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2017 ; 37
(11
): ä Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Fumarate Mediates a Chronic Proliferative Signal in Fumarate
Hydratase-Inactivated Cancer Cells by Increasing Transcription and Translation of
Ferritin Genes
#MMPMID28289076
Kerins MJ
; Vashisht AA
; Liang BX
; Duckworth SJ
; Praslicka BJ
; Wohlschlegel JA
; Ooi A
Mol Cell Biol
2017[Jun]; 37
(11
): ä PMID28289076
show ga
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.