title: Molecular pathogenesis of tuber formation in tuberous sclerosis complex.
abstract: Tuberous sclerosis complex results from mutations in the TSC1 (hamartin) and TSC2 (tuberin) genes. Tubers are cortical developmental malformations in patients with tuberous sclerosis complex that are associated with intractable epilepsy and are composed of histologically distinct cell types, including giant cells and dysplastic neurons. We recently showed that tubers can be dynamic lesions characterized by populations of cells undergoing proliferation, migration, and death. We demonstrate that there is cell-specific activation of the mammalian target of rapamycin (mTOR)/p70S6 kinase/ribosomal S6 cascade in tubers and that giant cells express activated (phosphorylated) p70S6 kinase and ribosomal S6 protein. These findings support impaired hamartin- and tuberin-mediated mTOR pathway regulation. Tubers likely form by constitutive activation of the mTOR cascade during brain development as a consequence of impaired hamartin or tuberin function.
authors.affiliation: PENN Epilepsy Center and Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA. crinop@mail.med.upenn.edu
authors.forename: Peter B
authors.initials: PB
authors.lastname: Crino
mesh_terms: D001921:Brain / Q000254:growth & development / Q000473:pathology*; D049109:Cell Proliferation; D002648:Child; D004827:Epilepsy / Q000209:etiology; D016147:Genes, Tumor Suppressor; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics* / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000503:physiopathology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
chemical_list: D006133:Growth Substances; D011506:Proteins; D012097:Repressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases