Tuberous sclerosis complex 2 loss-of-function mutation regulates reactive oxygen species production through Rac1 activation |
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Authors: | Suzuki Tsukasa Das Swadesh K Inoue Hirohumi Kazami Machiko Hino Okio Kobayashi Toshiyuki Yeung Raymond S Kobayashi Ken-Ichi Tadokoro Tadahiro Yamamoto Yuji |
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Affiliation: | a Department of Applied Biology and Chemistry, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya-ku, Tokyo 156-8502, Japan b Department of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan c Department of Surgery and Pathology, University of Washington, 1959 NE Pacific St. Box 356410, Seattle, WA 98195, USA |
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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 TSC2Y1571H cannot form a hetero-complex with hamartin, we further analyzed another mutant, TSC2R611Q, 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. |
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Keywords: | Tuberous sclerosis complex (TSC) Tuberin Hamartin Rac1 Reactive oxygen species (ROS) Migration |
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