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

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Abstract

Germline mutations in the fumarate hydratase (FH) tumor suppressor gene predispose to leiomyomatosis, renal cysts, and renal cell cancer (HLRCC). HLRCC tumors overexpress HIF1α and hypoxia pathway genes. We conditionally inactivated mouse Fh1 in the kidney. Fh1 mutants developed multiple clonal renal cysts that overexpressed Hif1α and Hif2α. 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 HIF1α (and HIF2α) 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 (US)
Pages (from-to)311-319
Number of pages9
JournalCancer Cell
Volume11
Issue number4
DOIs
StatePublished - Apr 10 2007

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Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Pollard, P. J., Spencer-Dene, B., Shukla, D., Howarth, K., Nye, E., El-Bahrawy, M., Deheragoda, M., Joannou, M., McDonald, S., Martin, A., Igarashi, P., Varsani-Brown, S., Rosewell, I., Poulsom, R., Maxwell, P., Stamp, G. W., & Tomlinson, I. P. M. (2007). Targeted Inactivation of Fh1 Causes Proliferative Renal Cyst Development and Activation of the Hypoxia Pathway. Cancer Cell, 11(4), 311-319. https://doi.org/10.1016/j.ccr.2007.02.005