Centrosome overduplication, increased ploidy and transformation in cells expressing endoplasmic reticulum-associated cyclin A2
Centrosome overduplication, increased ploidy and transformation in cells expressing endoplasmic reticulum-associated cyclin A2
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DOI：
10.1038/sj.onc.1205215
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发表时间：
2002-02-28
期刊：
影响因子：
8
通讯作者：
Sobczak-Thépot, J
中科院分区：
文献类型：
--
作者：
Faivre, J;Frank-Vaillant, M;Sobczak-Thépot, J
细胞周期蛋白A2主要，但不是唯一，定位于细胞核从G1/S过渡向前。当细胞在核膜破裂后进入有丝分裂时降解。我们以前表明，融合蛋白（S2 A）之间的肝炎B病毒（HBV）表面抗原蛋白和人类细胞周期蛋白A2（Delta 152）的不可降解片段驻留在内质网膜，逃避降解和转化正常大鼠成纤维细胞。本研究探讨细胞质细胞周期蛋白A2是否可能在肿瘤发生中发挥作用。我们表明，螯合的不可降解的细胞周期蛋白A2-Delta 152的细胞ER靶向结构域（PRL-A2）导致细胞转化时，与激活的Ha-ras共表达。发现组成性表达PRL-A2的REF 52细胞具有高发生率的多核巨细胞、多倍性和异常中心体数目，从而引起多极纺锤体的成核。将这些细胞注射到无胸腺裸鼠中会导致肿瘤，即使在没有协同Ha-ras癌基因的情况下也是如此。这些结果表明，独立于任何病毒背景，不可降解的细胞周期蛋白A2的细胞内再分布能够解除正常细胞周期的调节，达到促进非整倍性和癌症的程度。
Cyclin A2 is predominantly, but not exclusively, localized in the nucleus from G1/S transition onwards. It is degraded when cells enter mitosis after nuclear envelope breakdown. We previously showed that a fusion protein (S2A) between the hepatitis B virus (HBV) surface antigen protein and a non-degradable fragment of human cyclin A2 (Delta152) resides in the endoplasmic reticulum membranes, escapes degradation and transforms normal rat fibroblasts. The present study investigates whether cytoplasmic cyclin A2 may play a role in oncogenesis. We show that the sequestration of non-degradable cyclin A2-Delta152 by a cellular ER targeting domain (PRL-A2) leads to cell transformation when coexpressed with activated Ha-ras. REF52 cells constitutively expressing PRL-A2 are found to have a high incidence of multinucleate giant cells, polyploidy and abnormal centrosome numbers, giving rise to the nucleation of multipolar spindles. Injection of these cells into athymic nude mice causes tumors, even in the absence of a cooperating Ha-ras oncogene. These results demonstrate that, independently of any viral context, an intracellular redistribution of non-degradable cyclin A2 is capable of deregulating the normal cell cycle to the point where it promotes aneuploidy and cancer.