STATs 蛋白是細胞內一群能被多種細胞激素、賀爾蒙，以及生長因子所活化的轉錄因子。在STAT蛋白家族中，STAT3經常被報導跟人類惡性腫瘤相關，以及參與腫瘤細胞的生存以及他們對動物體免疫系統。相對地，STAT1蛋白則能夠促進腫瘤細胞的細胞凋亡，也能夠引起動物體免疫系統對腫瘤細胞的免疫反應。在之前的研究中，我們將活化態的STAT1蛋白（S1C，由cysteine去取代SH2 domain中的arginine-656和asparagine-658這兩個氨基酸所構成，能夠自發性地在細胞中形成STAT1雙體，並且不需細胞激素刺激即具有轉錄因子的活性，能進行基因調控） 轉染至老鼠的Lewis氏肺癌細胞 （一種STAT3處於高度活化態的化學藥物誘導生成的自發性癌細胞）中，製造出了LL2/S1C穩定細胞株。另外，我們也將單體的STAT1蛋白轉染至LL2細胞中，製造出能夠穩定高度表達STAT1蛋白單體的穩定細胞株。由於一般在動物體內，STAT1蛋白是由interferon-γ 所活化，因此我們給予這細胞interferon-γ的刺激，觀察STAT1蛋白和STAT3蛋白在此細胞株中如何進行交互作用，進而影響其在動物體內的免疫反應。有趣的是，我們偶然發現這樣的刺激會引起STAT5蛋白的異常活化。一般認為STAT蛋白的活化是有受體專一性的：不同細胞激素或是賀爾蒙受體會經由其在細胞內N端附近的氨基酸去選擇特定的STAT蛋白進行活化以及下游的基因調控。然而這樣的機制無法全然解釋何以STAT5蛋白在LL2/S1C 細胞中被interferon-γ 異常地活化。JAK-STAT這條訊息傳遞路徑主要可以被三個家族的負回饋調控因子所調控，他們分別是：suppressor of cytokine signaling (SOCS) protein，the protein inhibitors of activated STAT (PIAS) 以及數種 protein tyrosine phosphatases (PTPs)。為了瞭解這些調控因子是否參與STAT5的異常活化現象，我們利用西方點漬法去分析他們在蛋白質層級上的變化。SOCS1，SOCS3，PIAS1，PIAS3，以及SHP2蛋白們的表達量變化，在LL2/S1C細胞和293T/S1C 細胞中都很難全然解釋何以STAT5蛋白能夠被interferon-γ 所異常活化。另外，我們也檢視了這條活化路徑的上游，也就是在訊息傳遞剛開始的位置：JAK2 激酶以及 interferon-γ 受體在蛋白層級上的變化。然而他們的變化似乎也難以解釋STAT5蛋白的異常活化現象。因此，我們懷疑S1C 這個活化態的蛋白會去刺激未知JAK-STAT調控因子的表達，進而影響STAT5蛋白的活性。為找尋未知的調控因子，我們利用免疫沈澱法將LL2/S1C細胞中的STAT1蛋白沈澱出來，並且利用液相層析質譜分析儀去辨識這所有跟STAT1蛋白有交互作用的蛋白質。經由序列分析，我們共定到138個蛋白質。他們依功能跟所參與的細胞事件，能被分成許多種類；由此我們也得知：STAT1蛋白參與了許多細胞的生理事件的調控。在這些蛋白中，我們懷疑Asb-1可能是我們所要找的未知調控因子。Asb-1蛋白含有SOCS box。目前已知SOCS box能夠跟其他含有SOCS box的蛋白進行交互作用，也能跟elongin B和elongin C進行交互作用，將蛋白質帶向proteosome進行降解。我們利用西方點漬法發現在293T/S1C細胞中，Asb-1蛋白的表現量跟STAT5蛋白的活化狀態有發生時間上的相關性。未來我們仍需要更多的實驗去證明Asb-1能夠調控JAK-STAT 這條訊息傳遞路徑。

STATs are a family of transcription factors that activated by a variety of cytokines, hormones, and growth factors. Among them, STAT3 is frequently activated in many human carcinomas and implicated in promoting tumor cell survival and immune evasion. On the contrary, STAT1 is known to promote tumor cell apoptosis and activate immune responses. In previous study, we generated LL2/S1C cells by transfecting mouse Lewis lung carcinoma (LL2) cells (in which STAT3 is constitutively activated) with S1C (an active form of STAT1, generated by substituting Cys residues of both Arg-656 and Asn-658 within the STAT1 SH2 domain) to see how STAT1 and STAT3 cooperatively regulate tumor immune responses. Also we generated LL2/S1 cells which stably expressed free form STAT1 protein. STAT1 is the predominant STAT activated by IFN-γ. Interestingly, we found that IFN-γ aberrantly activated STAT5 in S1C-overexpressing cells, as well as in some S1-overexpressing cells. It is believed that activation of STATs is relatively ligand-specific, but this concept can not explain how IFN-γ causes the aberrant STAT5 activation in LL2/S1C cells. The JAK-STAT signaling pathway is modulated mainly by three families of proteins, including the suppressor of cytokine signaling (SOCS) protein, the protein inhibitors of activated STAT (PIAS) and various protein tyrosine phosphatases (PTPs). To elucidate why IFN-γ induces STAT5 activation, we screened changes in protein expression or activation status of those regulators by western blot. The expression of SOCS1, SOCS3, PIAS1, PIAS3, and SHP2 proteins in LL2/S1C, LL2/S1, 293T/S1C, and 293T/S1 cells could not entirely and consistently account for the aberrant STAT5 activation. Also, changes in Jak2 (Janus kinase 2, the main kinase responsible for Stat5 phosphorylation) and IFNGR (interferon-γ receptor alpha chain) correlated poorly with aberrant STAT5 phosphorylation. Therefore, we speculated that (an) unknown protein(s) in S1C-overexpressing cells may mediate the aberrant STAT5 activation. STAT1 proteins in LL2/S1C cells were immunoprecipitated. The product was separated by one-dimensional SDS-PAGE, digested by trypsin, and analyzed by LC-MS/MS to identify unknown STAT1-associated protein(s). Data acquired from LC-MS/MS were analyzed by MASCOT software. To avoid signals of LC-MS/MS being interfered by immunoglobulin fragments in the immunoprecipitated products, we conducted the experiments with dimethylpimelimidate (DMP)- crosslinking immunoprecipitation procedure as well as using Pierce Seize X kit to get rid of antibody fragments from the immunoprecipitated complex. 138 proteins which participate in diverse cellular biological processes were identified. Among them, we deduced that the SOCS box-containing protein, Asb-1, could probably be a novel regulator of JAK-STAT pathway. SOCS box can recruit other SOCS box-containing proteins and interact with elongins BC complex to form E3 ubiquitin ligase core complex. Protein expression level of Asb-1 was correlated with the IFN-γ-induced aberrant STAT5 phosphorylation in 293T/S1C cell. Therefore, we supposed that Asb-1 could possibly be a novel regulator of JAK-STAT signaling pathway.

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