中文摘要
核醣蛋白P0為核糖體stalk結構中重要一員，核醣體stalk位於真核生物中60S subunit 上在蛋白質合成中扮演一個重要的角色，會影響生物存活與否。利用Yeast-two-hybrid以P0為餌找出與P0作用的蛋白-GCIP，另一方面同時以Mammalian-two-hybrid、共同免疫沈澱法及GST pull down等方法證實並找出P0及GCIP這2個蛋白質作用的區域，P0與GCIP作用區域是在N端，而GCIP則位於N-或C-端區域；另外利用蔗糖梯度離心法證實P0及GCIP蛋白與polysome及ribosome出現在不同的蔗糖梯度中暗示這2個蛋白是以free form狀態結合。
先前已有作者在COS7細胞中發現GCIP會部分抑制Rb磷酸化，在我們的實驗中將GCIP送入MCF7細胞也有相同結果，而將P0及GCIP同時送入時此現象會被反轉；另一方面我們也在MCF7和HepG2細胞中建立起P0持續表現細胞株，我們發現會加快細胞生長速率以及強化了在Soft agar中形成colony能力，同時檢測Cyclin D1及Rb-S780蛋白質的量的確都是增加，最後利用RT-PCR檢測12組正常乳房組織/乳癌組織中P0 mRNA量，發現P0在乳癌組織中會過度表現，而Stalk的另一個組成成分P1則沒有。
另一方面我們也比較了aggressive/non-aggressive細胞MDA-MB-231、MDA-MB-435S/ZR75-1、MCF7這些細胞株中GCIP的表現發現在MDA-MB-231、MDA-MB-435S中GCIP蛋白遠比ZR75-1、MCF7低很多，所以我們假設GCIP會抑制細胞生長速率，所以我們利用siRNA技術在MCF7細胞中降低GCIP表現量會加快細胞生長速率，而在MDA-MB-231、MDA-MB-435S增加GCIP表現量實驗結果顯示不論是暫時將GCIP送入MDA-MB-435S或是在MDA-MB-231建立起GCIP持續表現細胞株中的確都會減緩細胞生長速率，而這2株細胞株爬行能力、入侵能力及Soft agar中形成colony能力都降低，因此我們相信GCIP在乳癌中扮演tumor suppressor protein角色。

ABSTRACT
The ribosomal acidic P0 protein, an essential component of eukaryotic ribosomal stalk, was found to interact with a newly identified helix-loop-helix (HLH) protein GCIP. In vivo and in vitro interaction assays using yeast two-hybrid, mammalian two-hybrid, glutathione S-transferase pull-down, and coimmunoprecipitation methods prove that P0 can interact with both the N- and C-terminus of GCIP via its N-terminal 45-90 amino acid residues. Although the P0-GCIP complex was detected mainly in cytoplasmic fraction, a polysome profile analysis indicated that the P0-GCIP complex was not coeluted with either polysomes or 60S ribosomes, indicating endogenous GCIP protein associated with free form of P0. In consistent with previous study that showed transient overexpression of GCIP in COS-7 cells partially reduced the phosphorylation of Rb protein, the reporter experiments in this study also revealed that transfected GCIP into MCF-7 cells resulted in the level of phosphorylation of Rb was reduced. Additional cotransfection of P0 with GCIP, however, resulted in GCIP-mediated reduction of Rb phosphorylation level was repressed by P0 in a dose-dependent manner. Furthermore, we also established the stable overexpression of P0 in breast and hepatocellular cancer cells. Both the MCF-7 and HepG2 cells stably expressing P0 demonstrate several phenotypes of transformation; namely, enhanced rate of proliferation and improved efficiency in forming colonies in soft agar. An enhancement of expressed cyclin D1 and an increased phosphorylation of pRb at Ser780 was also observed in the P0 overexpressing cell lines. Additionally, using a competitive RT (reverse transcriptase)-PCR analysis of mRNA on 12 pairs of cancer/noncancer tissues P0 expression was found to be significantly higher in breast cancer tissue than in noncancer tissue. Taken together, these data indicate that overexpression of P0 can cause oncogenesis in breast and liver tissues through inhibiting the tumor suppression of GCIP, suggesting P0 is a oncogenic molecule in breast and liver tissues.
We have investigated the role and mechanism of GCIP in breast tumorigenesis. Westerning blot analysis revealed that markedly decreased GCIP levels in aggressive and invasive breast cancer cells MDA-MB435S and MDA-MB231, as compared to nonaggressive/differentiated breast cancer cells ZR75-1 and MCF-7. Expression of GCIP protein in MDA-MB435S cells and in MDA-MB231 cells resulted in a significant reduction of the cell proliferation on plastic surface, decreased anchorage-independent growth in soft agar and the migration capacity in Boyden chambers as well as reduced the invasion capability in matrix gel assay. Using the MDA-MB231 cells, we also generated stable cell clones constitutively expressing GCIP, and their mock-transfected counterparts. In consistent with transient transfection experiments, stable overexpression of GCIP resulted in dramatically decreased anchorage-independent growth, the migration capacity and the invasion capability, indicating that GCIP expression level was negatively associated with cell proliferation, cell migration and invasiveness. In addition, RT-PCR and gelatin zymography identified reduced MMP-2 and MMP-9 secretion by GCIP-overexpressing melanoma cells as compared with their control counterparts. We also found that GCIP function as a transcriptional suppressor of cyclin D1 and the phosphorylation levels of ERK1/2, P38 and JNK of MAPK (Mitogen-Activated Protein Kinase) pathway were much lower in GCIP-overexpressing melanoma cells as compared with their control counterparts. Together, these studies demonstrate that GCIP is a newly identified tumor suppressor of breast cancer cells and contributes to inhibit tumor cell aggressiveness through inhibition of MAPK pathway.

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