Fumarate Mediates a Chronic Proliferative Signal in Fumarate Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of Ferritin Genes
| Autor: | Ajay A. Vashisht, Spencer Jordan Duckworth, Michael J. Kerins, James A. Wohlschlegel, Aikseng Ooi, Brandon Praslicka, Benjamin Xi Tong Liang |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cell signaling Transcription Genetic NF-E2-Related Factor 2 Intracellular Space Succinic Acid Models Biological Fumarate Hydratase 03 medical and health sciences 0302 clinical medicine Fumarates Transcription (biology) Cell Line Tumor Leiomyomatosis Humans Amino Acid Sequence Molecular Biology Transcription factor Carcinoma Renal Cell Iron Regulatory Protein 2 Cell Proliferation Regulation of gene expression biology Forkhead Box Protein M1 Cell Biology Kidney Neoplasms Cell biology Ferritin 030104 developmental biology 030220 oncology & carcinogenesis Fumarase Protein Biosynthesis Immunology Cancer cell Ferritins biology.protein FOXM1 Signal Transduction Research Article |
| Zdroj: | Molecular and cellular biology. 37(11) |
| ISSN: | 1098-5549 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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