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J. Biol. Chem., Vol. 282, Issue 34, 24583-24590, August 24, 2007

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The Birt-Hogg-Dube and Tuberous Sclerosis Complex Homologs Have Opposing Roles in Amino Acid Homeostasis in Schizosaccharomyces pombe^*

From the Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

Birt-Hogg-Dube (BHD) is a tumor suppressor gene disorder characterized by skin hamartomas, cystic lung disease, and renal cell carcinoma. The fact that hamartomas, lung cysts, and renal cell carcinoma can also occur in tuberous sclerosis complex (TSC) suggests that the BHD and TSC proteins may function within a common pathway. To evaluate this hypothesis, we deleted the BHD homolog in Schizosaccharomyces pombe. Expression profiling revealed that six permease and transporter genes, known to be down-regulated in tsc1 and tsc2, were up-regulated in bhd, and levels of specific intracellular amino acids known to be low in tsc1 and tsc2 were elevated in bhd. This "opposite" profile was unexpected, given the overlapping clinical phenotypes. The TSC1/2 proteins inhibit Rheb in mammals, and Tsc1/Tsc2 inhibit Rhb1 in S. pombe. Expression of a hypomorphic allele of rhb1⁺ dramatically increased permease expression levels in bhd but not in wild-type yeast. Loss of Bhd sensitized yeast to rapamycin-induced increases in permease expression levels, and rapamycin induced lethality in bhd yeast expressing the hypomorphic Rhb1 allele. In S. pombe, it is known that Rhb1 binds Tor2, and Tor2 inhibition leads to up-regulation of permeases including those that are regulated by Bhd. Our data, therefore, suggest that Bhd activates Tor2. If the mammalian BHD protein, folliculin, similarly activates mammalian target of rapamycin, it will be of great interest to determine how mammalian target of rapamycin inhibition in BHD patients and mammalian target of rapamycin activation in TSC patients lead to overlapping clinical phenotypes.

Received for publication, January 30, 2007 , and in revised form, June 7, 2007.

^* This work was supported by National Institutes of Health Grant R21 HL 82746. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1 and S2.

¹ Both authors contributed equally to this work.

² Current address: Laboratory of Pediatrics, Erasmus University, Dr. Molewaterplein 50 3015 GE, Rotterdam, The Netherlands.

³ To whom correspondence should be addressed: 333 Cottman Ave., Philadelphia, PA 19111. Tel.: 215-728-2428; Fax: 215-214-1623; E-mail: Elizabeth.Henske{at}FCCC.edu.

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