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Retinoblastoma loss modulates DNA damage response favoring tumor progression.

Seoane M, Iglesias P, Gonzalez T, Dominguez F, Fraga M, Aliste C, Forteza J, Costoya JA - PLoS ONE (2008)

Bottom Line: It has been described in premalignant lesions that OIS requires DNA damage response (DDR) activation, safeguard of the integrity of the genome.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.Moreover, Rb loss inactivates the stress kinase DDR-associated p38MAPK by specific Wip1-dependent dephosphorylation.

View Article: PubMed Central - PubMed

Affiliation: Molecular Oncology Lab, Departamento de Fisioloxia, Facultade de Medicina, 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 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.

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DDR is modulated by Rb loss switching premalignant lesion to cancer.
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pone-0003632-g006: DDR is modulated by Rb loss switching premalignant lesion to cancer.

Mentions: Given that p38MAPK-deficient cells are sensitized to HRasV12-induced transformation [25] and although the inactivation of Wip1 is related to the inhibition of tumorigenesis [55], our data point out that the cooperation between Ras and loss of Rb could be due to the increase of Wip1 and consequently p38MAPK inactivation. In this way, Rb loss in HRasV12-expressing astrocytes confers a double advantage. On one hand, Rb absence increases the astrocytes proliferative rate but on the other hand, in a Rb knock-out context, E2F-1 is activated and up-regulates both DNA damage response in an DNA damage-independent manner, favoring repair mechanisms, and Wip1 [30], leading to an inactivation of p38MAPK and thus increasing cellular transformation. All of this may explain the low latency of cRb−/−/RasV12 tumors versus cRbloxP/loxP/RasV12 tumors and the high Wip1 expression observed in high-grade human gliomas. Interestingly enough, Wip1 chemical inhibition in cRb−/−/RasV12 astrocytes leads to a significant fall in the proliferative rate of these cells, which eventually enter senescence as opposed to cells where Wip1 remains unaffected. Lately, several authors have proposed the use of selective therapeutic inhibitors targeting Wip1 as a promising treatment for different types of cancer [56]–[58]. This study sheds new lights on the possible mechanisms behind the progression from preneoplastic lesions to malignant tumors (Figure 6), and according to our glioma model identifies Wip1 as a potential druggable target for new therapeutic approaches for a tumor whose bad prognosis has not significantly changed over the past two decades.


Retinoblastoma loss modulates DNA damage response favoring tumor progression.

Seoane M, Iglesias P, Gonzalez T, Dominguez F, Fraga M, Aliste C, Forteza J, Costoya JA - PLoS ONE (2008)

DDR is modulated by Rb loss switching premalignant lesion to cancer.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2573954&req=5

pone-0003632-g006: DDR is modulated by Rb loss switching premalignant lesion to cancer.
Mentions: Given that p38MAPK-deficient cells are sensitized to HRasV12-induced transformation [25] and although the inactivation of Wip1 is related to the inhibition of tumorigenesis [55], our data point out that the cooperation between Ras and loss of Rb could be due to the increase of Wip1 and consequently p38MAPK inactivation. In this way, Rb loss in HRasV12-expressing astrocytes confers a double advantage. On one hand, Rb absence increases the astrocytes proliferative rate but on the other hand, in a Rb knock-out context, E2F-1 is activated and up-regulates both DNA damage response in an DNA damage-independent manner, favoring repair mechanisms, and Wip1 [30], leading to an inactivation of p38MAPK and thus increasing cellular transformation. All of this may explain the low latency of cRb−/−/RasV12 tumors versus cRbloxP/loxP/RasV12 tumors and the high Wip1 expression observed in high-grade human gliomas. Interestingly enough, Wip1 chemical inhibition in cRb−/−/RasV12 astrocytes leads to a significant fall in the proliferative rate of these cells, which eventually enter senescence as opposed to cells where Wip1 remains unaffected. Lately, several authors have proposed the use of selective therapeutic inhibitors targeting Wip1 as a promising treatment for different types of cancer [56]–[58]. This study sheds new lights on the possible mechanisms behind the progression from preneoplastic lesions to malignant tumors (Figure 6), and according to our glioma model identifies Wip1 as a potential druggable target for new therapeutic approaches for a tumor whose bad prognosis has not significantly changed over the past two decades.

Bottom Line: It has been described in premalignant lesions that OIS requires DNA damage response (DDR) activation, safeguard of the integrity of the genome.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.Moreover, Rb loss inactivates the stress kinase DDR-associated p38MAPK by specific Wip1-dependent dephosphorylation.

View Article: PubMed Central - PubMed

Affiliation: Molecular Oncology Lab, Departamento de Fisioloxia, Facultade de Medicina, 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 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.

Show MeSH
Related in: MedlinePlus