Petrovic Vladimir, Costa Robert H, Lau Lester F, Raychaudhuri Pradip, Tyner Angela L
Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, Chicago, Illinois 60607.
Department of Biochemistry and Molecular Genetics, University of Illinois College of Medicine, Chicago, Illinois 60607.
J Biol Chem. 2008 Jan 4;283(1):453-460. doi: 10.1074/jbc.M705792200. Epub 2007 Nov 5.
The Forkhead box M1 (FoxM1) transcription factor is essential for cell cycle progression and mitosis. FoxM1 regulates expression of Skp2 and Cks1, subunits of the SCF ubiquitin ligase complex, which ubiquitinates p27(Kip1) and targets it for degradation. Kinase-interacting stathmin (KIS) is a growth factor-dependent nuclear kinase that regulates cell cycle progression by phosphorylating p27(Kip1) to promote its nuclear export. Here we present an additional mechanism of FoxM1-mediated regulation of p27(Kip1) and provide evidence that FoxM1 regulates growth factor-induced expression of KIS. In cells harboring FoxM1 deletion or expressing FoxM1-short interfering RNA, the expression of KIS is impaired, leading to an accumulation of p27(Kip1) in the nucleus. Furthermore, we show that KIS is a direct transcriptional target of FoxM1. Thus FoxM1 promotes cell cycle progression by down-regulating p27(Kip1) through multiple mechanisms.
叉头框M1（FoxM1）转录因子对于细胞周期进程和有丝分裂至关重要。FoxM1调节SCF泛素连接酶复合体的亚基Skp2和Cks1的表达，该复合体会使p27（Kip1）泛素化并将其靶向降解。激酶相互作用的微管相关蛋白（KIS）是一种依赖生长因子的核激酶，它通过磷酸化p27（Kip1）来促进其核输出，从而调节细胞周期进程。在此，我们提出了FoxM1介导的p27（Kip1）调控的另一种机制，并提供证据表明FoxM1调节生长因子诱导的KIS表达。在缺失FoxM1或表达FoxM1短发夹RNA的细胞中，KIS的表达受损，导致p27（Kip1）在细胞核中积累。此外，我们表明KIS是FoxM1的直接转录靶点。因此，FoxM1通过多种机制下调p27（Kip1）来促进细胞周期进程。
