Mad1 destabilizes p53 by preventing PML from sequestering MDM2
Mad1 destabilizes p53 by preventing PML from sequestering MDM2
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DOI：
10.1038/s41467-019-09471-9
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发表时间：
2019-04
影响因子：
16.6
通讯作者：
Jun Wan;Samuel Block;Christina M. Scribano;Rebecca Thiry;K. Esbona;A. Audhya;Beth A. Weaver
中科院分区：
文献类型：
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作者：
Jun Wan;Samuel Block;Christina M. Scribano;Rebecca Thiry;K. Esbona;A. Audhya;Beth A. Weaver
有丝分裂停滞缺陷 1 (Mad1) 在有丝分裂检查点中发挥着明确的作用。然而，Mad1 不影响有丝分裂检查点功能的间期作用在很大程度上仍然未知。在这里，我们发现 Mad1 的上调（在人类乳腺癌中很常见）可以阻止多种细胞类型中应激诱导的肿瘤抑制因子 p53 的稳定。上调的 Mad1 定位于乳腺癌和培养细胞中的早幼粒细胞白血病 (PML) 核体。 Mad1 的 C 末端直接与 PML 相互作用，并且这种相互作用通过 sumoylation 得到增强。 PML 通过将 MDM2（一种以 p53 降解为目标的 E3 泛素连接酶）隔离到核仁来稳定 p53。上调的 Mad1 取代了 PML 中的 MDM2，使其得以泛素化 p53。 Mad1 的上调会加速原位乳腺肿瘤的生长，这表明 p53 及其下游效应子 p21 的水平降低。这些结果表明 Mad1 在通过 p53 不稳定促进肿瘤生长过程中发挥了意想不到的间期作用。
Mitotic arrest deficient 1 (Mad1) plays a well-characterized role in the mitotic checkpoint. However, interphase roles of Mad1 that do not impact mitotic checkpoint function remain largely uncharacterized. Here we show that upregulation of Mad1, which is common in human breast cancer, prevents stress-induced stabilization of the tumor suppressor p53 in multiple cell types. Upregulated Mad1 localizes to ProMyelocytic Leukemia (PML) nuclear bodies in breast cancer and cultured cells. The C-terminus of Mad1 directly interacts with PML, and this interaction is enhanced by sumoylation. PML stabilizes p53 by sequestering MDM2, an E3 ubiquitin ligase that targets p53 for degradation, to the nucleolus. Upregulated Mad1 displaces MDM2 from PML, freeing it to ubiquitinate p53. Upregulation of Mad1 accelerates growth of orthotopic mammary tumors, which show decreased levels of p53 and its downstream effector p21. These results demonstrate an unexpected interphase role for Mad1 in tumor promotion via p53 destabilization.