Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma.
Malignant astrocytoma, the most prevalent primary brain tumor, is resistant to all known therapies and frequently harbors mutations that inactivate p53 and activate Ras signaling. We have generated mouse strains that lack p53 and harbor a conditional allele of the NF1 tumor suppressor that negatively regulates Ras signaling. The mice develop malignant astrocytomas with complete penetrance. The majority of tumors display characteristics of glioblastoma multiforme with concomitant alteration of signaling pathways previously described in the human counterparts of this neoplasm. We find that the sequence of tumor suppressor inactivation influences tumorigenicity and that earliest evidence of tumor formation localizes to regions of the brain that contain a multipotent stem cell population capable of in vivo differentiation into neurons and glia.
Zhu
Yuan
Y
Center for Developmental Biology and Kent Waldrep Foundation Center for Basic Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Guignard
Frantz
F
Zhao
Dawen
D
Liu
Li
L
Burns
Dennis K
DK
Mason
Ralph P
RP
Messing
Albee
A
Parada
Luis F
LF
D000818:Animals; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D020868:Gene Silencing; D016514:Genes, Neurofibromatosis 1; D016158:Genes, p53 / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D019683:Penetrance; D013234:Stem Cells / Q000473:pathology