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

Akt kinase is activated by transforming growth factor-beta1 (TGF-β) in diabetic kidneys and plays important roles in fibrosis, hypertrophy and cell survival in glomerular mesangial cells (MC)1–11. However, the mechanisms of Akt activation by TGF-β are not fully understood. Here we show that TGF-β ac...

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Detalles Bibliográficos
Autores principales: Kato, Mitsuo, Putta, Sumanth, Wang, Mei, Yuan, Hang, Lanting, Linda, Nair, Indu, Gunn, Amanda, Nakagawa, Yoshimi, Shimano, Hitoshi, Todorov, Ivan, Rossi, John J., Natarajan, Rama
Formato: Texto
Lenguaje:English
Publicado: 2009
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2744130/
https://www.ncbi.nlm.nih.gov/pubmed/19543271
http://dx.doi.org/10.1038/ncb1897
Descripción
Sumario:Akt kinase is activated by transforming growth factor-beta1 (TGF-β) in diabetic kidneys and plays important roles in fibrosis, hypertrophy and cell survival in glomerular mesangial cells (MC)1–11. However, the mechanisms of Akt activation by TGF-β are not fully understood. Here we show that TGF-β activates Akt in MC by inducing microRNA-216a (miR-216a) and miR-217, both of which target phosphatase and tensin homologue (PTEN). Both these miRs are located within the second intron of a non-coding RNA (RP23-298H6.1-001). The RP23 promoter was activated by TGF-β and also by miR-192 via E-box-regulated mechanisms as shown previously3. Akt activation by these miRs also led to MC survival and hypertrophy similar to TGF-β. These studies reveal a mechanism of Akt activation via PTEN downregulation by two miRs regulated by upstream miR-192 and TGF-β. Due to the diversity of PTEN function12, 13, this miR amplifying circuit may play key roles not only in kidney disorders, but also other diseases.

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