TGF-beta activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN.
TGF-beta activates Akt kinase through a microRNA-dependent amplifying circuit targeting PTEN.
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DOI：
10.1038/ncb1897
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发表时间：
2009-07
影响因子：
21.3
通讯作者：
Natarajan, Rama
中科院分区：
文献类型：
--
作者：
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
转化生长因子-β1(TGFR-β)在糖尿病肾组织中被激活，在肾小球系膜细胞(MC)的纤维化、肥大和细胞存活中发挥重要作用。然而，转化生长因子-β激活Akt的机制尚不完全清楚。在这里，我们发现转化生长因子-β通过诱导microRNA-216a(miR-216a)和miR-217来激活MC中的Akt，两者都以磷酸酶和张力蛋白同源物(PTEN)为靶标。这两个miR都位于非编码RNA(RP23-298H6.1-001)的第二内含子内。如前所述，RP23启动子被转化生长因子β激活，也被miR-192通过E-box调控机制激活。这些MIR激活AKT也导致MC存活和肥大，类似于转化生长因子-β。这些研究揭示了由上游miR-192和转化生长因子-β调控的两个miRs下调PTEN激活Akt的机制。由于PTEN功能的多样性，这个miR扩增电路可能不仅在肾脏疾病中发挥关键作用，而且在其他疾病中也可能发挥关键作用。
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). 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 previously. 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 function, this miR amplifying circuit may play key roles not only in kidney disorders, but also other diseases.
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影响因子：
14.9
作者：
Sun, YQ;Koo, S;Perera, RJ
通讯作者：
Perera, RJ
影响因子：
8.8
作者：
Omori, K.;Valiente, L.;Mullen, Y.
通讯作者：
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影响因子：
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作者：
Lim, LP;Glasner, ME;Bartel, DP
通讯作者：
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影响因子：
4.6
作者：
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通讯作者：
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DOI：
10.1073/pnas.0611192104
发表时间：
2007-02-27
影响因子：
11.1
作者：
Kato, Mitsuo;Zhang, Jane;Natarajan, Rama
通讯作者：
Natarajan, Rama