title: The microRNA-21-PDCD4 axis prevents type 1 diabetes by blocking pancreatic beta cell death.
abstract: Death of pancreatic β cells is a pathological hallmark of type 1 diabetes (T1D). However, the molecular mechanisms of β cell death and its regulation are poorly understood. Here we describe a unique regulatory pathway of β cell death that comprises microRNA-21, its target tumor suppressor PDCD4, and its upstream transcriptional activator nuclear factor-κB (NF-κB). In pancreatic β cells, c-Rel and p65 of the NF-κB family activated the mir21 gene promoter and increased miR-21 RNA levels; miR-21 in turn decreased the level of PDCD4, which is able to induce cell death through the Bax family of apoptotic proteins. Consequently, PDCD4 deficiency in pancreatic β cells renders them resistant to death, and PDCD4 deficiency in NOD or C57BL/6 mice conferred resistance to spontaneous diabetes and diabetes induced by autoimmune T cells or the β cell toxin streptozotocin (STZ). Thus, the NF-κB-microRNA-21-PDCD4 axis plays a crucial role in T1D and represents a unique therapeutic target for treating the disease.
authors: Department of Pathology and Laboratory of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors: Qingguo
authors: Q
authors: Ruan
authors: Ting
authors: T
authors: Wang
authors: Vasumathi
authors: V
authors: Kameswaran
authors: Qin
authors: Q
authors: Wei
authors: Derek S
authors: DS
authors: Johnson
authors: Franz
authors: F
authors: Matschinsky
authors: Weiyun
authors: W
authors: Shi
authors: Youhai H
authors: YH
authors: Chen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000517:prevention & control; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D015151:Immunoblotting; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D016328:NF-kappa B; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins