Tanori Mirella, Mancuso Mariateresa, Pasquali Emanuela, Leonardi Simona, Rebessi Simonetta, Di Majo Vincenzo, Guilly Marie-Noëlle, Giangaspero Felice, Covelli Vincenzo, Pazzaglia Simonetta, Saran Anna
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.
Carcinogenesis. 2008 Oct;29(10):1911-9. doi: 10.1093/carcin/bgn174. Epub 2008 Jul 27.
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.
patched（Ptc1）蛋白是音猬因子信号通路的负调节因子，该遗传通路的扰动会导致发育缺陷以及易患特定恶性肿瘤。Ptc1发生突变的人类和小鼠易患髓母细胞瘤和基底细胞癌（BCC），这两种肿瘤都显示出对辐射损伤的依赖性，从而快速发病且具有高外显率。聚（ADP - 核糖）聚合酶（PARP - 1）是一种核酶，在DNA损伤信号传导和修复中发挥多功能作用。在健康且可育的PARP - 1基因敲除小鼠中，辐射暴露显示出极高的敏感性和高基因组不稳定性。为了测试PARP - 1与音猬因子信号通路之间的相互作用，将PARP - 1基因敲除小鼠与Ptc1杂合小鼠杂交。PARP - 1缺失进一步加速了受辐射的Ptc1（+/-）小鼠的髓母细胞瘤发展，表明PARP - 1失活使小脑细胞对辐射致瘤效应敏感。除了γ - H2AX焦点形成增加和消失动力学减慢外，我们还观察到辐射后PARP - 1缺陷的颗粒细胞祖细胞凋亡增加。双突变小鼠对BCC也明显更易感，超过50%的动物在30周龄内出现多个大的浸润性肿瘤。这些结果提供了遗传学证据，表明PARP - 1功能可抑制因环境应激而产生的与音猬因子通路相关的肿瘤。
