1. ¹Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan
2. ²PhoenixBio Inc., Tochigi, Japan
3. ³Division of Proteomics and BioMolecular Science, Juntendo University School of Medicine, Tokyo, Japan
4. ⁴Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan
5. ⁵Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan
6. ⁶Department of Pathology, Saitama Medical Center, Saitama Medical University, Saitama, Japan

Correspondence: Dr O Hino, Department of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail: ohino@juntendo.ac.jp

Received 17 December 2007; Revised 30 June 2008; Accepted 4 July 2008; Published online 11 August 2008.

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.