Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation.
Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation.
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DOI：
10.1016/j.canlet.2016.10.021
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发表时间：
2017-01-28
期刊：
影响因子：
9.7
通讯作者：
Zhang, Jinfang
中科院分区：
文献类型：
--
作者：
Wu, Fei;Dai, Bxiangpeng;Gan, Wenjian;Wan, Lixin;Li, Min;Mitsiades, Nicholas;Wei, Wenyi;Ding, Qiang;Zhang, Jinfang
最近的研究表明，高达15%的前列腺癌患者会发生SPOP(斑点型POZ蛋白)突变。然而，SPOP在调节前列腺癌发生中的生理作用仍不清楚。在这里，我们确定了CDC20癌蛋白是SPOP的一种新的泛素底物。因此，MLN4924对基于cullin的E3连接酶的药理抑制可以稳定细胞内内源性Cdc20。此外，我们发现cullin 3，以及cullin 1，在较小的程度上，与Cdc20特异地相互作用。耗尽cullin 3，而不是cullin 1，可以通过延长cdc20的半衰期来上调cdc20的表达。此外，作为cullin 3家族E3连接酶的接头蛋白，SPOP能与CDc20特异地相互作用，并以降解依赖的方式促进CDc20的多泛素化和随后的降解。重要的是，前列腺癌来源的SPOP突变体未能与CDC20相互作用以促进其降解。结果，具有高表达CDC20的SPOP缺陷的前列腺癌细胞对一种药理的CDC20抑制剂产生了抗药性。因此，我们的结果揭示了SPOP在肿瘤发生中的新作用，部分是通过促进CDC20癌蛋白的降解来实现的。
Recent studies revealed that mutations in SPOP (Speckle-type POZ protein) occur in up to 15% of patients with prostate cancer. However, the physiological role of SPOP in regulating prostate tumorigenesis remains elusive. Here, we identified the Cdc20 oncoprotein as a novel ubiquitin substrate of SPOP. As such, pharmacological inhibition of Cullin-based E3 ligases by MLN4924 could stabilize endogenous Cdc20 in cells. Furthermore, we found that Cullin 3, and, to a less extent, Cullin 1, specifically interacted with Cdc20. Depletion of Cullin 3, but not Cullin 1, could upregulate the abudance of Cdc20 largely via prolonging Cdc20 half-life. Moreover, SPOP, the adaptor protein of Cullin 3 family E3 ligase, specifically interacted with Cdc20, and promoted the poly-ubiquitinaton and subsequent degradation of Cdc20 in a degron-dependent manner. Importantly, prostate cancer-derived SPOP mutants failed to interact with Cdc20 to promote its degradation. As a result, SPOP-deficient prostate cancer cells with elevated Cdc20 expression became resistant to a pharmacological Cdc20 inhibitor. Therefore, our results revealed a novel role of SPOP in tumorigenesis in part by promoting the degradation of the Cdc20 oncoprotein.
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影响因子：
64.5
作者：
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通讯作者：
O'Malley, B. W.
影响因子：
64.8
作者：
Berger, Michael F.;Lawrence, Michael S.;Demichelis, Francesca;Drier, Yotam;Cibulskis, Kristian;Sivachenko, Andrey Y.;Sboner, Andrea;Esgueva, Raquel;Pflueger, Dorothee;Sougnez, Carrie;Onofrio, Robert;Carter, Scott L.;Park, Kyung;Habegger, Lukas;Ambrogio, Lauren;Fennell, Timothy;Parkin, Melissa;Saksena, Gordon;Voet, Douglas;Ramos, Alex H.;Pugh, Trevor J.;Wilkinson, Jane;Fisher, Sheila;Winckler, Wendy;Mahan, Scott;Ardlie, Kristin;Baldwin, Jennifer;Simons, Jonathan W.;Kitabayashi, Naoki;MacDonald, Theresa Y.;Kantoff, Philip W.;Chin, Lynda;Gabriel, Stacey B.;Gerstein, Mark B.;Golub, Todd R.;Meyerson, Matthew;Tewari, Ashutosh;Lander, Eric S.;Getz, Gad;Rubin, Mark A.;Garraway, Levi A.
通讯作者：
Garraway, Levi A.