Research ExplorerPublicationsRetinoblastoma loss modulates DNA damage response favoring t...

Retinoblastoma loss modulates DNA damage response favoring tumor progression

Standard

Retinoblastoma loss modulates DNA damage response favoring tumor progression. / Seoane, Marcos; Iglesias, Pablo; Gonzalez, Teresa; Dominguez, Fernando; Fraga, Maximo; Aliste, Carlos; Forteza, Jeronimo; Costoya, Jose A.

In: PLOS ONE, Vol. 3, No. 11, 2008, p. e3632.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Seoane, M, Iglesias, P, Gonzalez, T, Dominguez, F, Fraga, M, Aliste, C, Forteza, J & Costoya, JA 2008, 'Retinoblastoma loss modulates DNA damage response favoring tumor progression', PLOS ONE, vol. 3, no. 11, pp. e3632. https://doi.org/10.1371/journal.pone.0003632

APA

Seoane, M., Iglesias, P., Gonzalez, T., Dominguez, F., Fraga, M., Aliste, C., Forteza, J., & Costoya, J. A. (2008). Retinoblastoma loss modulates DNA damage response favoring tumor progression. PLOS ONE, 3(11), e3632. https://doi.org/10.1371/journal.pone.0003632

Vancouver

Seoane M, Iglesias P, Gonzalez T, Dominguez F, Fraga M, Aliste C et al. Retinoblastoma loss modulates DNA damage response favoring tumor progression. PLOS ONE. 2008;3(11):e3632. https://doi.org/10.1371/journal.pone.0003632

Bibtex

@article{cbdf534471f642a6bdc3d4a787388d84,
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.",
keywords = "Animals, Animals, Newborn, Astrocytes/metabolism, Cell Proliferation, Cell Transformation, Neoplastic/genetics, Cells, Cultured, DNA Damage/physiology, Disease Progression, Genes, ras/physiology, Humans, Mice, Mice, SCID, Models, Biological, Neoplasms/genetics, Neovascularization, Pathologic/genetics, Retinoblastoma Protein/genetics, Transplantation, Heterologous, Tumor Burden/genetics",
author = "Marcos Seoane and Pablo Iglesias and Teresa Gonzalez and Fernando Dominguez and Maximo Fraga and Carlos Aliste and Jeronimo Forteza and Costoya, {Jose A}",
year = "2008",
doi = "10.1371/journal.pone.0003632",
language = "English",
volume = "3",
pages = "e3632",
journal = "PLOS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "11",

}

RIS

TY - JOUR

T1 - Retinoblastoma loss modulates DNA damage response favoring tumor progression

AU - Seoane, Marcos

AU - Iglesias, Pablo

AU - Gonzalez, Teresa

AU - Dominguez, Fernando

AU - Fraga, Maximo

AU - Aliste, Carlos

AU - Forteza, Jeronimo

AU - Costoya, Jose A

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

KW - Animals

KW - Animals, Newborn

KW - Astrocytes/metabolism

KW - Cell Proliferation

KW - Cell Transformation, Neoplastic/genetics

KW - Cells, Cultured

KW - DNA Damage/physiology

KW - Disease Progression

KW - Genes, ras/physiology

KW - Humans

KW - Mice

KW - Mice, SCID

KW - Models, Biological

KW - Neoplasms/genetics

KW - Neovascularization, Pathologic/genetics

KW - Retinoblastoma Protein/genetics

KW - Transplantation, Heterologous

KW - Tumor Burden/genetics

U2 - 10.1371/journal.pone.0003632

DO - 10.1371/journal.pone.0003632

M3 - SCORING: Journal article

C2 - 18985151

VL - 3

SP - e3632

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 11

ER -