核醣體是由核醣體蛋白及核醣體核糖核酸所構成。過去認為在核醣體轉譯蛋白時，核醣體蛋白只是扮演著協助的角色。但是近來越來越多的研究指出，其實核醣體蛋白也具有調控蛋白質生成的功能，但是目前還不清楚核醣體蛋白透過什麼機制來調控蛋白質的生合成。週期素D1(cyclin D1)具有調節細胞週期的功能，它會在G1時期開始合成，當cyclin D1累積到一定的量之後會促使細胞啟動S時期的基因使細胞進入S時期。過去的研究發現核醣體蛋白L19(RPL19)具有調控cyclin D1的能力，這可能代表著RPL19會透過調控cyclin D1來影響細胞週期的變化。我們發現RPL19 會和hnRNP A1共同調控cyclin D1的表現量，這個調控是透過影響cyclin D1的五端非轉譯區內之核醣體結合區(IRES)活性。更進一步，我們發現RPL19和hnRNP A1的共同調控只發生在S時期的後期，並且我們也確認缺乏RPL19的表現會使cyclin D1的轉譯效率下降，進而會使細胞被屏障在G1時期。除了cyclin D1外，我們也驗證了RPL19會經由調控cyclin E1的IRES活性和轉譯效率使得cyclin E1的表現量下降，並且RPL19與cyclin E1 mRNA結合的時間點也與cyclin E1的蛋白質生成一致。為了要更大範圍地檢視會被RPL19調控的基因，我們使用核醣體圖譜定序分析RPL19缺少時對細胞造成的影響。經由生物資訊分析，RPL19的缺少主要會影響細胞週期和細胞凋亡，藉由此我們也發現MAPK1的IRES活性和轉譯效率也會受到RPL19的調控。本篇研究指出RPL19會透過調控特定基因如cyclin D1、cyclin E1、MAPK1的IRES活性和轉譯效率來調節其表現量，進一步對細胞週期的運行產生變化。

The ribosome is a complex composed of rRNAs and ribosomal proteins. Traditionally, ribosome can translate proteins and ribosomal proteins were considered as co-factors to execute the protein translation. But in the last decade, numerous studies have demonstrated that ribosomal proteins not only play a role as co-factors of translation complex but also regulate the protein synthesis of specific mRNAs. However the mechanism of these ribosomal proteins to regulate the protein synthesis is still unclear. Cyclin D1 plays an important role in cell cycle progression. The synthesis of cyclin D1 is initiated during G1 phase and drives the G1/S phase transition. From the previous study, the ribosomal protein L19(RPL19) was reported to regulate the cyclin D1 protein expression. It indicated RPL19 may be a regulator of cell cycle through controlling cyclin D1 protein expression. And then we identified that RPL19 can cooperate with heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) to regulate cell cycle progression through regulating the internal ribosome entry site (IRES) activity of cyclin D1. Furthermore, we confirmed that silencing RPL19 expression would reduce cyclin D1 translation efficiency and block the cell cycle in G1 phase. Besides, we are also interested in that if there are other cell cycle process genes being regulated by RPL19. Cyclin E1 has been considered an essential and master regulator of progression through G1 phase of the cell cycle. We find that the 5’UTR of cyclin E1 mRNA carries an IRES element and RPL19 plays a role in regulating the IRES activity and translation efficiency of cyclin E1.We also see that RPL19 has interaction with cyclin E1 mRNA at G1 phase. To better understand the role of RPL19 in cell process, we analyzed ribosomal profiling of knock-down RPL19 and found that RPL19 main impact cell-cycle and apoptosis progress. Mitogen-activated protein kinase 1(MAPK1) have a positive role in controlling normal and Ras-dependent cell proliferation. Furthermore, we identified MAPK1 is regulated by RPL19 through IRES activity and translation efficiency. We think that RPL19 may be a model to explain the mechanism of the ribosomal proteins to regulate the specific protein synthesis. To sum up, we identified that RPL19 regulates cyclin D1, cyclin E1 and MAPK1’s protein expression through regulating their IRES activities and translation efficiency. Through these mechanisms, RPL19 can mainly regulate cell cycle and apoptosis process.

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