title: Upregulation of the WNT pathway in tuberous sclerosis-associated subependymal giant cell astrocytomas.
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.
authors.affiliation: Department of Histology and Embryology, Center for Biostructure Research, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Jozwiak
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kotulska
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Grajkowska
authors.forename: Sergiusz
authors.initials: S
authors.lastname: Jozwiak
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zalewski
authors.forename: Monika
authors.initials: M
authors.lastname: Oldak
authors.forename: Magdalena
authors.initials: M
authors.lastname: Lojek
authors.forename: Kamila
authors.initials: K
authors.lastname: Rainko
authors.forename: Radosław
authors.initials: R
authors.lastname: Maksym
authors.forename: Maciej
authors.initials: M
authors.lastname: Lazarczyk
authors.forename: Piotr
authors.initials: P
authors.lastname: Skopinski
authors.forename: Pawel
authors.initials: P
authors.lastname: Wlodarski
mesh_terms: D001254:Astrocytoma / Q000150:complications* / Q000503:physiopathology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000150:complications* / Q000503:physiopathology*; D002467:Cell Nucleus / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology; D016259:Genes, myc / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D014178:Translocation, Genetic / Q000235:genetics; D014402:Tuberous Sclerosis / Q000209:etiology* / Q000503:physiopathology*; D015854:Up-Regulation / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1