Mutual regulation between Polo-like kinase 3 and SIAH2 E3 ubiquitin ligase defines a regulatory network that fine-tunes the cellular response to hypoxia and nickel
Mutual regulation between Polo-like kinase 3 and SIAH2 E3 ubiquitin ligase defines a regulatory network that fine-tunes the cellular response to hypoxia and nickel
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DOI：
10.1074/jbc.m116.767178
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发表时间：
2017-07-07
影响因子：
4.8
通讯作者：
Xu, Dazhong
中科院分区：
文献类型：
--
作者：
Li, Cen;Park, Soyoung;Xu, Dazhong
细胞对缺氧的反应升高，有助于细胞转化和肿瘤进展，是实体瘤恶性细胞的一个显著特征。polo样激酶3 （Plk3）是一种丝氨酸/苏氨酸蛋白激酶，已知可抑制细胞对缺氧和肿瘤发生的反应。镍化合物是公认的人类致癌物，部分通过其模拟缺氧的作用诱导肿瘤发生。尽管以前的研究努力，Plk3在缺氧或镍诱导的缺氧反应中的作用尚未完全了解。在这里，我们发现NiCl2 （Ni(II)）或缺氧以泛素-蛋白酶体依赖的方式降低了蛋白水平并缩短了细胞质Plk3的半衰期。我们发现SIAH2，一种与细胞缺氧反应相关的环指E3泛素连接酶，是介导Plk3降解的泛素E3连接酶。我们发现SIAH2与Plk3结合并主要通过其polo-box结构域介导其泛素化。我们报道了USP28，一种已知可被Ni（II）或缺氧抑制的去泛素酶，也可能有助于Ni（II）抑制Plk3蛋白。我们还发现Plk3反过来以激酶活性依赖的方式抑制SIAH2蛋白水平。我们的研究揭示了Plk3和SIAH2之间有趣的相互调节，并发现了一个调节细胞缺氧反应的调节网络。我们认为，抑制Plk3的表达有助于镍化合物诱导的癌变和肿瘤进展。
Elevated cellular response to hypoxia, which contributes to cell transformation and tumor progression, is a prominent feature of malignant cells in solid tumors. Polo-like kinase 3 (Plk3) is a serine/threonine protein kinase known to inhibit the cellular response to hypoxia and tumorigenesis. Nickel compounds are well-established human carcinogens that induce tumorigenesis partly through their hypoxia-mimicking effects. Despite previous research efforts, the role of Plk3 in the hypoxic response induced by hypoxia or nickel is not completely understood. Here, we show that NiCl2 (Ni(II)) or hypoxia reduces the protein level and shortens the half-life of cytoplasmic Plk3 in a ubiquitin- proteasome-dependent manner. We identify SIAH2, a RING finger E3 ubiquitin ligase associated with the cellular hypoxic response, to be the ubiquitin E3 ligase that mediates the degradation of Plk3. We show that SIAH2 binds to Plk3 and mediates its ubiquitination primarily through its polo-box domain. We report that USP28, a deubiquitinase known to be inhibitable by Ni(II) or hypoxia, may also contribute to the suppression of the Plk3 protein by Ni(II). We also show that Plk3 in turn suppresses the SIAH2 protein level in a kinase activity-dependent manner. Our study revealed an interesting mutual regulation between Plk3 and SIAH2 and uncovered a regulatory network that functions to fine-tune the cellular hypoxic response. We propose that suppression of Plk3 expression contributes to carcinogenesis and tumor progression induced by nickel compounds.