The role of the Birt–Hogg–Dubé protein in mTOR activation and renal tumorigenesis
Autor: | Andres J. Klein-Szanto, Elizabeth P. Henske, Tiffiney R. Hartman, Emmanuelle Nicolas, Tahseen Al-Saleem, T P Cash, M. C. Simon |
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Rok vydání: | 2009 |
Předmět: |
Male
Cancer Research Tumor suppressor gene Mice Transgenic mTORC1 Biology Birt–Hogg–Dubé syndrome Article Mice Amino acid homeostasis Proto-Oncogene Proteins Testis Genetics medicine Animals Humans RNA Messenger Folliculin Lung Molecular Biology Cells Cultured PI3K/AKT/mTOR pathway TOR Serine-Threonine Kinases Tumor Suppressor Proteins Carcinoma Ovary Brain medicine.disease Kidney Neoplasms Gene Expression Regulation Neoplastic Mice Inbred C57BL Cell Transformation Neoplastic medicine.anatomical_structure Cancer research Female TSC1 TSC2 Glioblastoma Protein Kinases |
Zdroj: | Oncogene. 28:1594-1604 |
ISSN: | 1476-5594 0950-9232 |
Popis: | 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. |
Databáze: | OpenAIRE |
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