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首页> 外文期刊>Genes to cells : >Nuclear accumulation of Calcineurin B Homologous Protein 2 (CHP2) results in enhanced proliferation of tumor cells
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Nuclear accumulation of Calcineurin B Homologous Protein 2 (CHP2) results in enhanced proliferation of tumor cells

机译：钙调神经磷酸酶B同源蛋白2（CHP2）的核积累导致肿瘤细胞增殖增强

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摘要

The interaction between calcineurin B homologous protein 2 (CHP2) and Na+/H+ exchanger 1 (NHE1), two membrane proteins, is essential for protecting cells from serum deprivation-induced death. Although four putative EF-hands in CHP2 had been predicted for years, Ca2+-binding activities of these motifs have not been tested yet, their role in this process remain poorly understood. To identify Ca2+-binding motifs required for the stable formation of CHP2/NHE1 complexes, we developed a mutagenesis-based assay in PS120 cells. We found that 45Ca2+ bond to two EF-hand motifs (EF3 and 4) of CHP2 proteins with high affinity. Complex formation between CHP2 and the CHP2 binding domain of NHE1 resulted in a marked increase in the Ca2+-binding affinity of CHP2. Co-immunoprecipitation and distribution of GFP-tagged CHP2-EF3m/4m also indicated that Ca2+ affected the membrane location of CHP2 to interact with NHE1. The C-terminal region of CHP2 contains a nuclear export sequence (NES). When the six leucines of NES were mutated to alanines, the resulting CHP2 protein was predominantly localized to the nucleus. Furthermore, mutation of the NES resulted in enhanced proliferation and oncogenic potential of HeLa cells. Together, these results show that calcium and NES control the subcellular distribution of CHP2 and then distinctively regulate cell proliferation.
机译：钙调神经磷酸酶B同源蛋白2（CHP2）和Na + / H +交换蛋白1（NHE1）这两种膜蛋白之间的相互作用对于保护细胞免于血清剥夺引起的死亡至关重要。尽管已经预测了CHP2中的四个推定的EF手，但是尚未测试这些基序的Ca2 +结合活性，但它们在该过程中的作用仍知之甚少。为了鉴定稳定形成CHP2 / NHE1复合物所需的Ca2 +结合基序，我们在PS120细胞中开发了基于诱变的检测方法。我们发现45Ca2 +以高亲和力结合到CHP2蛋白的两个EF手基序（EF3和4）。 CHP2和NHE1的CHP2结合域之间形成复合物，导致CHP2的Ca2 +结合亲和力显着增加。 GFP标记的CHP2-EF3m / 4m的共免疫沉淀和分布也表明Ca2 +影响CHP2的膜位置以与NHE1相互作用。 CHP2的C端区域包含一个核输出序列（NES）。当NES的6个亮氨酸突变为丙氨酸时，所得的CHP2蛋白主要位于细胞核中。此外，NES的突变导致HeLa细胞的增殖和致癌潜力增强。在一起，这些结果表明钙和NES控制CHP2的亚细胞分布，然后显着调节细胞增殖。

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