Sudarsha, S. and Sourbier, C. and Kong, H.S. and Block, K. and Valera Romero, V.A. and Yang, Y. and Galindo, C. and Mollapour, M. and Scroggins, B. and Goode, N. and Lee, M.J. and Gourlay, C.W. and Trepel, J. and Linehan, W.M. and Neckers, L. (2009) Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1 alpha stabilization by glucose-dependent generation of reactive oxygen species. Molecular and Cellular Biology, 29 (15). pp. 4080-4090. ISSN 0270-7306 .
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Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited cancer syndrome linked to biallelic inactivation of the gene encoding the tricarboxylic acid cycle enzyme fumarate hydratase (FH). Individuals with HLRCC are at risk to develop cutaneous and uterine leiomyomas and an aggressive form of kidney cancer. Pseudohypoxic drive-the aberrant activation of cellular hypoxia response pathways despite normal oxygen tension-is considered to be a likely mechanism underlying the etiology of this tumor. Pseudohypoxia requires the oxygen-independent stabilization of the alpha subunit of the hypoxia-inducible transcription factor (HIF-1alpha). Under normoxic conditions, proline hydroxylation of HIF-1alpha permits VHL recognition and subsequent targeting for proteasomal degradation. Here, we demonstrate that inactivating mutations of FH in an HLRCC-derived cell line result in glucose-mediated generation of cellular reactive oxygen species (ROS) and ROS-dependent HIF-1alpha stabilization. Additionally, we demonstrate that stable knockdown of FH in immortalized renal epithelial cells results in ROS-dependent HIF-1alpha stabilization. These data reveal that the obligate glycolytic switch present in HLRCC is critical to HIF stabilization via ROS generation.
|Subjects:||Q Science > QH Natural history > QH426 Genetics|
|Divisions:||Faculties > Science Technology and Medical Studies > School of Biosciences|
|Depositing User:||Campbell Gourlay|
|Date Deposited:||14 Sep 2009 21:05|
|Last Modified:||14 Sep 2009 21:05|
|Resource URI:||http://kar.kent.ac.uk/id/eprint/22635 (The current URI for this page, for reference purposes)|
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