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研究生:林筱蒨
研究生(外文):Hsiao-Chien Lin
論文名稱:探討在不同細胞中表現 HLA-B27 蛋白質而產生之內質網壓力反應
論文名稱(外文):Investigation of the ER stress response of cell lines expressing HLA-B27 proteins
指導教授:曾銘仁
指導教授(外文):Min-Jen Tseng
口試委員:黃憲斌李沁劉怡文
口試委員(外文):Hsien-Bin HuangChin LiYi-Wen Liu
口試日期:100年06月27日
學位類別:碩士
校院名稱:國立中正大學
系所名稱:分子生物研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:119
中文關鍵詞:僵直性脊椎炎人類白血球抗原內質網壓力反應
外文關鍵詞:Ankylosing spondylitis (AS)HLA-B27ER stress
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僵直性脊椎炎 (Ankylosing spondylitis, AS) 是一慢性免疫風濕性疾病,起因迄今未能完全了解,但近幾十年來的研究發現僵直性脊椎炎和 B27 型人類白血球抗原有很大的關聯。許多文獻提出與 AS 相關之 HLA-B27 容易於內質網中錯誤摺疊而堆積,以至造成內質網壓力,而引發內質網壓力反應進而誘發發炎反應。
當細胞內產生內質網壓力時,會促使伴護蛋白 (chaperone) – GRP78 的表現增加來幫助蛋白質摺疊;內質網壓力反應使 IRE1α 活化而進行 XBP-1 mRNA 剪接 (XBP-1s ,是從 XBP-1 mRNA 剪切26 個鹼基的 intron 再加以連接) 。在 HEK293 Tet-on、 HEK293、 HeLa、 293T 細胞株中短暫轉染表現質體以大量表現 B2704 蛋白質可觀察到內質網壓力反應:產生 XBP-1 splicing 的現象,和 GRP78 蛋白質的表現量增加,尤其在 293T 細胞株中,因為它帶有 SV40 large T-antigen ,可以使帶有 SV40 複製起始點的質體在細胞內進行基因附體的複製 (episomal replication),讓轉染的質體增加,使得蛋白質表現量更提高。當過量表現 B2704 蛋白質時,甚至會造成 293T 細胞的細胞凋亡和 NF-κB 活化的現象。
篩選出數株能穩定表現 B2704 蛋白質的 HEK293 Tet-on、HEK293、和 HeLa 細胞株,以 doxycycline 處理 HEK293 Tet-on stable clones 中,以誘導 B2704 蛋白質的表現,可發現 GRP78 的表現量和 XBP-1 splicing 皆有些許增加;但是在穩定表現 B2704 蛋白質的 HEK293 和 HeLa 細胞株卻無法觀察到有內質網壓力反應的發生。比較 HEK293 Tet-on、HEK293、和 HeLa 細胞株以及它們的相對 stable cell lines ,在細胞型態、生長速率、以及對造成內質網壓力之藥劑的靈敏度都沒有很大的不同。
B2704 蛋白質可能是經由降解途徑使之不會堆積在內質網引起細胞壓力。與質網相關的降解系統有泛素蛋白酶體系統 (ubiquitin proteasome system) 和 巨型細胞自噬溶酶體系統 (macrophagy-lysosome system)。以蛋白酶體抑制劑 - MG132 處理 HEK293 和 HeLa stable cell lines,可發現 B2704 蛋白質的表現量增加;而以溶酶體抑制劑 – chloroquine (CQ)、NH4Cl 處理時,只有在 HeLa stable cell line #2 的 B2704 蛋白質表現增加。也就是說, HEK293 和 HeLa 的 stable cell lines 的 B2704 蛋白質會經由 ERAD pathway 降解,而 HeLa stable cell line #2 的 B2704 蛋白質則會同時經由 ERAD 和ERAA pathway 降解。
文獻提到錯誤摺疊的 HLA-B27 蛋白質不會被醣基化且不送至細胞膜表面,而是被送到細胞質的降解機制降解或者堆積在內質網中。所以和 AS 相關的 HLA-B2704 以及和 AS 不相關的 HLA-B2706差別可能在於是否有醣基化。 然而在 293T 細胞中表現的 B2706 和 B2704蛋白質分子量大小一樣,並且 B2704 或 B2706 蛋白質表現增加都會造成 XBP-1 splicing 和 GRP78 表現量增加。這些結果顯示這兩個 HLA-B27 型蛋白質的表現都會造成內質網壓力反應,然而大量表現能被醣基化修飾而轉位至細胞膜的蛋白質 (somatostatin receptor) 或 Notch 下游會被送入細胞核的基因- Herp (轉錄因子) 時,則不影響 GRP78 的表現量,即不會產生內質網壓力。因此需更多的實驗來證實是否是因為 HLA-B27 型蛋白質在內質網的摺疊速率較慢或是因不進行醣基化而累積在內質網當中,進而引發內質網壓力反應。

Ankylosing spondylitis (AS) is a chronic and progressive inflammatory rheumatic disease. The exact cause of AS and other spondyloarthropathies is still unknown, but a strong link between AS and the HLA-B27 gene has been definitively confirmed. There have been increasing interests in the critical role of the misfolding and unfolded protein response (UPR) of the heavy chain HLA-B27 in modulation of the inflammatory response and progression of AS.
