PPAR-γ agonist stabilizes KLF4 protein via activating Akt signaling and reducing KLF4 ubiquitination.
PPAR-γ agonist stabilizes KLF4 protein via activating Akt signaling and reducing KLF4 ubiquitination.
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DOI：
10.1016/j.bbrc.2013.11.129
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发表时间：
2014-01
影响因子：
3.1
通讯作者：
Yan Sun;Bin Zheng;Xinhua Zhang;M. He;Zong-wei Guo;J. Wen
中科院分区：
文献类型：
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作者：
Yan Sun;Bin Zheng;Xinhua Zhang;M. He;Zong-wei Guo;J. Wen
过氧化物酶体增殖物激活受体γ（Peroxisome proliferator activated receptor γ，PPAR-γ）在细胞周期调控、分化和凋亡中起重要作用。Krüppel样因子4（KLF 4）调节血管平滑肌细胞（VSMC）表型。KLF 4和PPAR-γ均参与VSMC的增殖和分化。然而，KLF 4和PPAR-γ在VSMCs中的实际关系尚不清楚。在这项研究中，我们发现PPAR-γ激动剂吡格列酮增加KLF 4蛋白水平，但不影响KLF 4基因转录。PPAR-γ过表达增加，而PPAR-γ敲低降低KLF 4表达，表明吡格列酮诱导的KLF 4蛋白水平增加具有PPAR-γ依赖性。进一步的研究表明，吡格列酮通过减少KLF 4泛素化而增强KLF 4蛋白的稳定性。此外，我们证明吡格列酮对KLF 4的稳定性与Akt信号通路的激活有关。综上所述，我们揭示了PPAR-γ激动剂吡格列酮通过激活Akt信号和减少KLF 4泛素化来稳定KLF 4蛋白，从而进一步了解了VSMCs中PPAR-γ和KLF 4相互调控的表达。
Peroxisome proliferator activated receptor γ (PPAR-γ) plays important roles in cell cycle regulation, differentiation and apoptosis. Krüppel-like factor 4 (KLF4) modulates vascular smooth muscle cell (VSMC) phenotype. Both KLF4 and PPAR-γ are involved in VSMC proliferation and differentiation. However, the actual relationship between KLF4 and PPAR-γ in VSMCs is not clear. In this study, we found that PPAR-γ agonist pioglitazone increases KLF4 protein levels but does not influence KLF4 gene transcription. PPAR-γ overexpression increases, while PPAR-γ knockdown reduces KLF4 expression, suggesting that the increase in KLF4 protein levels induced by pioglitazone is PPAR-γ-dependent. Further study showed that pioglitazone enhances KLF4 protein stability through reducing KLF4 ubiquitination. Furthermore, we demonstrated that stabilization of KLF4 by pioglitazone was related to the activation of Akt signaling pathway. Taken together, we revealed that PPAR-γ agonist pioglitazone stabilizes KLF4 protein via activating Akt signaling and reducing KLF4 ubiquitination, providing further insights into PPAR-γ and KLF4 in regulating each other’s expression in VSMCs.