title: No complementation between TP53 or RB-1 and v-src in astrocytomas of GFAP-v-src transgenic mice.
abstract: Human low-grade astrocytomas frequently recur and progress to states of higher malignancy. During tumor progression TP53 alterations are among the first genetic changes, while derangement of the p16/p14ARF/RB-1 system occurs later. To probe the pathogenetic significance of TP53 and RB-1 alterations, we introduced a v-src transgene driven by glial fibrillary acidic protein (GFAP) regulatory elements (which causes preneoplastic astrocytic lesions and stochastically astrocytomas of varying degrees of malignancy) into TP53+/- or RB-1+/- mice. Hemizygosity for TP53 or RB-1 did not increase the incidence or shorten the latency of astrocytic tumors in GFAP-v-src mice over a period of up to 76 weeks. Single strand conformation analysis of exons 5 to 8 of non-ablated TP53 alleles revealed altered migration patterns in only 3/16 tumors analyzed. Wild-type RB-1 alleles were retained in all RB-1+/-GFAP-v-src mice-derived astrocytic tumors analyzed, and pRb immunostaining revealed protein expression in all tumors. Conversely, the GFAP-v-src transgene did not influence the development of extraneural tumors related to TP53 or RB-1 hemizygosity. Therefore, the present study indicates that neither loss of RB-1 nor of TP53 confer a growth advantage in vivo to preneoplastic astrocytes expressing v-src, and suggests that RB-1 and TP53 belong to one single complementation group along with v-src in this transgenic model of astrocytoma development. The stochastic development of astrocytic tumors in GFAP-v-src, TP53+/- GFAP-v-src, and RB-1+/- GFAP-v-src transgenic mice indicates that additional hitherto unknown genetic lesions of astrocytes contribute to tumorigenesis, whose elucidation may prove important for our understanding of astrocytoma initiation and progression.
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Switzerland.
authors.forename: A S
authors.initials: AS
authors.lastname: Maddalena
authors.forename: J A
authors.initials: JA
authors.lastname: Hainfellner
authors.forename: M E
authors.initials: ME
authors.lastname: Hegi
authors.forename: M
authors.initials: M
authors.lastname: Glatzel
authors.forename: A
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D001932:Brain Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D015197:Carcinogenicity Tests; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016391:Genes, src / Q000235:genetics*; D005816:Genetic Complementation Test; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D016160:Retinoblastoma Protein / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53