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

TitoloPARP-1 cooperates with Ptc1 to suppress medulloblastoma and basal cell carcinoma
Tipo di pubblicazioneArticolo su Rivista peer-reviewed
Anno di Pubblicazione2008
AutoriTanori, Mirella, Mancuso Mariateresa, Pasquali Emanuela, Leonardi Simona, Rebessi S., Di Majo V., Guilly M.-N., Giangaspero F., Covelli V., Pazzaglia Simonetta, and Saran Anna
RivistaCarcinogenesis
Volume29
Paginazione1911-1919
ISSN01433334
Parole chiaveanimal cell, animal tissue, Animals, Apoptosis, article, Basal Cell, basal cell carcinoma, brain cell, cancer infiltration, cancer susceptibility, Carcinoma, Cell Surface, cerebellum, controlled study, DNA damage, Environmental stress, gamma histone H2AX, gene deletion, gene inactivation, genomic instability, granule cell, heterozygosity, histone H2AX, Histones, Inbred C57BL, medulloblastoma, Mice, mouse, mouse mutant, nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1, nonhuman, Poly(ADP-ribose) Polymerases, Precancerous Conditions, priority journal, protein defect, protein function, protein Patched 1, protein protein interaction, radiation carcinogenesis, Receptors, signal transduction, sonic hedgehog protein, unclassified drug
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. © The Author 2008. Published by Oxford University Press. All rights reserved.

Note

cited By 16

URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-53349153003&doi=10.1093%2fcarcin%2fbgn174&partnerID=40&md5=26926be6db4faeebd55cb2b5e3f4f34a
DOI10.1093/carcin/bgn174
Citation KeyTanori20081911