Regulation of subcellular distribution and oncogenic potential of nucleophosmin by plakoglobin.
Regulation of subcellular distribution and oncogenic potential of nucleophosmin by plakoglobin.
复制标题
通过plakoglobin的细胞亚分布和亲核剂的致癌潜力的调节。
DOI：
10.1038/oncsis.2012.4
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发表时间：
2012-03-19
期刊：
影响因子：
6.2
通讯作者：
Pasdar, M.
中科院分区：
文献类型：
--
作者：
Lam, L.;Aktary, Z.;Bishay, M.;Werkman, C.;Kuo, C-Y;Heacock, M.;Srivastava, N.;Mackey, J. R.;Pasdar, M.
核磷蛋白（NPM）是一种参与许多细胞过程的核仁磷蛋白，具有致癌和生长抑制活性。NPM主要定位于核仁中，但在细胞核和细胞质之间穿梭，持续的细胞质分布有助于其促肿瘤活性。斑珠蛋白（Plakoglobin，PG，γ-catenin）是β-catenin的同系物，具有粘附和信号传导双重功能。这些蛋白质与钙粘蛋白相互作用并介导粘附，而它们的信号传导活性通过与各种细胞内伴侣的结合来调节。尽管有这些相似之处，β-连环蛋白具有明确的致癌活性，而PG通过未知的机制作为肿瘤/转移抑制剂。PG表达低或无PG表达的癌细胞系与其PG表达转染体的蛋白质组学谱的比较已经鉴定出NPM在PG表达后上调。在这里，我们检查了NPM亚细胞分布和体外肿瘤发生/转移，在高度侵袭性和非常低的PG表达的MDA-MB-231（MDA-231）乳腺癌细胞及其表达增加的PG（MDA-231-PG）或NPM shRNA（MDA-231-NPM-KD）或两者（MDA-231-NPM-KD+PG）的转染子中。PG表达增加可增加核仁NPM的水平，免疫共沉淀研究表明NPM与PG相互作用。PG表达或NPM敲低可显著降低MDA-231细胞的生长速率，并且这种降低在MDA-231-NPM-KD+PG细胞中进一步降低。在体外肿瘤发生/转移测定中，相对于MDA-231亲本细胞，MDA-231-PG细胞显示出显著较低的侵袭性，而MDA-231-NPM-KD细胞显示出显著较高的侵袭性，并且PG和NPM shRNA的共表达导致MDA-231-PG细胞的侵袭性甚至进一步降低。此外，转移性浸润性导管癌的原发性活检组织中PG和NPM的水平和定位的检查显示PG和NPM的协调表达。总之，这些数据表明，PG可以调节NPM亚细胞分布，这可能潜在地改变NPM蛋白的功能，从致癌到肿瘤抑制。
Nucleophosmin (NPM) is a nucleolar phosphoprotein that is involved in many cellular processes and has both oncogenic and growth suppressing activities. NPM is localized primarily in nucleoli but shuttles between the nucleus and the cytoplasm, and sustained cytoplasmic distribution contributes to its tumor promoting activities. Plakoglobin (PG, γ-catenin) is a homolog of β-catenin with dual adhesive and signaling functions. These proteins interact with cadherins and mediate adhesion, while their signaling activities are regulated by association with various intracellular partners. Despite these similarities, β-catenin has a well-defined oncogenic activity, whereas PG acts as a tumor/metastasis suppressor through unknown mechanisms. Comparison of the proteomic profiles of carcinoma cell lines with low- or no PG expression with their PG-expressing transfectants has identified NPM as being upregulated upon PG expression. Here, we examined NPM subcellular distribution and in vitro tumorigenesis/metastasis in the highly invasive and very low PG expressing MDA-MB-231 (MDA-231) breast cancer cells and their transfectants expressing increased PG (MDA-231-PG) or NPM shRNA (MDA-231-NPM-KD) or both (MDA-231-NPM-KD+PG). Increased PG expression increased the levels of nucleolar NPM and coimmunoprecipitation studies showed that NPM interacts with PG. PG expression or NPM knockdown decreased the growth rate of MDA-231 cells substantially and this reduction was decreased further in MDA-231-NPM-KD+PG cells. In in vitro tumorigenesis/metastasis assays, MDA-231-PG cells showed substantially lower and MDA-231-NPM-KD cells substantially higher invasiveness relative to the MDA-231 parental cells, and the co-expression of PG and NPM shRNA led to even further reduction of the invasiveness of MDA-231-PG cells. Furthermore, examination of the levels and localization of PG and NPM in primary biopsies of metastatic infiltrating ductal carcinomas revealed coordinated expression of PG and NPM. Together, the data suggest that PG may regulate NPM subcellular distribution, which may potentially change the function of the NPM protein from oncogenic to tumor suppression.
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影响因子：
5.3
作者：
Colombo, E;Bonetti, P;Pelicci, PG
通讯作者：
Pelicci, PG
影响因子：
21.3
作者：
Colombo, E;Marine, JC;Pelicci, PG
通讯作者：
Pelicci, PG
影响因子：
2.9
作者：
CHAN, WY;LIU, QR;CHAN, PK
通讯作者：
CHAN, PK
影响因子：
4.8
作者：
Hakimelahi, S;Parker, HR;Pasdar, M
通讯作者：
Pasdar, M
影响因子：
4.7
作者：
Gastaldi, Tamara;Bonvini, Paolo;Rosolen, Angelo
通讯作者：
Rosolen, Angelo