Impaired DNA damage checkpoint response in MIF-deficient mice
Impaired DNA damage checkpoint response in MIF-deficient mice
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DOI：
10.1038/sj.emboj.7601564
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发表时间：
2007-02-21
期刊：
影响因子：
11.4
通讯作者：
Petrenko, Oleksi
中科院分区：
文献类型：
--
作者：
Nemajerova, Alice;Mena, Patricio;Petrenko, Oleksi
最近的研究表明，促炎性迁移抑制因子（MIF）阻断p53依赖的细胞凋亡，并干扰p53的肿瘤抑制活性。为了探索MIF-p53关系的机制，我们研究了基因匹配的p53（-/-）和MIF-/- p53（-/-）小鼠的自发性肿瘤发生。我们发现，MIF表达的丧失使p53（-/-）小鼠的肿瘤易感表型增加，并使它们易于发生更广泛的肿瘤谱，包括B细胞淋巴瘤和癌。DNA损伤反应受损是MIF-/- p53（-/-）小鼠肿瘤易感性的根源。我们提供的证据表明，MIF在调节含Cull的SCF泛素连接酶的活性中起作用。MIF表达的丧失将Chk 1/Chk 2响应性DNA损伤检查点与关键细胞周期调节因子如Cdc 25 A、E2 F1和DP 1的SCF依赖性降解解偶联，从而为细胞的遗传不稳定性创造条件。这些MIF效应依赖于其与COP 9/CSN信号体的Jab 1/CSN 5亚基的结合。鉴于CSN在体内SCF复合物的组装中起着核心作用，需要通过MIF调节Jab 1/CSN 5以维持SCF复合物的最佳组成和功能。
Recent studies demonstrated that proinflammatory migration inhibitory factor(MIF) blocks p53-dependent apoptosis and interferes with the tumor suppressor activity of p53. To explore the mechanism underlying this MIF-p53 relationship, we studied spontaneous tumorigenesis in genetically matched p53(-/-) and MIF-/- p53(-/-) mice. We show that the loss of MIF expression aggravates the tumor-prone phenotype of p53(-/-) mice and predisposes them to a broader tumor spectrum, including B-cell lymphomas and carcinomas. Impaired DNA damage response is at the root of tumor predisposition of MIF-/- p53(-/-) mice. We provide evidence that MIF plays a role in regulating the activity of Cull-containing SCF ubiquitin ligases. The loss of MIF expression uncouples Chk1/Chk2-responsive DNA damage checkpoints from SCF- dependent degradation of key cell-cycle regulators such as Cdc25A, E2F1 and DP1, creating conditions for the genetic instability of cells. These MIF effects depend on its association with the Jab1/CSN5 subunit of the COP9/CSN signalosome. Given that CSN plays a central role in the assembly of SCF complexes in vivo, regulation of Jab1/CSN5 by MIF is required to sustain optimal composition and function of the SCF complex.