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 journalArticle

122 Citations (Scopus)

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

Fingerprint

Cysts
Kidney
Fumarate Hydratase
Leiomyomatosis
Germ-Line Mutation
Hydroxylation
Embryonic Stem Cells
Tumor Suppressor Genes
Renal Cell Carcinoma
Vascular Endothelial Growth Factor A
Carcinoma
Hypoxia
Genes
Neoplasms
Therapeutics

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Pollard, P. J., Spencer-Dene, B., Shukla, D., Howarth, K., Nye, E., El-Bahrawy, M., ... 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

Targeted Inactivation of Fh1 Causes Proliferative Renal Cyst Development and Activation of the Hypoxia Pathway. / 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.

In: Cancer Cell, Vol. 11, No. 4, 10.04.2007, p. 311-319.

Research output: Contribution to journalArticle

Pollard, PJ, 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, GW & Tomlinson, IPM 2007, 'Targeted Inactivation of Fh1 Causes Proliferative Renal Cyst Development and Activation of the Hypoxia Pathway', Cancer Cell, vol. 11, no. 4, pp. 311-319. https://doi.org/10.1016/j.ccr.2007.02.005
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. / Targeted Inactivation of Fh1 Causes Proliferative Renal Cyst Development and Activation of the Hypoxia Pathway. In: Cancer Cell. 2007 ; Vol. 11, No. 4. pp. 311-319.
@article{e062410f9f19413c9fcd2807062664c6,
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 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.",
keywords = "CELLCYCLE",
author = "Pollard, {Patrick J.} and Bradley Spencer-Dene and Deepa Shukla and Kimberley Howarth and Emma Nye and Mona El-Bahrawy and Maesha Deheragoda and Maria Joannou and Stuart McDonald and Alison Martin and Peter Igarashi and Sunita Varsani-Brown and Ian Rosewell and Richard Poulsom and Patrick Maxwell and Stamp, {Gordon W.} and Tomlinson, {Ian P M}",
year = "2007",
month = "4",
day = "10",
doi = "10.1016/j.ccr.2007.02.005",
language = "English (US)",
volume = "11",
pages = "311--319",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",

}

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

VL - 11

SP - 311

EP - 319

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 4

ER -