No complementation between TP53 or RB-1 and v-src in astrocytomas of GFAP-v-src transgenic mice

Human low-grade astrocytomas frequently recur and progress to states of hig her malignancy. During tumor progression TP53 alterations are among the fir st 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 a nd 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 ov er 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 immunosta ining 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 n either loss of RB-1 nor of TP53 confer a growth advantage in vivo to preneo plastic astrocytes expressing v-src, and suggests that RB-1 and TP53 belong to one single complementation group along with v-src in this transgenic mo del of astrocytoma development. The stochastic development of astrocytic tu mors in GFAP-v-src, TP53(+/-) GFAP-v-src, and RB-1(+/-) GFAP-v-src transgen ic mice indicates that additional hitherto unknown genetic lesions of astro cytes contribute to tumorigenesis, whose elucidation may prove important fo r our understanding of astrocytoma initiation and progression.