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Targeting CERT sensitizes AML Cells to FLT3 Inhibitors through activating GRP78-ATF6-CHOP Axis

ABSTRACT: Targeting CERT sensitizes AML Cells to FLT3 Inhibitors through activating GRP78-ATF6-CHOP Axis

PROVIDER: PRJNA1178294 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31130900_1.fastq.gz	Fastqsanger.gz
	SRR31130900_2.fastq.gz	Fastqsanger.gz
	SRR31130901_1.fastq.gz	Fastqsanger.gz
	SRR31130901_2.fastq.gz	Fastqsanger.gz
	SRR31130902_1.fastq.gz	Fastqsanger.gz

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Project description:Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, has been linked to endoplasmic reticulum (ER) stress. To investigate a causal role for ER stress in BPD pathogenesis, we generated mice (cGrp78f/f) with lung epithelial cell-specific knockout (KO) of Grp78, a gene encoding the ER chaperone 78-kDa glucose-regulated protein (GRP78), a master regulator of ER homeostasis and the unfolded protein response (UPR). Lung epithelial-specific Grp78 KO disrupted lung morphogenesis, causing developmental arrest, increased alveolar epithelial type II cell apoptosis and decreased surfactant protein and type I cell marker expression in perinatal lungs. cGrp78f/f pups died immediately after birth, likely due to respiratory distress. Importantly, Grp78 KO triggered UPR activation with marked induction of pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Increased expression of genes involved in oxidative stress and cell death and decreased expression of genes encoding antioxidant enzymes suggest a role for oxidative stress in alveolar epithelial cell (AEC) apoptosis. Increased Smad3 phosphorylation and expression of transforming growth factor-Î² (TGF-Î²)/Smad3 targets Cdkn1a (encoding p21) and Gadd45a suggest that interactions among the apoptotic arm of the UPR, oxidative stress and TGF-Î²/Smad signaling pathways contribute to Grp78 KO-induced AEC apoptosis and developmental arrest. Chemical chaperone taursodeoxycholic acid reduced UPR activation and apoptosis in cGrp78f/f lungs cultured ex vivo, confirming a role for ER stress in observed AEC abnormalities. These results demonstrate a key role for GRP78 in AEC survival and gene expression during lung development through modulation of ER stress and suggest the UPR as a potential therapeutic target in BPD. Whole-genome expression profiling was performed using MouseRef-8 v2.0 Expression BeadChips (Illumina) on RNA isolated from lungs of four Grp78f/f and three cGrp78f/f mice at E18.

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Targeting CERT sensitizes AML Cells to FLT3 Inhibitors through activating GRP78-ATF6-CHOP Axis

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