Upregulation of the WNT pathway in tuberous sclerosis-associated subependymal giant cell astrocytomas

Brain Dev. 2007 Jun;29(5):273-80. doi: 10.1016/j.braindev.2006.09.009. Epub 2006 Oct 27.

Abstract

Tuberous sclerosis (TS), autosomal dominant disorder manifested by the formation of usually benign tumors in the brain, heart, kidneys and skin, results from an inactivating mutation in one of two tumor suppressor genes TSC1 or TSC2. Protein products of these genes, hamartin and tuberin, respectively, have been shown to participate in the mTOR pathway controlling translation of approx. 10-15% of all proteins. In the current paper, we aimed at verifying whether hamartin and tuberin may also be implicated in the control of gene transcription. Very recently it has been hypothesized that the pathway triggered by WNT, one of embryonic growth factors involved in cell differentiation and migration, could be disturbed in TS. In order to test this hypothesis we evaluated samples of four subependymal giant cell astrocytomas (SEGAs), brain tumors developing in the progress of TS. We found that beta-catenin, transcription factor and mediator of WNT pathway activity is indeed present and active in SEGAs. mRNA transcripts for c-Myc and N-Myc, proteins whose transcription is regulated by beta-catenin, were upregulated in two of four SEGAs, while cyclin D1 mRNA was significantly higher in three SEGAs. At the same time, c-Myc and N-Myc proteins were detected in the same two samples. Thus, we show for the first time that aberrant WNT signaling may contribute to the pathogenesis of TS-associated SEGAs.

MeSH terms

  • Astrocytoma / complications*
  • Astrocytoma / physiopathology*
  • Blotting, Western
  • Brain Neoplasms / complications*
  • Brain Neoplasms / physiopathology*
  • Cell Nucleus / genetics
  • Cyclin D1 / genetics
  • Cyclin D1 / physiology
  • Genes, myc / physiology
  • Humans
  • Immunohistochemistry
  • Nerve Tissue Proteins / metabolism
  • Phosphorylation
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Transcription, Genetic
  • Translocation, Genetic / genetics
  • Tuberous Sclerosis / etiology*
  • Tuberous Sclerosis / physiopathology*
  • Up-Regulation / physiology*
  • Wnt Proteins / physiology*
  • beta Catenin / biosynthesis
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Nerve Tissue Proteins
  • RNA, Messenger
  • Wnt Proteins
  • beta Catenin
  • Cyclin D1