Nuclear annexin II negatively regulates growth of LNCaP cells and substitution of ser 11 and 25 to glu prevents nucleo-cytoplasmic shuttling of annexin II.
Nuclear annexin II negatively regulates growth of LNCaP cells and substitution of ser 11 and 25 to glu prevents nucleo-cytoplasmic shuttling of annexin II.
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DOI：
10.1186/1471-2091-4-10
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发表时间：
2003-09-09
期刊：
影响因子：
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通讯作者：
Vishwanatha JK
中科院分区：
文献类型：
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作者：
Liu J;Rothermund CA;Ayala-Sanmartin J;Vishwanatha JK
膜联蛋白II重链（也称为p36，calpactin I）在前列腺癌和大多数前列腺上皮内瘤变（PIN）中丢失。膜联蛋白II重链的缺失似乎对前列腺癌具有特异性，因为在大多数人类癌症（包括胰腺癌、乳腺癌和脑肿瘤）中观察到膜联蛋白II的过表达。膜联蛋白II以与蛋白质配体p11（S100 A10）复合的异源四聚体和单体形式存在。不同的细胞功能提出了两种形式的膜联蛋白II。单体参与DNA合成。在膜联蛋白II的N-末端的富含亮氨酸的核输出信号（内斯）通过CRM 1介导的核输出途径调节其核输出。内斯序列的突变导致膜联蛋白II的核滞留。位于细胞核中的膜联蛋白II被磷酸化，并且核磷酸化膜联蛋白II的出现是细胞周期依赖性的，表明磷酸化可能在膜联蛋白II的核进入、保留或输出中起作用。通过外源性表达膜联蛋白II的膜联蛋白II无效LNCaP细胞，我们表明，野生型膜联蛋白II被排除在细胞核之外，而内斯突变体膜联蛋白II定位于细胞核和细胞质。膜联蛋白II的核滞留导致细胞增殖减少和细胞倍增时间增加。野生型和内斯突变体膜联蛋白II的表达引起细胞的形态学变化。通过位点特异性取代谷氨酸的丝氨酸11和25在N-末端的地方，我们表明，同时磷酸化的丝氨酸11和25，但不是单独的，防止核定位的膜联蛋白II。我们的数据表明，核膜联蛋白II磷酸化的细胞周期依赖性的方式和丝氨酸11和25的取代抑制膜联蛋白II的核进入。核膜联蛋白II的异常积累延缓LNCaP细胞的增殖。
Annexin II heavy chain (also called p36, calpactin I) is lost in prostate cancers and in a majority of prostate intraepithelial neoplasia (PIN). Loss of annexin II heavy chain appears to be specific for prostate cancer since overexpression of annexin II is observed in a majority of human cancers, including pancreatic cancer, breast cancer and brain tumors. Annexin II exists as a heterotetramer in complex with a protein ligand p11 (S100A10), and as a monomer. Diverse cellular functions are proposed for the two forms of annexin II. The monomer is involved in DNA synthesis. A leucine-rich nuclear export signal (NES) in the N-terminus of annexin II regulates its nuclear export by the CRM1-mediated nuclear export pathway. Mutation of the NES sequence results in nuclear retention of annexin II. Annexin II localized in the nucleus is phosphorylated, and the appearance of nuclear phosphorylated annexin II is cell cycle dependent, indicating that phosphorylation may play a role in nuclear entry, retention or export of annexin II. By exogenous expression of annexin II in the annexin II-null LNCaP cells, we show that wild-type annexin II is excluded from the nucleus, whereas the NES mutant annexin II localizes in both the nucleus and cytoplasm. Nuclear retention of annexin II results in reduced cell proliferation and increased doubling time of cells. Expression of annexin II, both wild type and NES mutant, causes morphological changes of the cells. By site-specific substitution of glutamic acid in the place of serines 11 and 25 in the N-terminus, we show that simultaneous phosphorylation of both serines 11 and 25, but not either one alone, prevents nuclear localization of annexin II. Our data show that nuclear annexin II is phosphorylated in a cell cycle-dependent manner and that substitution of serines 11 and 25 inhibit nuclear entry of annexin II. Aberrant accumulation of nuclear annexin II retards proliferation of LNCaP cells.