Transgenic expression of dominant negative tuberin through a strong constitutive promoter results in a tissue-specific tuberous sclerosis phenotype in the skin and brain

Baskaran Govindarajan, Daniel J. Brat, Marie Csete, William D. Martin, Emma Murad, Karin Litani, Cynthia Cohen, Francesca Cerimele, Matthew Nunnelley, Benjamin Lefkove, Toshiyuki Yamamoto, Chunsik Lee, Jack L. Arbiser*

*Corresponding author for this work

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Tuberous sclerosis (TS) is a common autosomal dominant disorder caused by loss or malfunction of hamartin (tsc1) or tuberin (tsc2). Many lesions in TS do not demonstrate loss of heterozygosity for these genes, implying that dominant negative forms of these genes may account for some hamartomas and neoplasms in TS. To test this hypothesis, we expressed a dominant negative allele of tuberin (ΔRG) behind the cytomegalovirus promoter in NIH3T3 cells and transgenic mice. This allele binds hamartin but has a deletion in the C terminus of tuberin, leading to constitutive activation of rap1 and rab5/rabaptin. Expression of ΔRG in NIH3T3 cells led to a strong induction of reactive oxygen species, induction of vascular endothelial growth factor, and malignant transformation in vivo. Expression of ΔRG driven by the constitutive cytomegalovirus promoter led to high level expression in all murine tissues examined, including skin, kidney, liver, and brain. Surprisingly, mice expressing the ΔRG transgene developed a fibrovascular collagenoma in the dermis, which closely resembles the Shagreen patch observed in human patients with TS. In addition, numerous small subpial collections of external granule cells in the cerebellum were observed, which may be the murine equivalent of subependymal giant cell astrocytomas or tubers commonly seen in TS patients. Thus, expression of a dominant negative tuberin in multiple tissues can lead to a tissue-specific phenotype resembling some of the findings in human TS. Our data are the first to demonstrate that specific signaling abnormalities underlie specific hamartomas in a model of a human genetic disorder.

Original languageEnglish (US)
Pages (from-to)5870-5874
Number of pages5
JournalJournal of Biological Chemistry
Volume280
Issue number7
DOIs
StatePublished - Feb 18 2005

ASJC Scopus subject areas

  • Biochemistry

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    Govindarajan, B., Brat, D. J., Csete, M., Martin, W. D., Murad, E., Litani, K., Cohen, C., Cerimele, F., Nunnelley, M., Lefkove, B., Yamamoto, T., Lee, C., & Arbiser, J. L. (2005). Transgenic expression of dominant negative tuberin through a strong constitutive promoter results in a tissue-specific tuberous sclerosis phenotype in the skin and brain. Journal of Biological Chemistry, 280(7), 5870-5874. https://doi.org/10.1074/jbc.M411768200