Institute of Molecular Biology, Medical School Hannover, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
Biochem Biophys Res Commun. 2013 Feb 22;431(4):753-9. doi: 10.1016/j.bbrc.2013.01.037. Epub 2013 Jan 16.
Anders et al. (2011) [11] reported that cyclinD1/Cdk4 and cyclinD3/Cdk6 enhance the transcriptional activity of FOXM1c by phosphorylating its TAD. They defined 12 Cdk consensus sites as essential for the activation of FOXM1c by cyclinD1/Cdk4 and cyclinD3/Cdk6 and stated that the 12 Cdk-sites are positioned within the TAD of FOXM1c. In contrast, this study demonstrates that all potential cyclin/Cdk phosphorylation sites S/T-P of FOXM1c are located outside its TAD so that the TAD of FOXM1c contains no potential cyclin/Cdk site, which excludes a phosphorylation of the FOXM1c-TAD by cyclinD1/Cdk4 and cyclinD3/Cdk6. This study shows that the activation of FOXM1c by cyclinD1/Cdk4 is lost without removal of any cyclin/Cdk site and gained without addition of any cyclin/Cdk site because it depends on a FOXM1c domain with no potential cyclin/Cdk site, namely on the interaction domain for the tumor suppressor RB, which binds to and represses FOXM1c. CyclinD1/Cdk4 activates FOXM1c because cyclinD1/Cdk4 releases FOXM1c from its repression by RB through removal of RB from FOXM1c. For this purpose, cyclinD1/Cdk4 phosphorylates only RB, but not FOXM1c, so that cyclinD1/Cdk4 increases the transcriptional activity of FOXM1c without phosphorylating FOXM1c and activates FOXM1c independently of cyclin/Cdk phosphorylation sites in FOXM1c. In summary, this study changes the model of Anders et al. (2011) [11] completely because it disproves their central conclusion that cyclinD1/Cdk4 and cyclinD3/Cdk6 enhance the transcriptional activity of FOXM1c by phosphorylating its TAD at the 12 Cdk-sites.
安德斯等人（2011 年）[11]报道称，cyclinD1/Cdk4 和 cyclinD3/Cdk6 通过磷酸化其 TAD 来增强 FOXM1c 的转录活性。他们将 12 个 Cdk 共有位点定义为 cyclinD1/Cdk4 和 cyclinD3/Cdk6 激活 FOXM1c 所必需的，并指出这 12 个 Cdk 位点位于 FOXM1c 的 TAD 内。相比之下，本研究表明，FOXM1c 的所有潜在 cyclin/Cdk 磷酸化位点 S/T-P 都位于其 TAD 之外，因此 FOXM1c 的 TAD 内没有潜在的 cyclin/Cdk 位点，这排除了 cyclinD1/Cdk4 和 cyclinD3/Cdk6 对 FOXM1c-TAD 的磷酸化。本研究表明，cyclinD1/Cdk4 对 FOXM1c 的激活既不需要去除任何 cyclin/Cdk 位点，也不需要添加任何 cyclin/Cdk 位点，因为它依赖于一个没有潜在 cyclin/Cdk 位点的 FOXM1c 结构域，即与肿瘤抑制因子 RB 的相互作用结构域，RB 结合并抑制 FOXM1c。cyclinD1/Cdk4 激活 FOXM1c 是因为 cyclinD1/Cdk4 通过从 FOXM1c 上去除 RB 来解除 RB 对 FOXM1c 的抑制。为此，cyclinD1/Cdk4 只磷酸化 RB，而不磷酸化 FOXM1c，因此 cyclinD1/Cdk4 增加了 FOXM1c 的转录活性，而不磷酸化 FOXM1c，并独立于 FOXM1c 中的 cyclin/Cdk 磷酸化位点激活 FOXM1c。总之，本研究完全改变了安德斯等人（2011 年）[11]的模型，因为它推翻了他们的核心结论，即 cyclinD1/Cdk4 和 cyclinD3/Cdk6 通过磷酸化其 TAD 上的 12 个 Cdk 位点增强 FOXM1c 的转录活性。
