Cancer cell · 2007
Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway.
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Pollard Patrick J, Spencer-Dene Bradley, Shukla Deepa, Howarth Kimberley, Nye Emma, El-Bahrawy Mona, Deheragoda Maesha, Joannou Maria, McDonald Stuart, Martin Alison, Igarashi Peter, Varsani-Brown Sunita, Rosewell Ian, Poulsom Richard, Maxwell Patrick, Stamp Gordon W, Tomlinson Ian P M
Аннотация
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.
Предметные рубрики MeSH
AnimalsBasic Helix-Loop-Helix ProteinsCarcinoma, Renal CellCell HypoxiaCell ProliferationFemaleFumarate HydrataseGene SilencingGlucose Transporter Type 1Hypoxia-Inducible Factor 1, alpha SubunitKidney Diseases, CysticKidney NeoplasmsMaleMiceMice, Inbred C57BLMice, KnockoutSignal TransductionVascular Endothelial Growth Factor AEndothelial PAS Domain-Containing Protein 1