Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis.
Nat Cell Biol
; 9(5): 493-505, 2007 May.
Article
em En
| MEDLINE
| ID: mdl-17450133
ABSTRACT
Activating Ras mutations can induce either proliferation or senescence depending on the cellular context. To determine whether Ras activation has context-dependent effects in the mammary gland, we generated doxycycline-inducible transgenic mice that permit Ras activation to be titrated. Low levels of Ras activation - similar to those found in non-transformed mouse tissues expressing endogenous oncogenic Kras2 - stimulate cellular proliferation and mammary epithelial hyperplasias. In contrast, high levels of Ras activation - similar to those found in tumours bearing endogenous Kras2 mutations - induce cellular senescence that is Ink4a-Arf- dependent and irreversible following Ras downregulation. Chronic low-level Ras induction results in tumour formation, but only after the spontaneous upregulation of activated Ras and evasion of senescence checkpoints. Thus, high-level, but not low-level, Ras activation activates tumour suppressor pathways and triggers an irreversible senescent growth arrest in vivo. We suggest a three-stage model for Ras-induced tumorigenesis consisting of an initial activating Ras mutation, overexpression of the activated Ras allele and, finally, evasion of p53-Ink4a-Arf-dependent senescence checkpoints.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Lesões Pré-Cancerosas
/
Proteína Oncogênica p21(ras)
/
Transformação Celular Neoplásica
/
Senescência Celular
/
Células Epiteliais
/
Glândulas Mamárias Animais
/
Neoplasias Mamárias Experimentais
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Nat Cell Biol
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Estados Unidos