Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes
dc.contributor.author | Kerins, Michael John | |
dc.contributor.author | Vashisht, Ajay Amar | |
dc.contributor.author | Liang, Benjamin Xi-Tong | |
dc.contributor.author | Duckworth, Spencer Jordan | |
dc.contributor.author | Praslicka, Brandon John | |
dc.contributor.author | Wohlschlegel, James Akira | |
dc.contributor.author | Ooi, Aikseng | |
dc.date.accessioned | 2017-06-19T23:42:45Z | |
dc.date.available | 2017-06-19T23:42:45Z | |
dc.date.issued | 2017-06-01 | |
dc.identifier.citation | Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes 2017, 37 (11):e00079-17 Molecular and Cellular Biology | en |
dc.identifier.issn | 0270-7306 | |
dc.identifier.issn | 1098-5549 | |
dc.identifier.doi | 10.1128/MCB.00079-17 | |
dc.identifier.uri | http://hdl.handle.net/10150/624216 | |
dc.description.abstract | Germ line mutations of the gene encoding the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) cause a hereditary cancer syndrome known as hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC-associated tumors harbor biallelic FH inactivation that results in the accumulation of the TCA cycle metabolite fumarate. Although it is known that fumarate accumulation can alter cellular signaling, if and how fumarate confers a growth advantage remain unclear. Here we show that fumarate accumulation confers a chronic proliferative signal by disrupting cellular iron signaling. Specifically, fumarate covalently modifies cysteine residues on iron regulatory protein 2 (IRP2), rendering it unable to repress ferritin mRNA translation. Simultaneously, fumarate increases ferritin gene transcription by activating the NRF2 (nuclear factor [erythroid-derived 2]-like 2) transcription factor. In turn, increased ferritin protein levels promote the expression of the promitotic transcription factor FOXM1 (Forkhead box protein M1). Consistently, clinical HLRCC tissues showed increased expression levels of both FOXM1 and its proliferation-associated target genes. This finding demonstrates how FH inactivation can endow cells with a growth advantage. | |
dc.description.sponsorship | National Science Foundation Graduate Research Fellowship Program [DGE-1143953]; University of Arizona College of Pharmacy; University of Arizona Health Sciences grant [214565] | en |
dc.language.iso | en | en |
dc.publisher | AMER SOC MICROBIOLOGY | en |
dc.relation.url | http://mcb.asm.org/lookup/doi/10.1128/MCB.00079-17 | en |
dc.rights | Copyright © 2017 American Society for Microbiology. | en |
dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | |
dc.subject | ferritin | en |
dc.subject | FH | en |
dc.subject | FOXM1 | en |
dc.subject | fumarate | en |
dc.subject | HLRCC | en |
dc.subject | NRF2 | en |
dc.title | Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes | en |
dc.type | Article | en |
dc.contributor.department | Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol | en |
dc.identifier.journal | Molecular and Cellular Biology | en |
dc.description.note | 6 month embargo; published online 13 March 2017. | en |
dc.description.collectioninformation | This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu. | en |
dc.eprint.version | Final published version | en |
refterms.dateFOA | 2017-09-14T00:00:00Z | |
html.description.abstract | Germ line mutations of the gene encoding the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) cause a hereditary cancer syndrome known as hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC-associated tumors harbor biallelic FH inactivation that results in the accumulation of the TCA cycle metabolite fumarate. Although it is known that fumarate accumulation can alter cellular signaling, if and how fumarate confers a growth advantage remain unclear. Here we show that fumarate accumulation confers a chronic proliferative signal by disrupting cellular iron signaling. Specifically, fumarate covalently modifies cysteine residues on iron regulatory protein 2 (IRP2), rendering it unable to repress ferritin mRNA translation. Simultaneously, fumarate increases ferritin gene transcription by activating the NRF2 (nuclear factor [erythroid-derived 2]-like 2) transcription factor. In turn, increased ferritin protein levels promote the expression of the promitotic transcription factor FOXM1 (Forkhead box protein M1). Consistently, clinical HLRCC tissues showed increased expression levels of both FOXM1 and its proliferation-associated target genes. This finding demonstrates how FH inactivation can endow cells with a growth advantage. |