No Complementation Between TP53 or RB-1 and v-srcin Astrocytomas of GFAP-v-srcTransgenic Mice
| Autor: | Alessia Maddalena, Markus Glatzel, Monika E. Hegi, Johannes A. Hainfellner, Adriano Aguzzi |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Male
Genetically modified mouse Pathology medicine.medical_specialty Carcinogenicity Tests Transgene Mice Transgenic Astrocytoma Biology medicine.disease_cause Polymerase Chain Reaction Retinoblastoma Protein Pathology and Forensic Medicine Mice p14arf Glial Fibrillary Acidic Protein Tumor Cells Cultured medicine Animals neoplasms Polymorphism Single-Stranded Conformational Glial fibrillary acidic protein Brain Neoplasms General Neuroscience Genetic Complementation Test medicine.disease Gene Expression Regulation Neoplastic Mice Inbred C57BL Genes src Tumor progression Cancer research biology.protein Female Neurology (clinical) Tumor Suppressor Protein p53 Carcinogenesis Immunostaining Research Article |
| Zdroj: | Brain Pathol |
| ISSN: | 1015-6305 |
| DOI: | 10.1111/j.1750-3639.1999.tb00544.x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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