Letter abstract
Nature Cell Biology 11, 881 - 889 (2009)
Published online: 21 June 2009 | doi:10.1038/ncb1897
TGF-
activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN
Mitsuo Kato1, Sumanth Putta1,2, Mei Wang1, Hang Yuan1, Linda Lanting1, Indu Nair1, Amanda Gunn2, Yoshimi Nakagawa4, Hitoshi Shimano4, Ivan Todorov1, John J. Rossi2,3 & Rama Natarajan1,2
Akt kinase is activated by transforming growth factor-
1 (TGF-) in diabetic kidneys, and has important roles in fibrosis, hypertrophy and cell survival in glomerular mesangial cells1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. However, the mechanisms of Akt activation by TGF- are not fully understood. Here we show that TGF- 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- and miR-192 through E-box-regulated mechanisms, as shown previously3. Akt activation by these miRs led to glomerular mesangial cell survival and hypertrophy, which were similar to the effects of activation by TGF-. These studies reveal a mechanism of Akt activation through PTEN downregulation by two miRs, which are regulated by upstream miR-192 and TGF-. Due to the diversity of PTEN function12, 13, this miR-amplifying circuit may have key roles, not only in kidney disorders, but also in other diseases.
- Gonda Diabetes Center, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
- Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
- Division of Molecular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
- Department of Internal Medicine, Metabolism and Endocrinology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Correspondence to: Mitsuo Kato1 e-mail: mkato@coh.org
Correspondence to: Rama Natarajan1,2 e-mail: rnatarajan@coh.org
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