Open AccessNo Complementation Between TP53 or RB‐1 and v‐ src in Astrocytomas of GFAP‐v‐ src Transgenic Mice
Author(s) -
Maddalena Alessia S.,
Hainfellner Johannes A.,
Hegi Monika E.,
Glatzel Markus,
Aguzzi Adriano
Publication year - 1999
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/j.1750-3639.1999.tb00544.x
Subject(s) - proto oncogene tyrosine protein kinase src , genetically modified mouse , biology , glial fibrillary acidic protein , transgene , astrocytoma , immunostaining , complementation , cancer research , astrocyte , microbiology and biotechnology , tumor progression , pathology , immunohistochemistry , glioma , cancer , genetics , gene , immunology , medicine , endocrinology , phenotype , signal transduction , central nervous system
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.