Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2 +/- cells

Erik J. Uhlmann, Anthony J. Apicelli, Rebecca L. Baldwin, Stephen P. Burke, M. Livia Bajenaru, Hiroaki Onda, David Kwiatkowski, David H. Gutmann

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57 Scopus citations

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor predisposition syndrome characterized by benign proliferations (hamartomas). In the brain, individuals with TSC develop autism, mental retardation and seizures associated with focal cortical dysplasias, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs). We hypothesize that dysregulated astrocyte function due to mutations in the tumor suppressor genes, TSC1 and TSC2, may contribute to the pathogenesis of these brain abnormalities. In this report, we demonstrate that mice heterozygous for a targeted defect in either the Tsc1 or Tsc2 genes (Tsc1+/- and Tsc2+/- mice) exhibit a 1.5-fold increase in the number of astrocytes in vivo. Whereas increased astrocyte numbers in vivo were suggestive of a proliferative advantage, Tsc2+/- primary astrocyte cultures did not show a cell-autonomous growth advantage, anchorage-independent growth, increased saturation density, or increased fluid-phase endocytosis compared to wild type astrocytes. Tsc2 null mouse embryonic fibroblasts (MEFs) however, did exhibit increased saturation density compared to Tsc2 wild type controls. In both Tsc2+/- astrocytes and Tsc2 null mouse embryonic fibroblasts, p27-Kip1 expression was decreased compared to wild type cells, and was reversed by tuberin re-expression in Tsc2-/- MEFs. In contrast, no change in endocytosis was observed upon tuberin re-expression in Tsc2-/- MEFs. Collectively, these results suggest Tsc heterozygosity may provide a non-cell-autonomous growth advantage for astrocytes that may involve p27-Kip1 expression.

Original languageEnglish (US)
Pages (from-to)4050-4059
Number of pages10
JournalOncogene
Volume21
Issue number25
DOIs
StatePublished - Jan 1 2002

Keywords

  • Astrocytoma
  • Glia
  • Hamartin
  • Tuberin
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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    Uhlmann, E. J., Apicelli, A. J., Baldwin, R. L., Burke, S. P., Livia Bajenaru, M., Onda, H., Kwiatkowski, D., & Gutmann, D. H. (2002). Heterozygosity for the tuberous sclerosis complex (TSC) gene products results in increased astrocyte numbers and decreased p27-Kip1 expression in TSC2 +/- cells. Oncogene, 21(25), 4050-4059. https://doi.org/10.1038/sj.onc.1205435