6533b82cfe1ef96bd128eacd
RESEARCH PRODUCT
Spontaneous and Fas-induced apoptosis of low-grade MDS erythroid precursors involves the endoplasmic reticulum
Emmanuel GyanCecile Pierre-eugenePatrick MayeuxClotilde RandriamampitaEmilie FrisanEric SolaryEric SolaryMichaela FontenayCatherine LacombeAnne Dubart-kupperschmittOdile Beyne-rauzyCarmen GarridoCarmen GarridoJ-c DescheminFrancois Dreyfussubject
Cancer ResearchProgrammed cell deathApoptosis[SDV.BC]Life Sciences [q-bio]/Cellular BiologyMitochondrionEndoplasmic Reticulum03 medical and health sciences0302 clinical medicinehemic and lymphatic diseasesmedicineHumansfas ReceptorErythropoietinComputingMilieux_MISCELLANEOUS030304 developmental biologyErythroid Precursor Cells0303 health sciencesbiologyCytochrome cEndoplasmic reticulumMembrane ProteinsAnemiaHematologyCaspase InhibitorsMitochondria3. Good healthCell biologyRed blood cellmedicine.anatomical_structureProto-Oncogene Proteins c-bcl-2OncologyErythropoietinApoptosisMyelodysplastic Syndromes030220 oncology & carcinogenesisCancer researchbiology.protein[SDV.IMM]Life Sciences [q-bio]/ImmunologyCalciumBone marrowmedicine.drugdescription
Spontaneous apoptosis of bone marrow erythroid precursors accounts for the anemia that characterizes most low-grade myelodysplastic syndromes (MDS). We have shown that death of these precursors involved the Fas-dependent activation of caspase-8. To explore the pathway leading from caspase-8 activation to apoptosis, we transduced MDS bone marrow CD34(+) cells with a lentivirus encoding wild-type (WT) or endoplasmic reticulum (ER)-targeted Bcl-2 protein before inducing their erythroid differentiation. Both WT-Bcl-2 and ER-targeted Bcl-2 prevented spontaneous and Fas-dependent apoptosis in MDS erythroid precursors. ER-targeted Bcl-2 inhibited mitochondrial membrane depolarization and cytochrome c release in MDS erythroid precursors undergoing apoptosis, indicating a role for the ER in the death pathway, upstream of the mitochondria. MDS erythroid precursors demonstrated elevated ER Ca(2+) stores and these stores remained unaffected by ER-targeted Bcl-2. The ER-associated protein Bcl-2-associated protein (BAP) 31 was cleaved by caspase-8 in MDS erythroid precursors undergoing apoptosis. The protective effect of ER-targeted Bcl-2 toward spontaneous and Fas-induced apoptosis correlated with inhibition of BAP31 cleavage. A protective effect of erythropoietin against Fas-induced BAP31 cleavage and apoptosis was observed. We propose that apoptosis of MDS erythroid precursors involves the ER, downstream of Fas and upstream of the mitochondria, through the cleavage of the ER-associated BAP31 protein.
year | journal | country | edition | language |
---|---|---|---|---|
2008-10-01 |