Curcumin Inhibits 3T3-L1 Preadipocyte Proliferation by Mechanisms Involving Post-transcriptional p27 Regulation.
Curcumin Inhibits 3T3-L1 Preadipocyte Proliferation by Mechanisms Involving Post-transcriptional p27 Regulation.
复制标题
DOI：
10.1016/j.bbrep.2015.11.014
复制
发表时间：
2016-03-01
影响因子：
2.7
通讯作者：
Morrison RF
中科院分区：
文献类型：
--
作者：
Ferguson BS;Nam H;Morrison RF
我们实验室之前的报告表明，在脂肪细胞分化过程中，Skp2是p27降解和细胞周期进程所必需的。本研究的数据表明，抗炎、抗肥胖的植物化学物质姜黄素在早期脂肪细胞增生过程中阻断了Skp2蛋白的积累。此外，姜黄素剂量依赖性诱导p27蛋白积累和同步复制3T3-L1前脂肪细胞G1阻滞。值得注意的是，p27蛋白的积累发生在p27 mRNA减少的情况下，这表明p27蛋白在转录后调控中起作用。姜黄素显著增加了p27蛋白的半衰期，并减弱了泛素蛋白酶体的活性，这表明抑制p27蛋白水解是通过姜黄素介导的Skp2和26S蛋白酶体活性的减弱来实现的。虽然我们观察到姜黄素在剂量小于20µM时没有细胞毒性作用，但重要的是要注意到浓度大于30µM时凋亡信号的增加。最后，本文的数据表明，姜黄素的抗增殖作用对抑制脂肪细胞分化和成熟脂肪细胞的发育至关重要。总的来说，我们的数据表明，姜黄素介导的p27转录后积累部分解释了在3T3-L1前脂肪细胞中观察到的抗增殖作用。姜黄素在细胞周期进程中抑制脂肪形成的早期阶段。姜黄素通过翻译后机制增加p27蛋白。姜黄素抑制Skp2蛋白，Skp2蛋白指导p27泛素化。p27的积累可能是G1晚期阻滞和脂肪形成抑制的原因。姜黄素抗肥胖作用的潜在机制。
Previous reports from our lab have shown that Skp2 is necessary for p27 degradation and cell cycle progression during adipocyte differentiation. Data presented here demonstrate that the anti-inflammatory, anti-obesity phytochemical curcumin blocked Skp2 protein accumulation during early adipocyte hyperplasia. In addition, curcumin dose-dependently induced p27 protein accumulation and G1 arrest of synchronously replicating 3T3-L1 preadipocytes. Of note, p27 protein accumulation occurred in the presence of decreased p27 mRNA suggesting a role for post-transcriptional regulation. In support of this hypothesis, curcumin markedly increased p27 protein half-life as well as attenuated ubiquitin proteasome activity suggesting that inhibition of targeted p27 proteolysis occurred through curcumin-mediated attenuation of Skp2 and 26S proteasome activity. While we observed no cytotoxic effects for curcumin at doses less than 20 µM, it is important to note an increase in apoptotic signaling at concentrations greater than 30 µM. Finally, data presented here demonstrate that the anti-proliferative effect of curcumin was critical for the suppression of adipocyte differentiation and the development of the mature adipocyte. Collectively, our data demonstrate that curcumin-mediated post-transcriptional accumulation of p27 accounts in part for the anti-proliferative effect observed in 3T3-L1 preadipocytes. Curcumin inhibited early stages of adipogenesis during cell cycle progression. Curcumin increased p27 protein through post-translational mechanisms. Curcumin suppressed Skp2 protein which directs p27 ubiquitylation. p27 accumulation may account for late G1 arrest and suppression of adipogenesis. Potential mechanism regarding anti-obesity effects of curcumin.