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The role of the Birt–Hogg–Dubé protein in mTOR activation and renal tumorigenesis
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The role of the Birt–Hogg–Dubé protein in mTOR activation and renal tumorigenesis
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Journal Article
The role of the Birt–Hogg–Dubé protein in mTOR activation and renal tumorigenesis
2009
Overview
Birt–Hogg–Dubé (BHD) syndrome is a tumor-suppressor gene disorder characterized by skin tumors, cystic lung disease and renal cell carcinoma. Very little is known about the molecular pathogenesis of BHD. Clinical similarities between BHD and tuberous sclerosis complex (TSC) suggest that the BHD and TSC proteins may function within a common pathway. The TSC proteins inhibit the activity of the mammalian target of rapamycin complex 1 (TORC1), and in
Schizosaccharomyces pombe
, Bhd and Tsc1/Tsc2 have opposing roles in the regulation of amino-acid homeostasis. We report here that in mammalian cells, downregulation of BHD reduces the phosphorylation of ribosomal protein S6, an indicator of TORC1 activity. To determine whether folliculin, the product of the
BHD
gene, regulates mammalian target of rapamycin activity
in vivo
, we generated a mouse with targeted inactivation of the
Bhd
gene. The mice developed spontaneous oncocytic cysts and tumors composed of cells that resemble the renal cell carcinomas in BHD patients. The cysts and tumors had low levels of phospho-S6. Taken together, these data indicate that folliculin regulates the activity of TORC1, and suggest a new paradigm in which both inappropriately high and inappropriately low levels of TORC1 activity can be associated with renal tumorigenesis.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Biological and medical sciences
/ Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
/ Cell Transformation, Neoplastic - genetics
/ Cysts
/ Female
/ Fundamental and applied biological sciences. Psychology
/ Gene Expression Regulation, Neoplastic
/ Genetics
/ Humans
/ Kidney Neoplasms - metabolism
/ Male
/ Medicine
/ Mice
/ Molecular and cellular biology
/ Oncology
/ Protein Kinases - metabolism
/ Proteins
/ Proto-Oncogene Proteins - physiology
/ TOR Serine-Threonine Kinases
/ Tumor Suppressor Proteins - physiology
/ Tumors
/ Yeast
