Transgenic E2F1 expression in the mouse brain induces a human-like bimodal pattern of tumors.
The Rb/E2F pathway is deregulated in most human brain tumors, and the finding that loss of E2F1 reduced pituitary tumorigenesis in Rb(+/-) mice suggests that loss of pRb induces brain tumors by activating E2F1. We therefore investigated the role of E2F1 in the development and maintenance of brain cancer using a transgenic mouse model engineered to express E2F1 specifically within glial cells (GFAP-tgE2F1). GFAP-tgE2F1 mice developed a highly penetrant phenotype characterized by neurologic defects, and examination of the brains revealed the presence of brain tumors in 20% of these animals. Importantly, the distribution of tumors according to mouse age suggests the existence of a bimodal pattern of tumor development, forcing a comparison with the human disease. Mice, at an early age, with deregulated E2F1 show the formation of embryonal brain tumors such as medulloblastoma, choroid plexus carcinoma, and primary neuroectodermal tumor. Conversely, at an older age, mice escaping embryonal tumor formation present with malignant gliomas, which are typically identified in the human adult population. Thus, this study offers the first evidence for a global role of E2F1 in the formation and maintenance of multilineage brain tumors, irrefutably establishing E2F1 as an oncogene in the brain.
Olson
Melissa V
MV
Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Johnson
David G
DG
Jiang
Hong
H
Xu
Jing
J
Alonso
Marta M
MM
Aldape
Kenneth D
KD
Fuller
Gregory N
GN
Bekele
B Nebiyou
BN
Yung
W K Alfred
WK
Gomez-Manzano
Candelaria
C
Fueyo
Juan
J
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009857:Oncogenes
D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human