RT Journal Article
T1 Retinoblastoma Loss Modulates DNA Damage Response Favoring Tumor Progression
A1 Seoane, Marcos
A1 Iglesias, Pablo
A1 González Martínez, Teresa
A1 Domínguez Puente, Fernando
A1 Fraga Rodríguez, Máximo
A1 Aliste Santos, Carlos
A1 Forteza Vila, Jerónimo
A1 Costoya Puente, José Antonio
AB Senescence is one of the main barriers against tumor progression. Oncogenic signals in primary cells result in oncogeneinduced senescence (OIS), crucial for protection against cancer development. It has been described in premalignant lesionsthat OIS requires DNA damage response (DDR) activation, safeguard of the integrity of the genome. Here we demonstratehow the cellular mechanisms involved in oncogenic transformation in a model of glioma uncouple OIS and DDR. We usethis tumor type as a paradigm of oncogenic transformation. In human gliomas most of the genetic alterations that havebeen 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 thisscenario, the absence of pRb confers a proliferative advantage and activates DDR to a greater extent in a DNA lesionindependent fashion than cells that express only HRasV12. Moreover, Rb loss inactivates the stress kinase DDR-associatedp38MAPK by specific Wip1-dependent dephosphorylation. Thus, Rb loss acts as a switch mediating the transition betweenpremalignant lesions and cancer through DDR modulation. These findings may have important implications for theunderstanding the biology of gliomas and anticipate a new target, Wip1 phosphatase, for novel therapeutic strategies.
PB PLOS
YR 2008
FD 2008
LK http://hdl.handle.net/10347/22889
UL http://hdl.handle.net/10347/22889
LA eng
NO Seoane M, Iglesias P, Gonzalez T, Dominguez F, Fraga M, Aliste C, et al. (2008) Retinoblastoma Loss Modulates DNA Damage Response Favoring Tumor Progression. PLoS ONE 3(11): e3632. https://doi.org/10.1371/journal.pone.0003632
NO This study was supported by Spanish Ministry of Education and Science (SAF2005-00306) and Xunta de Galicia grants (PGIDIT05PXIB20801PR); Grupos emerxentes 2007/064) (J.A.C.), and by Fundacion de Investigación Medica Mutua Madrileña (J.A.C., P.I.). J.A.C. is an Investigator of Ramon y Cajal Programme (Spanish Ministry of Education and Science)
DS Minerva
RD 23 abr 2026