Komatsu Yoko, Ito Ichiaki, Wayama Mitsutoshi, Fujimura Akiko, Akaogi Kensuke, Machida Hikaru, Nakajima Yuka, Kuroda Takao, Ohmori Kazuji, Murayama Akiko, Kimura Keiji, Yanagisawa Junn
Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan.
Biochem Biophys Res Commun. 2008 May 23;370(1):145-8. doi: 10.1016/j.bbrc.2008.03.046. Epub 2008 Mar 18.
PPARgamma is a nuclear hormone receptor that plays a key role in the induction of peroxisome proliferation. A number of studies showed that PPARgamma ligands suppress cell cycle progression; however, the mechanism remains to be determined. Here, we showed that PPARgamma ligand troglitazone inhibited G1/S transition in colon cancer cells, LS174T. Troglitazone did not affect on either expression of CDK inhibitor (p18) or Wnt signaling pathway, indicating that these pathways were not involved in the troglitazone-dependent cell cycle arrest. GeneChip and RT-PCR analyses revealed that troglitazone decreased mRNA levels of cell cycle regulatory factors E2F2 and cyclin-E1 whose expression is activated by E2F2. Down-regulation of E2F2 by troglitazone results in decrease of cyclin-E1 transcription, which could inhibit phosphorylation of Rb protein, and consequently evoke the suppression of E2F2 transcriptional activity. Thus, we propose that troglitazone suppresses the feedback loop containing E2F2, cyclin-E1, and Rb protein.
过氧化物酶体增殖物激活受体γ（PPARγ）是一种核激素受体，在过氧化物酶体增殖的诱导过程中起关键作用。多项研究表明，PPARγ配体可抑制细胞周期进程；然而，其机制仍有待确定。在此，我们发现PPARγ配体曲格列酮可抑制结肠癌细胞LS174T中的G1/S期转换。曲格列酮对细胞周期蛋白依赖性激酶抑制剂（p18）的表达或Wnt信号通路均无影响，这表明这些通路不参与曲格列酮依赖性细胞周期阻滞。基因芯片和逆转录-聚合酶链反应分析显示，曲格列酮可降低细胞周期调节因子E2F2和细胞周期蛋白E1的mRNA水平，而E2F2可激活细胞周期蛋白E1的表达。曲格列酮对E2F2的下调导致细胞周期蛋白E1转录减少，这可能抑制视网膜母细胞瘤蛋白（Rb蛋白）的磷酸化，从而抑制E2F2的转录活性。因此，我们提出曲格列酮可抑制包含E2F2、细胞周期蛋白E1和Rb蛋白的反馈环。
