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Cancer Cell. 2007 Apr;11(4):311-9.

Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway.

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  • 1Molecular and Population Genetics Laboratory, Histopathology Department, London Research Institute, Cancer Research UK, Hammersmith Hospital, Imperial College London, United Kingdom. patrick.pollard@cancer.org.uk

Abstract

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.

PMID:
17418408
DOI:
10.1016/j.ccr.2007.02.005
[PubMed - indexed for MEDLINE]
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