Control of cyclin G2 mRNA expression by forkhead transcription factors:: Novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkhead
Control of cyclin G2 mRNA expression by forkhead transcription factors:: Novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkhead
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DOI：
10.1128/mcb.24.5.2181-2189.2004
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发表时间：
2004-03-01
影响因子：
5.3
通讯作者：
Carrera, AC
中科院分区：
文献类型：
--
作者：
Martínez-Gac, L;Marqués, M;Carrera, AC
细胞周期蛋白G2是一种在有丝分裂后细胞中高度表达的非常规细胞周期蛋白。与促进细胞周期进程的经典细胞周期蛋白不同，细胞周期蛋白G2阻断细胞周期进入。在这里，我们研究了在细胞周期中调控cyclin G2 mRNA表达的机制。对同步NIH 3 T3细胞培养物的分析显示，G（0）时细胞周期蛋白G2 mRNA表达水平升高，随着细胞进入细胞周期，表达水平显着降低。细胞周期蛋白G2 mRNA水平的下调需要磷酸肌醇3-激酶的激活，这表明这种酶控制细胞周期蛋白G2 mRNA的表达。由于磷酸肌醇3-激酶途径抑制FoxO家族的叉头转录因子，我们研究了这些因子参与调控细胞周期蛋白G2的表达。我们发现，叉头转录因子FoxO 3a（FKHRL 1）的活性形式增加细胞周期蛋白G2 mRNA水平。细胞周期蛋白G2在其启动子中具有叉头共有基序，其被组成型活性FoxO 3a形式反式激活。最后，干扰叉头介导的转录过表达的非活性形式降低细胞周期蛋白G2 mRNA的表达水平。这些结果表明，FoxO基因调节细胞周期蛋白G2的表达，说明磷酸肌醇3-激酶和FoxO转录因子在控制细胞周期进入的新作用。
Cyclin G2 is an unconventional cyclin highly expressed in postmitotic cells. Unlike classical cyclins that promote cell cycle progression, cyclin G2 blocks cell cycle entry. Here we studied the mechanisms that regulate cyclin G2 mRNA expression during the cell cycle. Analysis of synchronized NIH 3T3 cell cultures showed elevated cyclin G2 mRNA expression levels at G(0), with a considerable reduction as cells enter cell cycle. Downregulation of cyclin G2 mRNA levels requires activation of phosphoinositide 3-kinase, suggesting that this enzyme controls cyclin G2 mRNA expression. Because the phosphoinositide 3-kinase pathway inhibits the FoxO family of forkhead transcription factors, we examined the involvement of these factors in the regulation of cyclin G2 expression. We show that active forms of the forkhead transcription factor FoxO3a (FKHRL1) increase cyclin G2 mRNA levels. Cyclin G2 has forkhead consensus motifs in its promoter, which are transactivated by constitutive active FoxO3a forms. Finally, interference with forkhead-mediated transcription by overexpression of an inactive form decreases cyclin G2 mRNA expression levels. These results show that FoxO genes regulate cyclin G2 expression, illustrating a new role for phosphoinositide 3-kinase and FoxO transcription factors in the control of cell cycle entry.