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.
journal_name
Proc Natl Acad Sci U S Aauthors
Ruan Q,Wang T,Kameswaran V,Wei Q,Johnson DS,Matschinsky F,Shi W,Chen YHdoi
10.1073/pnas.1101450108subject
Has Abstractpub_date
2011-07-19 00:00:00pages
12030-5issue
29eissn
0027-8424issn
1091-6490pii
1101450108journal_volume
108pub_type
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