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

Patrick J Pollard, Bradley Spencer-Dene, Deepa Shukla, Kimberley Howarth, Emma Nye, Mona El-Bahrawy, Maesha Deheragoda, Maria Joannou, Stuart McDonald, Alison Martin, Peter Igarashi, Sunita Varsani-Brown, Ian Rosewell, Richard Poulsom, Patrick Maxwell, Gordon W Stamp, Ian P M Tomlinson

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)311-9
Number of pages9
JournalCancer Cell
Volume11
Issue number4
DOIs
Publication statusPublished - Apr 2007

Keywords

  • 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

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