title: Tuberous sclerosis complex 2 loss-of-function mutation regulates reactive oxygen species production through Rac1 activation.
abstract: The products of the TSC1 (hamartin) and TCS2 (tuberin) tumor suppressor genes negatively regulate cell growth by inhibiting mTOR signaling. Recent research has led to the postulation that tuberin and/or hamartin are involved in tumor migration, presumably through Rho activation. Here we show that LEF-8 cells, which contain a Y1571 missense mutation in tuberin, express higher Rac1 activity than tuberin negative and positive cells. We also provide evidence of obvious lamellipodia formation in LEF-8 cells. Since the production of TSC2(Y1571H) cannot form a hetero-complex with hamartin, we further analyzed another mutant, TSC2(R611Q), which also lacks the ability to form a complex with hamartin. Introducing both forms of mutated TSC2 into COS-1 cells increased Rac1 activity as well as cell motility. We also found these two mutants interacted with Rac1. We further demonstrated that the introduction of mutated TSC2 into COS-1 cells can generate higher reactive oxygen species (ROS). These results indicate that loss-of-function mutated tuberin can activate Rac1 and thereby increase ROS production.
authors.affiliation: Department of Applied Biology and Chemistry, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Suzuki
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Hirohumi
authors.initials: H
authors.lastname: Inoue
authors.forename: Machiko
authors.initials: M
authors.lastname: Kazami
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Yeung
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Tadokoro
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D051379:Mice; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D020830:rac1 GTP-Binding Protein