TGF-β activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN

被引：514

作者：

Kato, Mitsuo ^{[1
]}

Putta, Sumanth ^{[1
,2
]}

Wang, Mei ^{[1
]}

Yuan, Hang ^{[1
]}

Lanting, Linda ^{[1
]}

Nair, Indu ^{[1
]}

Gunn, Amanda ^{[2
]}

Nakagawa, Yoshimi ^{[4
]}

Shimano, Hitoshi ^{[4
]}

Todorov, Ivan ^{[1
]}

Rossi, John J. ^{[2
,3
]}

Natarajan, Rama ^{[1
,2
]}

机构：

[1] City Hope Natl Med Ctr, Beckman Res Inst, Gonda Diabet Ctr, Duarte, CA 91010 USA

[2] City Hope Natl Med Ctr, Beckman Res Inst, Grad Sch Biol Sci, Duarte, CA 91010 USA

[3] City Hope Natl Med Ctr, Beckman Res Inst, Div Mol Biol, Duarte, CA 91010 USA

[4] Univ Tsukuba, Grad Sch Comprehens Human Sci, Dept Internal Med Metab & Endocrinol, Tsukuba, Ibaraki 3058575, Japan

来源：

NATURE CELL BIOLOGY | 2009年 / 11卷 / 07期

关键词：

GROWTH-FACTOR-BETA; DIABETIC KIDNEY-DISEASE; FIBRONECTIN PRODUCTION; EXPRESSION; HYPERTROPHY; NEPHROPATHY; PATHWAY; TRANSCRIPTION; CELLS; TFE3;

D O I：

10.1038/ncb1897

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：881 / U263

页数：18

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