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Pathogenesis of Tuberous Sclerosis Subependymal Giant Cell Astrocytomas: Biallelic Inactivation of TSC1 or TSC2 Leads to mTOR Activation

Journal of neuropathology and experimental neurology, 2004-12, Vol.63 (12), p.1236-1242 [Peer Reviewed Journal]

2004 American Association of Neuropathologists, Inc ;2005 INIST-CNRS ;Copyright American Association of Neuropathologists, Inc. Dec 2004 ;ISSN: 0022-3069 ;EISSN: 1554-6578 ;DOI: 10.1093/jnen/63.12.1236 ;PMID: 15624760 ;CODEN: JNENAD

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Title:
Pathogenesis of Tuberous Sclerosis Subependymal Giant Cell Astrocytomas: Biallelic Inactivation of TSC1 or TSC2 Leads to mTOR Activation
Author: CHAN, JENNIFER A ; ZHANG, HONGBING ; ROBERTS, PENELOPE S ; JOZWIAK, SERGIUSZ ; WIESLAWA, GRAJKOWSKA ; LEWIN-KOWALIK, JOANNA ; KOTULSKA, KATARZYNA ; KWIATKOWSKI, DAVID J
Subjects: Adolescent ; Alleles ; Astrocytoma - etiology ; Astrocytoma - genetics ; Astrocytoma - metabolism ; Biological and medical sciences ; Cerebral Ventricle Neoplasms - etiology ; Cerebral Ventricle Neoplasms - genetics ; Cerebral Ventricle Neoplasms - metabolism ; Child ; Child, Preschool ; DNA-Binding Proteins - metabolism ; Female ; Female genital diseases ; Gene Expression Regulation ; Gene Silencing ; Genes, Tumor Suppressor ; Gynecology. Andrology. Obstetrics ; Humans ; Lateral Ventricles ; Loss of Heterozygosity ; Male ; Medical sciences ; Mutation ; Neurology ; Phosphorylation ; Protein Kinases - genetics ; Protein Kinases - metabolism ; Proteins - genetics ; Repressor Proteins - genetics ; Ribosomal Protein S6 - metabolism ; Ribosomal Protein S6 Kinases - metabolism ; Signal Transduction ; STAT3 Transcription Factor ; TOR Serine-Threonine Kinases ; Trans-Activators - metabolism ; Tuberous Sclerosis - complications ; Tuberous Sclerosis - genetics ; Tuberous Sclerosis Complex 1 Protein ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins ; Tumors ; Tumors of the nervous system. Phacomatoses
Is Part Of: Journal of neuropathology and experimental neurology, 2004-12, Vol.63 (12), p.1236-1242
Description: In the central nervous system, tuberous sclerosis complex (TSC) is characterized by a range of lesions including cortical tubers, white matter heterotopias, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs). Recent studies have implicated an important role for the TSC genes TSC1 and TSC2, in a signaling pathway involving the mammalian target of rapamycin (mTOR) kinase. We performed immunohistochemical and genetic analyses on SEGAs from 7 TSC patients, 4 with mutations in TSC1, and 3 with mutations in TSC2. SEGA cells show high levels of phospho-S6K, phospho-S6, and phospho-Stat3, all proteins downstream of and indicative of mTOR activation. Such expression is not seen in histologically normal control tissue. Five of 6 SEGAs also showed evidence of biallelic mutation of TSC1 or TSC2, suggesting that SEGAs develop due to complete loss of a functional tuberin-hamartin complex. We conclude that TSC SEGAs likely arise through a two-hit mechanism of biallelic inactivation of TSC1 or TSC2, leading to activation of the mTOR kinase.
Publisher: Hagerstown, MD: American Association of Neuropathologists, Inc
Language: English
Identifier: ISSN: 0022-3069
EISSN: 1554-6578
DOI: 10.1093/jnen/63.12.1236
PMID: 15624760
CODEN: JNENAD
Source: MEDLINE
ProQuest Central

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Pathogenesis of Tuberous Sclerosis Subependymal Giant Cell Astrocytomas: Biallelic Inactivation of TSC1 or TSC2 Leads to mTOR Activation

2004 American Association of Neuropathologists, Inc ;2005 INIST-CNRS ;Copyright American Association of Neuropathologists, Inc. Dec 2004 ;ISSN: 0022-3069 ;EISSN: 1554-6578 ;DOI: 10.1093/jnen/63.12.1236 ;PMID: 15624760 ;CODEN: JNENAD

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