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Germline mutations in the fumarate hydratase (FH) tumor suppressor gene predispose to leiomyomatosis, renal cysts, and renal cell cancer (HLRCC). HLRCC tumors overexpress HIF1alpha and hypoxia pathway genes. We conditionally inactivated mouse Fh1 in the kidney. Fh1 mutants developed multiple clonal renal cysts that overexpressed Hif1alpha and Hif2alpha. Hif targets, such as Glut1 and Vegf, were upregulated. We found that Fh1-deficient murine embryonic stem cells and renal carcinomas from HLRCC showed similar overexpression of HIF and hypoxia pathway components to the mouse cysts. Our data have shown in vivo that pseudohypoxic drive, resulting from HIF1alpha (and HIF2alpha) overexpression, is a direct consequence of Fh1 inactivation. Our mouse may be useful for testing therapeutic interventions that target angiogenesis and HIF-prolyl hydroxylation.

Original publication




Journal article


Cancer Cell

Publication Date





311 - 319


Animals, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Renal Cell, Cell Hypoxia, Cell Proliferation, Female, Fumarate Hydratase, Gene Silencing, Glucose Transporter Type 1, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney Diseases, Cystic, Kidney Neoplasms, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Signal Transduction, Vascular Endothelial Growth Factor A