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PMID: 19543271 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature cell biology ·Vol. 11 ·No. 7 ·2009-07-00 ·Pages 881-9

Kato M, Putta S, Wang M, Yuan H, Lanting L, Nair I, Gunn A, Nakagawa Y, Shimano H, Todorov I, Rossi JJ, Natarajan R

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.

MeSH Terms
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
Chemicals
MicroRNAs Transforming Growth Factor beta Proto-Oncogene Proteins c-akt PTEN Phosphohydrolase
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Kato Mitsuo
Gonda Diabetes Center, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. [email protected]
Putta Sumanth
Wang Mei
Yuan Hang
Lanting Linda
Nair Indu
Gunn Amanda
Nakagawa Yoshimi
Shimano Hitoshi
Todorov Ivan
Rossi John J
Natarajan Rama
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Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb1897
Email
[email protected]
Published
2009-07-00
Epub
2009-00-21
Pages
881-9
Language
English
Region
England
NLM ID
100890575
PMCID
PMC2744130
Subset
IM
Grants
NIDDK NIH HHS · R21 DK076669-01 · United States
NIDDK NIH HHS · R21 DK076669-02 · United States
NIDDK NIH HHS · R01 DK081705 · United States
NIAID NIH HHS · R01 AI042552 · United States
NIDDK NIH HHS · R21 DK076669 · United States
External Links
PubMed source DOI: 10.1038/ncb1897 PMC Full Text View journal details
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