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The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

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The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. / Yan, Ming; Gingras, Marie Claude; Dunlop, Elaine A.; Nouët, Yann; Dupuy, Fanny; Jalali, Zahra; Possik, Elite; Coull, Barry J.; Kharitidi, Dmitri; Dydensborg, Anders Bondo; Faubert, Brandon; Kamps, Miriam; Sabourin, Sylvie; Preston, Rachael S.; Davies, David Mark; Roughead, Taren; Chotard, Laëtitia; Van Steensel, Maurice A.M.; Jones, Russell; Tee, Andrew R.; Pause, Arnim.

In: Journal of Clinical Investigation, Vol. 124, No. 6, 02.06.2014, p. 2640-2650.

Research output: Contribution to Journal/MagazineJournal articlepeer-review

Harvard

Yan, M, Gingras, MC, Dunlop, EA, Nouët, Y, Dupuy, F, Jalali, Z, Possik, E, Coull, BJ, Kharitidi, D, Dydensborg, AB, Faubert, B, Kamps, M, Sabourin, S, Preston, RS, Davies, DM, Roughead, T, Chotard, L, Van Steensel, MAM, Jones, R, Tee, AR & Pause, A 2014, 'The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation', Journal of Clinical Investigation, vol. 124, no. 6, pp. 2640-2650. https://doi.org/10.1172/JCI71749

APA

Yan, M., Gingras, M. C., Dunlop, E. A., Nouët, Y., Dupuy, F., Jalali, Z., Possik, E., Coull, B. J., Kharitidi, D., Dydensborg, A. B., Faubert, B., Kamps, M., Sabourin, S., Preston, R. S., Davies, D. M., Roughead, T., Chotard, L., Van Steensel, M. A. M., Jones, R., ... Pause, A. (2014). The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. Journal of Clinical Investigation, 124(6), 2640-2650. https://doi.org/10.1172/JCI71749

Vancouver

Yan M, Gingras MC, Dunlop EA, Nouët Y, Dupuy F, Jalali Z et al. The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. Journal of Clinical Investigation. 2014 Jun 2;124(6):2640-2650. https://doi.org/10.1172/JCI71749

Author

Yan, Ming ; Gingras, Marie Claude ; Dunlop, Elaine A. ; Nouët, Yann ; Dupuy, Fanny ; Jalali, Zahra ; Possik, Elite ; Coull, Barry J. ; Kharitidi, Dmitri ; Dydensborg, Anders Bondo ; Faubert, Brandon ; Kamps, Miriam ; Sabourin, Sylvie ; Preston, Rachael S. ; Davies, David Mark ; Roughead, Taren ; Chotard, Laëtitia ; Van Steensel, Maurice A.M. ; Jones, Russell ; Tee, Andrew R. ; Pause, Arnim. / The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 6. pp. 2640-2650.

Bibtex

@article{addad9b4044c41ffac381960c9eba54f,
title = "The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation",
abstract = "The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic glycolysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1α and HIF, respectively. In normoxia, AMPK induces PGC-1α, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dub{\'e} (BHD) syndrome, which is associated with an increased cancer risk. FLCN was identified as an AMPK binding partner, and we evaluated its role with respect to AMPK-dependent energy functions. We revealed that loss of FLCN constitutively activates AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis and increased ROS production. ROS induced HIF transcriptional activity and drove Warburg metabolic reprogramming, coupling AMPK-dependent mitochondrial biogenesis to HIF-dependent metabolic changes. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells. Moreover, this pathway is conserved in a BHD-derived tumor. These results indicate that FLCN inhibits tumorigenesis by preventing AMPK-dependent HIF activation and the subsequent Warburg metabolic transformation.",
author = "Ming Yan and Gingras, {Marie Claude} and Dunlop, {Elaine A.} and Yann Nou{\"e}t and Fanny Dupuy and Zahra Jalali and Elite Possik and Coull, {Barry J.} and Dmitri Kharitidi and Dydensborg, {Anders Bondo} and Brandon Faubert and Miriam Kamps and Sylvie Sabourin and Preston, {Rachael S.} and Davies, {David Mark} and Taren Roughead and La{\"e}titia Chotard and {Van Steensel}, {Maurice A.M.} and Russell Jones and Tee, {Andrew R.} and Arnim Pause",
year = "2014",
month = jun,
day = "2",
doi = "10.1172/JCI71749",
language = "English",
volume = "124",
pages = "2640--2650",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",

}

RIS

TY - JOUR

T1 - The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

AU - Yan, Ming

AU - Gingras, Marie Claude

AU - Dunlop, Elaine A.

AU - Nouët, Yann

AU - Dupuy, Fanny

AU - Jalali, Zahra

AU - Possik, Elite

AU - Coull, Barry J.

AU - Kharitidi, Dmitri

AU - Dydensborg, Anders Bondo

AU - Faubert, Brandon

AU - Kamps, Miriam

AU - Sabourin, Sylvie

AU - Preston, Rachael S.

AU - Davies, David Mark

AU - Roughead, Taren

AU - Chotard, Laëtitia

AU - Van Steensel, Maurice A.M.

AU - Jones, Russell

AU - Tee, Andrew R.

AU - Pause, Arnim

PY - 2014/6/2

Y1 - 2014/6/2

N2 - The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic glycolysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1α and HIF, respectively. In normoxia, AMPK induces PGC-1α, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dubé (BHD) syndrome, which is associated with an increased cancer risk. FLCN was identified as an AMPK binding partner, and we evaluated its role with respect to AMPK-dependent energy functions. We revealed that loss of FLCN constitutively activates AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis and increased ROS production. ROS induced HIF transcriptional activity and drove Warburg metabolic reprogramming, coupling AMPK-dependent mitochondrial biogenesis to HIF-dependent metabolic changes. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells. Moreover, this pathway is conserved in a BHD-derived tumor. These results indicate that FLCN inhibits tumorigenesis by preventing AMPK-dependent HIF activation and the subsequent Warburg metabolic transformation.

AB - The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic glycolysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1α and HIF, respectively. In normoxia, AMPK induces PGC-1α, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dubé (BHD) syndrome, which is associated with an increased cancer risk. FLCN was identified as an AMPK binding partner, and we evaluated its role with respect to AMPK-dependent energy functions. We revealed that loss of FLCN constitutively activates AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis and increased ROS production. ROS induced HIF transcriptional activity and drove Warburg metabolic reprogramming, coupling AMPK-dependent mitochondrial biogenesis to HIF-dependent metabolic changes. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells. Moreover, this pathway is conserved in a BHD-derived tumor. These results indicate that FLCN inhibits tumorigenesis by preventing AMPK-dependent HIF activation and the subsequent Warburg metabolic transformation.

U2 - 10.1172/JCI71749

DO - 10.1172/JCI71749

M3 - Journal article

C2 - 24762438

AN - SCOPUS:84902201289

VL - 124

SP - 2640

EP - 2650

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -