Luo Lingfei, Yang Xiaoping, Takihara Yoshihiro, Knoetgen Hendrik, Kessel Michael
Research Group Developmental Biology, Department of Molecular Cell Biology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
Nature. 2004 Feb 19;427(6976):749-53. doi: 10.1038/nature02305.
Embryonic development is tightly controlled. The clustered genes of the Hox family of homeobox proteins play an important part in regulating this development and also proliferation. They specify embryonic structures along the body axis, and are associated with normal and malignant cell growth. The cell-cycle regulator geminin controls replication by binding to the licensing factor Cdt1, and is involved in neural differentiation. Here, we show that murine geminin associates transiently with members of the Hox-repressing polycomb complex, with the chromatin of Hox regulatory DNA elements and with Hox proteins. Gain- and loss-of-function experiments in the chick neural tube demonstrate that geminin modulates the anterior boundary of Hoxb9 transcription, which suggests a polycomb-like activity for geminin. The interaction between geminin and Hox proteins prevents Hox proteins from binding to DNA, inhibits Hox-dependent transcriptional activation of reporter and endogenous downstream target genes, and displaces Cdt1 from its complex with geminin. By establishing competitive regulation, geminin functions as a coordinator of developmental and proliferative control.
胚胎发育受到严格调控。同源异型框蛋白Hox家族的成簇基因在调节这种发育以及增殖过程中发挥着重要作用。它们沿着身体轴线指定胚胎结构，并与正常和恶性细胞生长相关。细胞周期调节因子geminin通过与许可因子Cdt1结合来控制复制，并参与神经分化。在此，我们表明小鼠geminin与Hox抑制性多梳复合体的成员、Hox调控DNA元件的染色质以及Hox蛋白短暂结合。在鸡神经管中进行的功能获得和功能丧失实验表明，geminin调节Hoxb9转录的前边界，这表明geminin具有类似多梳的活性。geminin与Hox蛋白之间的相互作用可阻止Hox蛋白与DNA结合，抑制报告基因和内源性下游靶基因的Hox依赖性转录激活，并使Cdt1从其与geminin的复合物中解离。通过建立竞争性调控，geminin作为发育和增殖控制的协调者发挥作用。
