Germain Marc, Duronio Vincent
Department of Medicine, University of British Columbia and Vancouver Coastal Health Research Institute, Jack Bell Research Centre, Vancouver, British Columbia V6H 3Z6, Canada.
J Biol Chem. 2007 Nov 2;282(44):32233-42. doi: 10.1074/jbc.M706408200. Epub 2007 Sep 6.
The BCL-2 homologue MCL-1 plays an important role in the regulation of cell fate by blocking apoptosis as well as regulating cell cycle. MCL-1 has an unusual N-terminal extension, which contains a PEST domain and several phosphorylation sites that have been suggested to regulate its turnover. Here we report that the first 79 amino acids of MCL-1 regulate its subcellular localization. Deletion of this domain impairs both its mitochondrial localization and its anti-apoptotic activity. Conversely, expression of the N terminus of MCL-1 promotes both the association of MCL-1 with mitochondria and cell survival in a fashion that is dependent on the presence of endogenous MCL-1. In addition, the N terminus of MCL-1 has an antagonistic effect on proliferation. Although MCL-1 decreases proliferation through binding to proliferating cell nuclear antigen and cyclin-dependent kinase 1 in the nucleus, the N terminus of MCL-1 accelerates cell division. On the other hand, deletion of this region further increases the anti-proliferative activity of MCL-1. These results suggest that the N terminus of MCL-1 plays a major regulatory role, regulating coordinately the mitochondrial (anti-apoptotic) and nuclear (anti-proliferative) functions of MCL-1.
BCL-2同源物MCL-1通过阻止细胞凋亡以及调节细胞周期，在细胞命运调控中发挥重要作用。MCL-1具有一个不寻常的N端延伸，其中包含一个PEST结构域和几个磷酸化位点，这些位点被认为可调节其周转。在此我们报告，MCL-1的前79个氨基酸调节其亚细胞定位。缺失该结构域会损害其线粒体定位及其抗凋亡活性。相反，MCL-1 N端的表达以依赖内源性MCL-1存在的方式促进MCL-1与线粒体的结合以及细胞存活。此外，MCL-1的N端对增殖具有拮抗作用。虽然MCL-1通过与细胞核中的增殖细胞核抗原和细胞周期蛋白依赖性激酶1结合来降低增殖，但MCL-1的N端会加速细胞分裂。另一方面，缺失该区域会进一步增强MCL-1的抗增殖活性。这些结果表明，MCL-1的N端起主要调节作用，协同调节MCL-1的线粒体（抗凋亡）和细胞核（抗增殖）功能。
