The ARF tumor suppressor prevents chromosomal instability and ensures mitotic checkpoint fidelity through regulation of Aurora B.
The ARF tumor suppressor prevents chromosomal instability and ensures mitotic checkpoint fidelity through regulation of Aurora B.
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DOI：
10.1091/mbc.e14-05-0966
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发表时间：
2014-09-15
影响因子：
3.3
通讯作者：
Weaver BA
中科院分区：
文献类型：
--
作者：
Britigan EM;Wan J;Zasadil LM;Ryan SD;Weaver BA
ARF肿瘤抑制因子以其稳定p53的作用而闻名。本研究确定了不依赖p53的ARF在染色体分离和有丝分裂检查点中的功能。由ARF缺失引起的有丝分裂缺陷可通过Aurora B的过表达重现，并通过Aurora B的部分缺失得到修复。ARF肿瘤抑制因子是CDKN2A位点的一部分，在许多癌症中发生突变或无法检测到。ARF最典型的作用是稳定p53对细胞应激的反应。然而，在这一途径之外，ARF还具有肿瘤抑制功能，目前尚未完全确定。缺乏ARF肿瘤抑制因子的原代小鼠胚胎成纤维细胞（mef）含有异常数量的染色体。然而，ARF在细胞分裂中的作用尚未被提出。在这里，我们证明了ARF在有丝分裂检查点中的一种新颖的、不依赖于p53的作用。与此一致的是，ARF的缺失导致体外和体内的非整倍体。ARF−/−mef表现出有丝分裂缺陷，包括染色体错位和滞后、多极纺锤体和四倍体增加。ARF−/−细胞表现出Mad2、BubR1和Aurora B的过表达，但在ARF−/−mef中，只有Aurora B的过表达导致有丝分裂缺陷。在缺乏ARF的细胞中，将Aurora B恢复到接近正常的水平可以挽救有丝分裂表型。我们的研究结果确定了ARF在染色体分离和有丝分裂检查点功能中的意想不到的作用。他们进一步确立了维持染色体稳定性是ARF的额外肿瘤抑制功能之一，并为人类癌症中Aurora B的普遍上调提供了分子解释。
The ARF tumor suppressor is best known for its role in stabilizing p53. This study identifies p53-independent functions of ARF in chromosome segregation and the mitotic checkpoint. Mitotic defects caused by loss of ARF are recapitulated by Aurora B overexpression and rescued by partial depletion of Aurora B. The ARF tumor suppressor is part of the CDKN2A locus and is mutated or undetectable in numerous cancers. The best-characterized role for ARF is in stabilizing p53 in response to cellular stress. However, ARF has tumor suppressive functions outside this pathway that have not been fully defined. Primary mouse embryonic fibroblasts (MEFs) lacking the ARF tumor suppressor contain abnormal numbers of chromosomes. However, no role for ARF in cell division has previously been proposed. Here we demonstrate a novel, p53-independent role for ARF in the mitotic checkpoint. Consistent with this, loss of ARF results in aneuploidy in vitro and in vivo. ARF−/− MEFs exhibit mitotic defects including misaligned and lagging chromosomes, multipolar spindles, and increased tetraploidy. ARF−/− cells exhibit overexpression of Mad2, BubR1, and Aurora B, but only overexpression of Aurora B phenocopies mitotic defects observed in ARF−/− MEFs. Restoring Aurora B to near-normal levels rescues mitotic phenotypes in cells lacking ARF. Our results define an unexpected role for ARF in chromosome segregation and mitotic checkpoint function. They further establish maintenance of chromosomal stability as one of the additional tumor-suppressive functions of ARF and offer a molecular explanation for the common up-regulation of Aurora B in human cancers.