retinoblastoma loss modulates dna damage response favoring tumor progression视网膜母细胞瘤损失调节dna损伤反应有利于肿瘤的进展.pdfVIP

Retinoblastoma Loss Modulates DNA Damage Response Favoring Tumor Progression 1 1 2 2 3 Marcos Seoane , Pablo Iglesias , Teresa Gonzalez , Fernando Dominguez , Maximo Fraga , Carlos 3 3 1 Aliste , Jeronimo Forteza , Jose A. Costoya * 1 Molecular Oncology Lab, Departamento de Fisioloxia, Facultade de Medicina, Universidade de Santiago de Compostela, Santiago de Compostela, Spain, 2 Fundacion Galega de Medicina Xenomica, Servicio Galego de Saude, Santiago de Compostela, Spain, 3 Departamento de Anatomia Patoloxica e Ciencias Forenses, Universidade de Santiago de Compostela, Santiago de Compostela, Spain Abstract Senescence is one of the main barriers against tumor progression. Oncogenic signals in primary cells result in oncogene- induced senescence (OIS), crucial for protection against cancer development. It has been described in premalignant lesions that OIS requires DNA damage response (DDR) activation, safeguard of the integrity of the genome. Here we demonstrate how the cellular mechanisms involved in oncogenic transformation in a model of glioma uncouple OIS and DDR. We use this tumor type as a paradigm of oncogenic transformation. In human gliomas most of the genetic alterations that have been previously identified result in abnormal activation of cell growth signaling pathways and deregulation of cell cycle, features recapitulated in our model by oncogenic Ras expression and retinoblastoma (Rb) inactivation respectively. In this scenario, the absence of pRb confers a proliferative advantage and activates DDR to a greater extent in a DNA lesion- independent fashion than cells that express only HRasV12. Moreover, Rb loss inactivates the stress kinase DDR-associated