title: Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway.
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.
authors.affiliation: Molecular and Population Genetics Laboratory, Histopathology Department, London Research Institute, Cancer Research UK, Hammersmith Hospital, Imperial College London, United Kingdom. patrick.pollard@cancer.org.uk
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pollard
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.forename: Deepa
authors.initials: D
authors.lastname: Shukla
authors.forename: Kimberley
authors.initials: K
authors.lastname: Howarth
authors.forename: Emma
authors.initials: E
authors.lastname: Nye
authors.forename: Mona
authors.initials: M
authors.lastname: El-Bahrawy
authors.forename: Maesha
authors.initials: M
authors.lastname: Deheragoda
authors.forename: Maria
authors.initials: M
authors.lastname: Joannou
authors.forename: Stuart
authors.initials: S
authors.lastname: McDonald
authors.forename: Alison
authors.initials: A
authors.lastname: Martin
authors.forename: Peter
authors.initials: P
authors.lastname: Igarashi
authors.forename: Sunita
authors.initials: S
authors.lastname: Varsani-Brown
authors.forename: Ian
authors.initials: I
authors.lastname: Rosewell
authors.forename: Richard
authors.initials: R
authors.lastname: Poulsom
authors.forename: Patrick
authors.initials: P
authors.lastname: Maxwell
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Stamp
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D049109:Cell Proliferation; D005260:Female; D005649:Fumarate Hydratase / Q000235:genetics*; D020868:Gene Silencing / Q000502:physiology*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D052177:Kidney Diseases, Cystic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005649:Fumarate Hydratase; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C495678:Slc2a1 protein, mouse; C467480:vascular endothelial growth factor A, mouse