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

Mitsuo Kato*, Sumanth Putta, Mei Wang, Hang Yuan, Linda Lanting, Indu Nair, Amanda Gunn, Yoshimi Nakagawa, Hitoshi Shimano, Ivan Todorov, John J. Rossi, Rama Natarajan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

537 Scopus citations

Abstract

Akt kinase is activated by transforming growth factor-β1 (TGF-β) in diabetic kidneys, and has important roles in fibrosis, hypertrophy and cell survival in glomerular mesangial cells. However, the mechanisms of Akt activation by TGF-β are not fully understood. Here we show that TGF-β 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-β and miR-192 through E-box-regulated mechanisms, as shown previously. Akt activation by these miRs led to glomerular mesangial cell survival and hypertrophy, which were similar to the effects of activation by TGF-β. These studies reveal a mechanism of Akt activation through PTEN downregulation by two miRs, which are regulated by upstream miR-192 and TGF-β. Due to the diversity of PTEN function, this miR-amplifying circuit may have key roles, not only in kidney disorders, but also in other diseases.

Original languageEnglish
Pages (from-to)881-889
Number of pages9
JournalNature Cell Biology
Volume11
Issue number7
DOIs
StatePublished - 2009/07/01

ASJC Scopus subject areas

  • Cell Biology

Fingerprint

Dive into the research topics of 'TGF-β activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN'. Together they form a unique fingerprint.

Cite this