Glavic Alvaro, Molnar Cristina, Cotoras Darko, de Celis José F
Millennium Nucleus Center for Genomics of the Cell, Department of Biology, Faculty of Sciences, University of Chile, Las Palmeras 3425, Santiago, Chile.
Mech Dev. 2009 Mar-Apr;126(3-4):184-97. doi: 10.1016/j.mod.2008.11.005. Epub 2008 Nov 28.
Cell division rates and apoptosis sculpt the growing organs, and its regulation implements the developmental programmes that define organ size and shape. The balance between oncogenes and tumour suppressors modulate the cell cycle and the apoptotic machinery to achieve this goal, promoting and restricting proliferation or, in certain conditions, inducing the apoptotic programme. Analysis of human cancer cells with mutation in AXIN gene has uncovered the potential function of AXUD1 as a tumour suppressor. It has been described that Human AXUD1 is a nuclear protein. We find that a DAxud1-GFP fusion protein is localised to the nucleus during interphase, where it accumulates associated to the nuclear envelope, but becomes distributed in a diffused pattern in the nucleus of mitotic cells. We have analysed the function of the Drosophila AXUD1 homologue, and find that DAxud1 behaves as a tumour suppressor that regulates the proliferation rhythm of imaginal cells. Knocking down the activity of DAxud1 enhances the proliferation of these cells, causing in addition a reduction in cell size. Conversely, the increase in DAxud1 expression impedes cell cycle progression at mitosis through disturbance of Cdk1 activity, and induces the apoptosis of these cells in a JNK-dependent manner.
细胞分裂速率和细胞凋亡塑造了生长中的器官,而其调控执行着定义器官大小和形状的发育程序。原癌基因和肿瘤抑制因子之间的平衡调节细胞周期和凋亡机制以实现这一目标,促进和限制细胞增殖,或在某些情况下诱导凋亡程序。对AXIN基因突变的人类癌细胞的分析揭示了AXUD1作为肿瘤抑制因子的潜在功能。据描述,人类AXUD1是一种核蛋白。我们发现,DAxud1-GFP融合蛋白在间期定位于细胞核,在那里它与核膜相关联而积累,但在有丝分裂细胞的细胞核中呈弥散分布模式。我们分析了果蝇AXUD1同源物的功能,发现DAxud1作为一种肿瘤抑制因子,调节成虫盘细胞的增殖节奏。敲低DAxud1的活性会增强这些细胞的增殖,此外还会导致细胞大小减小。相反,DAxud1表达的增加通过干扰Cdk1活性在有丝分裂时阻碍细胞周期进程,并以JNK依赖的方式诱导这些细胞凋亡。