Retrovirus‐Mediated Oncogene Transfer into Neural Transplants

Od, Wiestler; Brüstle, Oliver; Rh, Eibl; Radner, H.; Aguzzi, Adriano; Kleihues, Paul

doi:10.1111/j.1750-3639.1991.tb00056.x

Cited by 24 publications

References 83 publications

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Tumor-derived p53 mutant C174Y is a gain-of-function mutant which activates the fos promoter and enhances colony formation

2000

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SV40 large T antigen–induced primitive neuroectodermal tumors of the rat provide a model system to study induction and progression of primitive neuroectodermal tumors at the molecular level. A cell line derived from such a tumor reproducibly gave rise to malignant derivatives that ceased large T‐antigen expression but harbored a mutant p53 allele with a common mutation at Cys174 to Tyr (C174Y). To determine whether this p53 mutation contributes to tumor progression, we analyzed mutant C174Y functionally. Co‐transfection experiments in Saos‐2 cells with mutant or wild‐type p53 and reporter genes linked to various p53‐responsive promoters revealed that mutant C174Y failed to transcriptionally transactivate the Mdm2, Waf1, Cyclin G and Bax promoters. Loss of transcriptional activation correlated with loss of DNA‐binding activity. Moreover, mutant C174Y exhibited a dominant negative effect on co‐expressed wild‐type p53. The ability of mutant p53 to repress the viral RSV, LTR or SV40 early promoters or the cellular fos promoter was likewise impaired. In contrast, it showed even induction of the fos promoter. Consistent with these observations, mutant C174Y was non‐functional in the suppression of Saos‐2 cell growth and even conferred a growth advantage to the cells. Surprisingly, mutant C174Y was also impaired in nuclear transport, as revealed by immunofluorescence analyses. Taken together, our results demonstrate that mutant C174Y possesses features that can positively contribute to cancer progression. Int. J. Cancer 88:162–171, 2000. © 2000 Wiley‐Liss, Inc.

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Tumor-derived p53 mutant C174Y is a gain-of-function mutant which activates the fos promoter and enhances colony formation

2000

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Transgenic and gene disruption techniques in the study of neurocarcinogenesis

Aguzzi

Brandner

Isenmann

et al. 1995

Glia

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Transgenic technologies have come of age, and the field of carcinogenesis has profited extensively from the availability of these methods. Both the inappropriate expression of dominant oncogenes in specific tissues and the ability to "knock out" tumor suppressor genes in mammalian organisms have enabled substantial advancements of our understanding of development and progression of the neoplastic phenotype. In the first part of this article, we review the most popular techniques for modification of the mammalian genome in vivo, i.e. microinjection of fertilized eggs, retrovirus-mediated gene transfer, and targeted gene deletion through homologous recombination. Subsequently, we attempt a critical evaluation of the available models of neurocarcinogenesis, and discuss their impact and future potential for the study of cancer in the nervous system.

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Overexpression of Pax5 is not sufficient for neoplastic transformation of mouse neuroectoderm

et al. 2001

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The developmental control genes of the Pax family are essential for brain development. Several Pax genes are also involved in chromosomal translocations causing malignancies in humans, and Pax5 expression is deregulated in medulloblastomas. We have investigated whether Pax5 can induce tumors in the developing mouse brain. Primary mouse embryonic neuroectodermal cells were retrovirally transduced with mouse Pax5 and transplanted into the brain of syngeneic host mice. No tumors developed in 36 transplants after one year, and there were no alterations in the differentiation pattern of the neural transplants. We then generated transgenic mice expressing human Pax5 under control of the Engrailed-2 promoter, which is expressed in the cerebellar external granule cell layer and in medulloblastomas. Sustained expression was achieved in the cerebellum of transgenic animals throughout lifetime. Expression levels were similar to those observed in human medulloblastomas. Again, cerebellar morphogenesis was undisturbed, and no tumors arose. These results strongly argue against a dominant transforming activity of PAX5 in NEC and in cerebellar granule cell precursors of mice, and underline the restricted tissue-specificity of PAX5 related oncogenesis.

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Retrovirus‐Mediated Oncogene Transfer into Neural Transplants

Cited by 24 publications

References 83 publications

Tumor-derived p53 mutant C174Y is a gain-of-function mutant which activates the fos promoter and enhances colony formation

Tumor-derived p53 mutant C174Y is a gain-of-function mutant which activates the fos promoter and enhances colony formation

Transgenic and gene disruption techniques in the study of neurocarcinogenesis

Overexpression of Pax5 is not sufficient for neoplastic transformation of mouse neuroectoderm

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