Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation.
We have inactivated pRb, p107, and p130 in astrocytes by transgenic expression of T(121) (a truncated SV40 T antigen) under the GFAP promoter. Founder mice died perinatally with extensive expansion of neural precursor and anaplastic astrocyte populations. In astrocytes, aberrant proliferation and extensive apoptosis were induced. Using a conditional allele of T(121), early lethality was circumvented, and adult mice developed high-grade astrocytoma, in which regions of decreased apoptosis expressed activated Akt. Indeed, astrocytoma development was accelerated in a PTEN(+/-), but not p53(+/-), background. These studies establish a highly penetrant preclinical model for astrocytoma based on events observed in the human disease and further provide insight into the role of PTEN mutation in astrocytoma progression.
Xiao
Andrew
A
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Wu
Hua
H
Pandolfi
Pier Paolo
PP
Louis
David N
DN
Van Dyke
Terry
T
D000375:Aging; D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D001921:Brain / Q000002:abnormalities / Q000473:pathology; D002455:Cell Division; D004789:Enzyme Activation; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009928:Organ Specificity; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase