Modulación de la expresión de CISD1 por la actividad del canal CFTR

MARIÁNGELES CLAUZURE; TOMÁS A. SANTA COLOMA; CONSUELO MORI; ANGEL GABRIEL VALDIVIESO; MARÍA MACARENA MASSIP COPIZ

Mar del Plata

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2016

Cystic fibrosis (CF) is an autosomic recessive disease causedby mutations affecting the activity of CFTR chloride channel,which indirectly affect the expression of a net of genes. CDGSHiron sulfur domain 1 (CISD1; initially cloned in this laboratoryas named successively CFTR-RG2, KLPX, ZCD1 and CISD1),also referred to as mitoNEET, is a protein localized on the outermembrane of mitochondria. Oriented toward the cytoplasm, theCDGSH domain of CISD1 contains a redox-active 2Fe-2S cluster,which is stabilized by pioglitazone. We have previously describedthat CISD1 gene expression was decreased in a CF cellular modeland restored in the same cells ectopically expressing wt-CFTR(CFDE and CFDE/6RepCFTR cells). The initial results were furthervalidated by using confocal FISH and real-time PCR, using CFDEand CFDE/6RepCFTR cells incubated or not with glibenclamide(50, 100 μM, 24h) or CFTR(inh)172 (2.5, 5 μM, 24h), another Cltransportinhibitor (more potent and specific than glibenclamide).A similar differential expression was obtained using another CFcellular model: IB3-1(CF cells) and S9 cells (IB3-1 correctedcells), now using CFTR-stimulation (isoproterenol, db-cAMP,IBMX) instead of CFTR-inhibition. Now we used another cellularmodel, human colon adenocarcinoma T84 cells (known toexpress the CFTR), and by real-time PCR we determined thatCISD1 gene expression was decreased in T84 cells treated withCFTR(inh)172 (10 μM, 24h), compared to control cells. Theseresults confirmed that CISD1 expression is decreased in CF cell sor in cells with impaired CFTR function. We are now studying th epossible mechanisms involved in this regulation, which will bediscussed. Acknowledgments: Grants from ANPCYT [PICT 2007-00628 and PICT 2012-1278], CONICET [PIP 112200801025512009-2011 and PIP 11220110100685 2012-2014] and UCA toTASC; and research fellowships from CONICET (to MMMC, CMand MC)