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Absence of the Birt-Hogg-Dube gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility

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Absence of the Birt-Hogg-Dube gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. / Preston, R. S.; Philp, A.; Claessens, T.; Gijezen, L.; Dydensborg, A. B.; Dunlop, E. A.; Harper, K. T.; Brinkhuizen, T.; Menko, F. H.; Davies, D. M.; Land, S.C.; Pause, A.; Baar, K.; van Steensel, M. A. M.; Tee, A. R.

In: Oncogene, Vol. 30, No. 10, 2011, p. 1159-1173.

Research output: Contribution to journalArticle

Harvard

Preston, RS, Philp, A, Claessens, T, Gijezen, L, Dydensborg, AB, Dunlop, EA, Harper, KT, Brinkhuizen, T, Menko, FH, Davies, DM, Land, SC, Pause, A, Baar, K, van Steensel, MAM & Tee, AR 2011, 'Absence of the Birt-Hogg-Dube gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility' Oncogene, vol 30, no. 10, pp. 1159-1173., 10.1038/onc.2010.497

APA

Preston, R. S., Philp, A., Claessens, T., Gijezen, L., Dydensborg, A. B., Dunlop, E. A., ... Tee, A. R. (2011). Absence of the Birt-Hogg-Dube gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene, 30(10), 1159-1173. 10.1038/onc.2010.497

Vancouver

Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA et al. Absence of the Birt-Hogg-Dube gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene. 2011;30(10):1159-1173. Available from: 10.1038/onc.2010.497

Author

Preston, R. S.; Philp, A.; Claessens, T.; Gijezen, L.; Dydensborg, A. B.; Dunlop, E. A.; Harper, K. T.; Brinkhuizen, T.; Menko, F. H.; Davies, D. M.; Land, S.C.; Pause, A.; Baar, K.; van Steensel, M. A. M.; Tee, A. R. / Absence of the Birt-Hogg-Dube gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility.

In: Oncogene, Vol. 30, No. 10, 2011, p. 1159-1173.

Research output: Contribution to journalArticle

Bibtex - Download

@article{c3c8039277414c2aa88bf1646b49bd5d,
title = "Absence of the Birt-Hogg-Dube gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility",
keywords = "Birt-Hogg-Dube, HIF, folliculin, warburg effect, RENAL-CELL CARCINOMA, MAMMALIAN TARGET, FUMARATE HYDRATASE, CANCER, ACTIVATION, EXPRESSION, AMPK, MTOR, PHOSPHORYLATION, RAPAMYCIN",
author = "Preston, {R. S.} and A. Philp and T. Claessens and L. Gijezen and Dydensborg, {A. B.} and Dunlop, {E. A.} and Harper, {K. T.} and T. Brinkhuizen and Menko, {F. H.} and Davies, {D. M.} and S.C. Land and A. Pause and K. Baar and {van Steensel}, {M. A. M.} and Tee, {A. R.}",
year = "2011",
doi = "10.1038/onc.2010.497",
volume = "30",
number = "10",
pages = "1159--1173",
journal = "Oncogene",
issn = "0950-9232",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Absence of the Birt-Hogg-Dube gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility

A1 - Preston,R. S.

A1 - Philp,A.

A1 - Claessens,T.

A1 - Gijezen,L.

A1 - Dydensborg,A. B.

A1 - Dunlop,E. A.

A1 - Harper,K. T.

A1 - Brinkhuizen,T.

A1 - Menko,F. H.

A1 - Davies,D. M.

A1 - Land,S.C.

A1 - Pause,A.

A1 - Baar,K.

A1 - van Steensel,M. A. M.

A1 - Tee,A. R.

AU - Preston,R. S.

AU - Philp,A.

AU - Claessens,T.

AU - Gijezen,L.

AU - Dydensborg,A. B.

AU - Dunlop,E. A.

AU - Harper,K. T.

AU - Brinkhuizen,T.

AU - Menko,F. H.

AU - Davies,D. M.

AU - Land,S.C.

AU - Pause,A.

AU - Baar,K.

AU - van Steensel,M. A. M.

AU - Tee,A. R.

