TY - JOUR
T1 - Targeted Inactivation of Fh1 Causes Proliferative Renal Cyst Development and Activation of the Hypoxia Pathway
AU - Pollard, Patrick J.
AU - Spencer-Dene, Bradley
AU - Shukla, Deepa
AU - Howarth, Kimberley
AU - Nye, Emma
AU - El-Bahrawy, Mona
AU - Deheragoda, Maesha
AU - Joannou, Maria
AU - McDonald, Stuart
AU - Martin, Alison
AU - Igarashi, Peter
AU - Varsani-Brown, Sunita
AU - Rosewell, Ian
AU - Poulsom, Richard
AU - Maxwell, Patrick
AU - Stamp, Gordon W.
AU - Tomlinson, Ian P M
PY - 2007/4/10
Y1 - 2007/4/10
N2 - 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.
AB - 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.
KW - CELLCYCLE
UR - http://www.scopus.com/inward/record.url?scp=34047167041&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34047167041&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2007.02.005
DO - 10.1016/j.ccr.2007.02.005
M3 - Article
C2 - 17418408
AN - SCOPUS:34047167041
SN - 1535-6108
VL - 11
SP - 311
EP - 319
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -
