Loss of Tsc1 accelerates malignant gliomagenesis when combined with oncogenic signals

Daisuke Yamada, Takayuki Hoshii, Shingo Tanaka, Ahmed M. Hegazy, Masahiko Kobayashi, Yuko Tadokoro, Kumiko Ohta, Masaya Ueno, Mohamed A.E. Ali, Atsushi Hirao

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Glioblastomas frequently harbour genetic lesions that stimulate the activity of mammalian target of rapamycin complex 1 (mTORC1). Loss of heterozygosity of tuberous sclerosis complex 1 (TSC1) or TSC2, which together form a critical negative regulator of mTORC1, is also seen in glioblastoma; however, it is not known how loss of the TSC complex affects the development of malignant gliomas. Here we investigated the role of Tsc1 in gliomagenesis in mice. Tsc1 deficiency up-regulated mTORC1 activity and suppressed the proliferation of neural stem/progenitor cells (NSPCs) in a serial neurosphere-forming assay, suggesting that Tsc1-deficient NSPCs have defective self-renewal activity. The neurosphere-forming capacity of Tsc1-deficient NSPCs was restored by p16Ink4ap19Arf deficiency. Combined Tsc1 and p16Ink4ap19Arf deficiency in NSPCs did not cause gliomagenesis in vivo. However, in a glioma model driven by an active mutant of epidermal growth factor receptor (EGFR), EGFRvIII, loss of Tsc1 resulted in an earlier onset of glioma development. The mTORC1 hyperactivation by Tsc1 deletion accelerated malignant phenotypes, including increased tumour mass and enhanced microvascular formation, leading to intracranial haemorrhage. These data demonstrate that, although mTORC1 hyperactivation itself may not be sufficient for gliomagenesis, it is a potent modifier of glioma development when combined with oncogenic signals.

Original languageEnglish
Pages (from-to)227-233
Number of pages7
JournalJournal of biochemistry
Volume155
Issue number4
DOIs
Publication statusPublished - Apr 2014
Externally publishedYes

Keywords

  • TSC1
  • gliomagenesis
  • mTORC1
  • neural stem
  • progenitor cells

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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  • Cite this

    Yamada, D., Hoshii, T., Tanaka, S., Hegazy, A. M., Kobayashi, M., Tadokoro, Y., Ohta, K., Ueno, M., Ali, M. A. E., & Hirao, A. (2014). Loss of Tsc1 accelerates malignant gliomagenesis when combined with oncogenic signals. Journal of biochemistry, 155(4), 227-233. https://doi.org/10.1093/jb/mvt112