commissariat à l'Énergie Atomique, Laboratoire de Cancérologie Expérimentale, F-92265, Fontenay-aux-Roses, France
3 Department of Experimental Medicine and Pathology, University of Rome ‘La Sapienza’, 00185 Rome, Italy
4 Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, 86077 Pozzilli, Italy
5 Radiation Protection Unit, ENEA CR-Casaccia, 00123 Rome, Italy

* To whom correspondence should be addressed. Tel: +39 06 30486535; Fax: +39 06 30483644; Email: pazzaglia{at}casaccia.enea.it

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 {gamma}-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.

Abbreviations: BCC, basal cell carcinoma; CNS, central nervous system; CGH, comparative genomic hybridization; DSB, double-strand break; EGL, external granule layer; GCP, granule cell progenitor; P1, post-natal day 1; PARP, poly(adenosine diphosphate-ribose) polymerase; Ptc, patched; SSB, single-strand break

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


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