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Notch1-induced brain tumor models the sonic hedgehog subgroup of human medulloblastoma.
Natarajan, Sivaraman; Li, Yaochen; Miller, Emily E; Shih, David J; Taylor, Michael D; Stearns, Timothy M; Bronson, Roderick T; Ackerman, Susan L; Yoon, Jeong K; Yun, Kyuson.
Afiliación
  • Natarajan S; The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609, USA.
Cancer Res ; 73(17): 5381-90, 2013 Sep 01.
Article en En | MEDLINE | ID: mdl-23852537
ABSTRACT
While activation of the Notch pathway is observed in many human cancers, it is unknown whether elevated Notch1 expression is sufficient to initiate tumorigenesis in most tissues. To test the oncogenic potential of Notch1 in solid tumors, we expressed an activated form of Notch1 (N1ICD) in the developing mouse brain. N1ICD;hGFAP-cre mice were viable but developed severe ataxia and seizures, and died by weaning age. Analysis of transgenic embryo brains revealed that N1ICD expression induced p53-dependent apoptosis. When apoptosis was blocked by genetic deletion of p53, 30% to 40% of N1ICD;GFAP-cre;p53(+/-) and N1ICD;GFAP-cre;p53(-/-) mice developed spontaneous medulloblastomas. Interestingly, N1ICD-induced medulloblastomas most closely resembled the sonic hedgehog subgroup of human medulloblastoma at the molecular level. Surprisingly, N1ICD-induced tumors do not maintain high levels of the Notch pathway gene expression, except for Notch2, showing that initiating oncogenic events may not be decipherable by analyzing growing tumors in some cases. In summary, this study shows that Notch1 has an oncogenic potential in the brain when combined with other oncogenic hits, such as p53 loss, and provides a novel mouse model of medulloblastoma. Cancer Res; 73(17); 5381-90. ©2013 AACR.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Biomarcadores de Tumor / Neoplasias Cerebelosas / Receptor Notch1 / Proteínas Hedgehog / Meduloblastoma Límite: Animals / Humans Idioma: En Revista: Cancer Res Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Biomarcadores de Tumor / Neoplasias Cerebelosas / Receptor Notch1 / Proteínas Hedgehog / Meduloblastoma Límite: Animals / Humans Idioma: En Revista: Cancer Res Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos