The Werner syndrome gene product (WRN): a repressor of hypoxia-inducible factor-1 activity.

[werner syndrome]

Werner syndrome (WS ) is a rare autosomal disease characterized by the premature onset of several age-associated pathologies . The protein defective in WS patients (WRN ) is a helicase /exonuclease involved in DNA repair , replication , transcription and telomere maintenance . Hypoxia-inducible factor -1 (HIF-1 ) is a decisive element for the transcriptional regulation of genes essential for adaptation to low oxygen conditions . HIF-1 is also implicated in the molecular mechanisms of ageing . Here , we show that the cellular depletion of WRN protein (by siRNA targeting ) leads to increased HIF-1 complex stabilization and activation . HIF-1 activation in the absence of WRN involves the generation of mitochondrial reactive oxygen species (mtROS ) since SkQ 1 , a mitochondrial -targeted antioxidant , and stigmatellin , an inhibitor of mitochondrial complex III , blocked increased HIF-1 levels . Ascorbate , an essential co -factor involved in HIF-1 stability , was decreased in WRN -depleted cells . Interestingly , expression levels of GLUT 1 , a known dehydroascorbic acid transporter , were also decreased in WRN -depleted cells . Ascorbate supplementation of WRN -depleted cells led to a dose-dependent inhibition of HIF-1 activation . These results indicate that WRN protein regulates HIF-1 activation by affecting mitochondrial ROS production and intracellular ascorbate levels . This work provides a novel mechanistic link between HIF-1 activity and different age-associated pathologies .

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Diseases presenting "were also decreased in wrn-depleted cells" symptom

werner syndrome

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