Targeted inactivation of Fh1 causes proliferative renal cyst development and activation of the hypoxia pathway

被引：150

作者：

Pollard, Patrick J.

Spencer-Dene, Bradley

Shukla, Deepa

Howarth, Kimberley

Nye, Emma

El-Bahrawy, Mona

Deheragoda, Maesha

Joannou, Maria

McDonald, Stuart

Martin, Alison

Igarashi, Peter

Varsani-Brown, Sunita

Rosewell, Ian

Poulsom, Richard

Maxwell, Patrick

Stamp, Gordon W.

Tomlinson, Ian P. M.

机构：

[1] Canc Res UK, London Res Inst, Mol & Populat Genet Lab, London WC2A 3PX, England

[2] Canc Res UK, London Res Inst, Expt Pathol Lab, London WC2A 3PX, England

[3] Canc Res UK, London Res Inst, In Situ Hybridisat Serv, London WC2A 3PX, England

[4] Canc Res UK, London Res Inst, Dept Histopathol, London WC2A 3PX, England

[5] Canc Res UK, London Res Inst, Transgen Serv, London WC2A 3PX, England

[6] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Histopathol, London W12 0NN, England

[7] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Div Renal Med, London W12 0NN, England

[8] Univ Texas, SW Med Ctr, Div Nephrol, Dallas, TX USA

[9] Queen Mary Univ London, Barts & London Sch Med, London E1 2AD, England

来源：

CANCER CELL | 2007年 / 11卷 / 04期

关键词：

D O I：

10.1016/j.ccr.2007.02.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Germline mutations in the fumarate hydratase (FM tumor suppressor gene predispose to leiomyomatosis, renal cysts, and renal cell cancer (HLRCC). HLRCC tumors overexpress HIR1 alpha and hypoxia pathway genes. We conditionally inactivated mouse Fh1 in the kidney. Fh1 mutants developed multiple clonal renal cysts that overexpressed Hif1 alpha and Hif2 alpha. 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 HIF1 alpha (and HIF2 alpha) overexpression, is a direct consequence of Fh1 inactivation. Our mouse may be useful for testing therapeutic interventions that target angiogenesis and HIF-prolyl hydroxylation.

引用

页码：311 / 319

页数：9

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