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

Abstract	Akt kinase is activated by transforming growth factor-beta1 (TGF-beta) 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-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. 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, this miR-amplifying circuit may have key roles, not only in kidney disorders, but also in other diseases.
Authors	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
Journal	Nature cell biology (Nat Cell Biol) Vol. 11 Issue 7 Pg. 881-9 (Jul 2009) ISSN: 1476-4679 [Electronic] England
PMID	19543271 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	MicroRNAs Transforming Growth Factor beta Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase
Topics	Animals Apoptosis (drug effects) Base Sequence Blotting, Western Cells, Cultured Hypertrophy (chemically induced) Immunohistochemistry In Situ Hybridization Mesangial Cells (cytology, drug effects, metabolism) Mice Mice, Inbred C57BL MicroRNAs (antagonists & inhibitors, genetics, physiology) PTEN Phosphohydrolase (metabolism) Proto-Oncogene Proteins c-akt (metabolism) Reverse Transcriptase Polymerase Chain Reaction Sequence Homology, Nucleic Acid Signal Transduction (drug effects) Transforming Growth Factor beta (pharmacology)

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