title: Retinoblastoma loss modulates DNA damage response favoring tumor progression.
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 HRas(V12). Moreover, Rb loss inactivates the stress kinase DDR-associated p38MAPK by specific Wip1-dependent dephosphorylation. Thus, Rb loss acts as a switch mediating the transition between premalignant lesions and cancer through DDR modulation. These findings may have important implications for the understanding the biology of gliomas and anticipate a new target, Wip1 phosphatase, for novel therapeutic strategies.
authors.affiliation: Molecular Oncology Lab, Departamento de Fisioloxia, Facultade de Medicina, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Seoane
authors.forename: Pablo
authors.initials: P
authors.lastname: Iglesias
authors.forename: Teresa
authors.initials: T
authors.lastname: Gonzalez
authors.forename: Fernando
authors.initials: F
authors.lastname: Dominguez
authors.forename: Maximo
authors.initials: M
authors.lastname: Fraga
authors.forename: Carlos
authors.initials: C
authors.lastname: Aliste
authors.forename: Jeronimo
authors.initials: J
authors.lastname: Forteza
authors.forename: Jose A
authors.initials: JA
authors.lastname: Costoya
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology; D018450:Disease Progression; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics
chemical_list: D016160:Retinoblastoma Protein