The Birt-Hogg-Dube and tuberous sclerosis complex homologs have opposing roles in amino acid homeostasis in Schizosaccharomyces pombe

Marjon Van Slegtenhorst, Damir Khabibullin, Tiffiney R. Hartman, Emmanuelle Nicolas, Warren D. Kruger, Elizabeth Petri Henske

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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 Δtsc1 and Δtsc2, were up-regulated in Δbhd, and levels of specific intracellular amino acids known to be low in Δtsc1 and Δtsc2 were elevated in Δbhd. 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 Δbhd but not in wild-type yeast. Loss of Bhd sensitized yeast to rapamycin-induced increases in permease expression levels, and rapamycin induced lethality in Δbhd yeast expressing the hypomorphic Rhb1 allele. In S. pombe, it is known that Rhb1 binds Tor2, and Tor2 inhibition leads to upregulation 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.

Original languageEnglish
Pages (from-to)24583-24590
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number34
DOIs
StatePublished - Aug 24 2007

Keywords

  • Alleles
  • Amino Acid Sequence
  • Amino Acids/metabolism
  • Animals
  • Canavanine/pharmacology
  • Ethionine/pharmacology
  • Gene Expression Regulation, Fungal
  • Humans
  • Models, Biological
  • Molecular Sequence Data
  • Phenotype
  • Proteins/genetics
  • Proto-Oncogene Proteins/genetics
  • Schizosaccharomyces pombe Proteins/genetics
  • Schizosaccharomyces/genetics
  • Sequence Homology, Amino Acid
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins/genetics

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