Journal
NATURE CELL BIOLOGY
Volume 11, Issue 7, Pages 881-U263Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1897
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Funding
- NIH
- Juvenile Diabetes Research Foundation
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Akt kinase is activated by transforming growth factor-beta 1 (TGF-beta) in diabetic kidneys, and has important roles in fibrosis, hypertrophy and cell survival in glomerular mesangial cells(1-11). However, the mechanisms of Akt activation by TGF-beta are not fully understood. Here we show that TGF-beta activates Akt in glomerular mesangial cells by inducing the microRNAs (miRNAs) miR-216a and miR-217, both of which target PTEN (phosphatase and tensin homologue), an inhibitor of Akt activation. These miRNAs are located within the second intron of a non-coding RNA (RP23-298H6.1-001). The RP23 promoter was activated by TGF-beta and miR-192 through E-box-regulated mechanisms, as shown previously(3). Akt activation by these miRs led to glomerular mesangial cell survival and hypertrophy, which were similar to the effects of activation by TGF-beta. These studies reveal a mechanism of Akt activation through PTEN downregulation by two miRs, which are regulated by upstream miR-192 and TGF-beta. Due to the diversity of PTEN function(12,13), this miR-amplifying circuit may have key roles, not only in kidney disorders, but also in other diseases.
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