PARP-1 cooperates with Ptc1 to suppress medulloblastoma and basal cell carcinoma.
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.
Tanori
Mirella
M
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.
Mancuso
Mariateresa
M
Pasquali
Emanuela
E
Leonardi
Simona
S
Rebessi
Simonetta
S
Di Majo
Vincenzo
V
Guilly
Marie-Noëlle
MN
Giangaspero
Felice
F
Covelli
Vincenzo
V
Pazzaglia
Simonetta
S
Saran
Anna
A
D000818:Animals; D017209:Apoptosis; D002280:Basal Cell Carcinoma / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002531:Cerebellum / Q000473:pathology / Q000528:radiation effects; D004249:DNA Damage; D042822:Genomic Instability; D006657:Histones / Q000032:analysis; D008527:Medulloblastoma / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D011230:Precancerous Conditions / Q000209:etiology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*
D006657:Histones; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C475961:gamma-H2AX protein, mouse; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases