Abstract
Tuberin, a tumor-suppressor protein produced by the tuberous sclerosis gene TSC2, downregulates the Rheb-mTOR-S6K pathway (mTOR axis). Comparison of the effects of human tuberin mutations, such as G1556S, suggests that pathways other than the mTOR axis might also be involved in the pathogenesis of tuberous sclerosis. Here we test this possibility using the rat G1556S-type mutation (GSM) and a transgenic Eker (Tsc2 mutant) rat system. Cells expressing GSM-tuberin failed to downregulate the mTOR axis. GSM-tuberin had an altered localization, which underlie its reduced ability to form a complex with hamartin, and a site-specific alteration in phosphorylation status indicating diverse regulation by Akt. GSM-transgenic (GSM-Tg) rats exhibited suppression of macroscopic renal tumors following N-ethyl-N-nitrosourea treatment. Intriguingly, rats with weaker GSM-Tg expression showed microscopic cystic and pre-tumorous lesions that were restricted in size and expansion, although they had hyper-phosphorylation of ribosomal protein S6. These results highlight a novel pathway involving tuberin that regulates tumor suppression independently of the mTOR inhibitory function. Identification of such a novel pathway will provide clear implications for generation of new therapeutic targets in the treatment of these tumors.
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Acknowledgements
This research was supported by a Grant-in-aid for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology and Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science and the Ministry of Health, Labour and Welfare of Japan. We also thank Ms N Otsuji (Department of Pathology and Oncology), Mr R Tsukada, Mr F Kanai, Ms T Hidano (Center for Biomedical Research Resources), Mr M Yoshida, Mr J Nakamoto (Division of Ultrastructural Research), Mr Y Watanabe, Mr K Matsunami, Ms K Ochiai (Division of Radioisotope Research), Dr T Fujimura (Division of Proteomics and BioMolecular Science), Ms Y Kojima, Dr H Kurihara (Division of Biomedical Imaging Research), Dr T Seki (Department of Developmental Neurobiology), Dr T Ueno and Dr E Kominami (Department of Biochemistry), all of Juntendo University, for their support.
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Shiono, M., Kobayashi, T., Takahashi, R. et al. The G1556S-type tuberin variant suppresses tumor formation in tuberous sclerosis 2 mutant (Eker) rats despite its deficiency in mTOR inhibition. Oncogene 27, 6690–6697 (2008). https://doi.org/10.1038/onc.2008.283
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DOI: https://doi.org/10.1038/onc.2008.283
