Daniels Matthew J, Marson Alexander, Venkitaraman Ashok R
University of Cambridge, Cancer Research UK Department of Oncology and The Medical Research Council Cancer Cell Unit, Hills Road, Cambridge CB2 2XZ, UK.
Nat Struct Mol Biol. 2004 Nov;11(11):1114-21. doi: 10.1038/nsmb837. Epub 2004 Oct 3.
Nuclear foci containing the promyelocytic leukemia protein (PML bodies), which occur in most cells, play a role in tumor suppression. Here, we demonstrate that CHFR, a mitotic checkpoint protein frequently inactivated in human cancers, is a dynamic component of PML bodies. Intermolecular fluorescence resonance energy transfer analysis identified a distinct fraction of CHFR that interacts with PML in living cells. This interaction modulates the nuclear distribution and mobility of CHFR. A trans-dominant mutant of CHFR that inhibits checkpoint function also prevents colocalization and interaction with PML. Conversely, the distribution and mobility of CHFR are perturbed in PML(-/-) cells, accompanied by aberrations in mitotic entry and the response to spindle depolymerization. Thus, PML bodies control the distribution, dynamics and function of CHFR. Our findings implicate the interaction between these tumor suppressors in a checkpoint response to microtubule poisons, an important class of anticancer drugs.
存在于大多数细胞中的含有早幼粒细胞白血病蛋白的核灶（PML小体）在肿瘤抑制中发挥作用。在此，我们证明CHFR是一种在人类癌症中经常失活的有丝分裂检查点蛋白，它是PML小体的动态组成部分。分子间荧光共振能量转移分析确定了在活细胞中与PML相互作用的CHFR的一个独特部分。这种相互作用调节了CHFR的核分布和流动性。抑制检查点功能的CHFR反式显性突变体也会阻止其与PML的共定位和相互作用。相反，在PML（-/-）细胞中CHFR的分布和流动性受到干扰，同时伴有有丝分裂进入和对纺锤体解聚反应的异常。因此，PML小体控制着CHFR的分布、动态变化和功能。我们的研究结果表明，这些肿瘤抑制因子之间的相互作用参与了对微管毒物（一类重要的抗癌药物）的检查点反应。
