The activation of NF-κB through Akt-induced FOXO1 phosphorylation during aging and its modulation by calorie restriction
The activation of NF-κB through Akt-induced FOXO1 phosphorylation during aging and its modulation by calorie restriction
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DOI：
10.1007/s10522-007-9114-6
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发表时间：
2008-02-01
期刊：
影响因子：
4.5
通讯作者：
Chung, Hae Young
中科院分区：
文献类型：
--
作者：
Kim, Dae Hyun;Kim, Ji Young;Chung, Hae Young
已知胰岛素诱导的PI 3 K/Akt活化抑制叉头转录因子（FOXO）家族，其可导致几种模式生物中氧化应激增加。NF-κ B是氧化应激激活的主要转录因子之一，负责产生许多促炎细胞因子。在本研究中，我们进行了确定FOXO 1和NF-κ B B激活之间的关系，使用HEK 293 T细胞和从自由采食（AL）和40%热量限制（CR）大鼠分离的老化肾脏。结果显示，老年大鼠FOXO 1磷酸化和NF-κ B B活化明显增强。此外，与24月龄AL大鼠相比，CR大鼠的FOXO 1磷酸化和NF-κ B活化显着降低。为了进一步探索FOXO和NF-κ B B之间的分子联系，我们在培养的HEK 293 T细胞中用FOXO突变质粒进行转染实验。用胰岛素处理细胞导致NF-κ B通过经由PI 3 K/Akt途径的FOXO磷酸化而活化。这些结果表明，胰岛素通过上调PI 3 K/Akt信号转导，通过FOXO 1磷酸化促进NF-κ B活化。我们的结论是，FOXO 1的磷酸化调节NF-κ B B核转位通过激活PI 3 K/Akt在老化过程中，这是抑制低胰岛素作用的CR。
Insulin-induced PI3K/Akt activation is known to inhibit a family of Forkhead transcription factors (FOXO), which can lead to increased oxidative stress in several model organisms. One of major transcription factors activated by oxidative stress and responsible for the production of many proinflammatory cytokines is NF-kappa B. In the present study, We were carried out to determine the relationship between FOXO1 and NF-kappa B activation using HEK293T cells and aged kidney isolated from ad libitum fed (AL) and 40% calorie restriction (CR) rats. Results showed that phosphorylation of FOXO1 and NF-kappa B activation were significantly increased in old rats. Moreover, FOXO1 phosphorylation and NF-kappa B activation were shown to be significantly lower in the CR rats compared with 24-month-old AL rats. To further explore the molecular link between FOXO and NF-kappa B, we performed transfection experiments with FOXO-mutant plasmid in cultured HEK293T cells. Treatment of the cell with insulin led to NF-kappa B activation through the phosphorylation of FOXO via the PI3K/Akt pathway. These results indicate that insulin promoted NF-kappa B activation through phosphorylation of FOXO1 by upregulating PI3K/Akt signaling. We conclude that the phosphorylation of FOXO1 regulates NF-kappa B nuclear translocation by activating PI3K/Akt during aging, which was suppressed by the hypoinsulinemic action of CR.