PY - 2011

Y1 - 2011

N2 - <p>Under conditions of reduced tissue oxygenation, hypoxia-inducible factor (HIF) controls many processes, including angiogenesis and cellular metabolism, and also influences cell proliferation and survival decisions. HIF is centrally involved in tumour growth in inherited diseases that give rise to renal cell carcinoma (RCC), such as Von Hippel-Lindau syndrome and tuberous sclerosis complex. In this study, we examined whether HIF is involved in tumour formation of RCC in Birt-Hogg-Dube syndrome. For this, we analysed a Birt-Hogg-Dube patient-derived renal tumour cell line (UOK257) that is devoid of the Birt-Hogg-Dube protein (BHD) and observed high levels of HIF activity. Knockdown of BHD expression also caused a threefold activation of HIF, which was not as a consequence of more HIF1 alpha or HIF2 alpha protein. Transcription of HIF target genes VEGF, BNIP3 and CCND1 was also increased. We found nuclear localization of HIF1 alpha and increased expression of VEGF, BNIP3 and GLUT1 in a chromophobe carcinoma from a Birt-Hogg-Dube patient. Our data also reveal that UOK257 cells have high lactate dehydrogenase, pyruvate kinase and 3-hydroxyacyl-CoA dehydrogenase activity. We observed increased expression of pyruvate dehydrogenase kinase 1 (a HIF gene target), which in turn leads to increased phosphorylation and inhibition of pyruvate dehydrogenase. Together with increased protein levels of GLUT1, our data reveal that UOK257 cells favour glycolytic rather than lipid metabolism (a cancer phenomenon termed the 'Warburg effect'). UOK257 cells also possessed a higher expression level of the L-lactate influx monocarboxylate transporter 1 and consequently utilized L-lactate as a metabolic fuel. As a result of their higher dependency on glycolysis, we were able to selectively inhibit the growth of these UOK257 cells by treatment with 2-deoxyglucose. This work suggests that targeting glycolytic metabolism may be used therapeutically to treat Birt-Hogg-Dube-associated renal lesions. Oncogene (2011) 30, 1159-1173; doi:10.1038/onc.2010.497; published online 8 November 2010</p>

AB - <p>Under conditions of reduced tissue oxygenation, hypoxia-inducible factor (HIF) controls many processes, including angiogenesis and cellular metabolism, and also influences cell proliferation and survival decisions. HIF is centrally involved in tumour growth in inherited diseases that give rise to renal cell carcinoma (RCC), such as Von Hippel-Lindau syndrome and tuberous sclerosis complex. In this study, we examined whether HIF is involved in tumour formation of RCC in Birt-Hogg-Dube syndrome. For this, we analysed a Birt-Hogg-Dube patient-derived renal tumour cell line (UOK257) that is devoid of the Birt-Hogg-Dube protein (BHD) and observed high levels of HIF activity. Knockdown of BHD expression also caused a threefold activation of HIF, which was not as a consequence of more HIF1 alpha or HIF2 alpha protein. Transcription of HIF target genes VEGF, BNIP3 and CCND1 was also increased. We found nuclear localization of HIF1 alpha and increased expression of VEGF, BNIP3 and GLUT1 in a chromophobe carcinoma from a Birt-Hogg-Dube patient. Our data also reveal that UOK257 cells have high lactate dehydrogenase, pyruvate kinase and 3-hydroxyacyl-CoA dehydrogenase activity. We observed increased expression of pyruvate dehydrogenase kinase 1 (a HIF gene target), which in turn leads to increased phosphorylation and inhibition of pyruvate dehydrogenase. Together with increased protein levels of GLUT1, our data reveal that UOK257 cells favour glycolytic rather than lipid metabolism (a cancer phenomenon termed the 'Warburg effect'). UOK257 cells also possessed a higher expression level of the L-lactate influx monocarboxylate transporter 1 and consequently utilized L-lactate as a metabolic fuel. As a result of their higher dependency on glycolysis, we were able to selectively inhibit the growth of these UOK257 cells by treatment with 2-deoxyglucose. This work suggests that targeting glycolytic metabolism may be used therapeutically to treat Birt-Hogg-Dube-associated renal lesions. Oncogene (2011) 30, 1159-1173; doi:10.1038/onc.2010.497; published online 8 November 2010</p>

KW - Birt-Hogg-Dube

KW - HIF

KW - folliculin

KW - warburg effect

KW - RENAL-CELL CARCINOMA

KW - MAMMALIAN TARGET

KW - FUMARATE HYDRATASE

KW - CANCER

KW - ACTIVATION

KW - EXPRESSION

KW - AMPK

KW - MTOR

KW - PHOSPHORYLATION

KW - RAPAMYCIN

U2 - 10.1038/onc.2010.497

DO - 10.1038/onc.2010.497

M1 - Article

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 10

VL - 30

SP - 1159

EP - 1173

ER -

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