Induction of endoplasmic reticulum (ER) chaperone GRP78/BiP increases protein folding capacity, as such, it represents a major survival arm of UPR. The appearance of spliced XBP1 mRNA (XBP1s, removal of a 26-base intron from XBP1 mRNA by IRE1α) is among the signatures of UPR. Transient over-expression of B2704 proteins in HEK293 Tet-on, HEK293, HeLa and 293T cell lines all led to UPR as demonstrated by splicing of XBP-1 transcript and slightly increasing GRP78 protein levels. Furthermore, over-expression of B2704 proteins in 293T cells resulted in apoptosis and NF-κB activation.
Several stable cell lines were established to constitutively express different levels of HLA-B2704. When the 293 Tet-on inducible stable cell lines expressing B2704 upon doxycycline addition could slightly promote the expression levels of GRP78 and increase XBP-1 splicing, however, this phenomenon in HEK293 and HeLa stable cell lines didn’t display similar upregulation. Comparing of the cell morphologies, the growth rates, and the sensitivities to thapsigargin (Tg), an inhibitor for ER Ca2+ ATPase, between original HEK293 and HeLa cell lines and their stable cell lines, there were not apparent differences in these cellular physiological characteristics.
We speculated that the B2704 proteins might undergo degradation to prevent ER stress in stable cell lines. The ER commands the degradation of misfolded proteins by the ubiquitin proteasome system (UPS) and macroautophagy lysosome system (MALS). The protein levels of B2704 increased in HEK293 and HeLa stable cell lines after treatment with proteasome inhibitor, MG132. Moreover, after treatment with lysosome inhibitor, chloroquine (CQ) or NH4Cl, the protein levels of B2704 also increased in HeLa stable cell line #2. These results suggested that misfolded HLA-B2704 proteins underwent degradation via proteasome system (UPS) in HEK293 and HeLa stable cell lines. In HeLa stable cell line#2, degradation of B2704 proteins was via both UPS and MALS. Degradation of HLA-B2704 proteins prevented the accumulation of these misfolded proteins in ER.
Previous study showed that HLA-B27 proteins were deglycosylated when misfolding, and then retrotranslocated to cytosol for degradation or accumulated in the ER. The molecular weight of HLA-B2706 protein, a no AS-associated HLA-B27 subtype, was the same as that of B2704 protein in the cell lines. This result showed that the B2706 protein might be also in a non-glycosylated state. And surprisingly, the GRP78 expression levels and XBP-1 splicing were also increased when over-expressing HLA- B2706 proteins in 293T cell lines. However, overexpressions of somatostatin receptors, another glycosylated cell membrane protein, and Herp protein, a transcription factor, didin’t induce ER-stress. In the future, we will attempt to examine whether the slower protein folding propensity or deglycosylation of HLA-B27 proteins is the major player in causing the accumulation of HLA-B27 proteins in ER and the sequential UPR.

致謝
中文摘要
英文摘要
目錄
第一章、序論
一、僵直性脊椎炎 (Ankylosing spondylitis) 1
二、B27型人類白血球抗原 (HLA-B27) 1
三、內質網壓力 (ER-stress) 3
四、內質網壓力反應 (Unfolded Protein Response, UPR) (Figure 2) 4
1. The IRE1α pathway: 5
2. The PERK pathway: 5
3. The ATF6 pathway: 6
4. Apoptotic response: (Figure 3) 6
5. NF-κB and JNK activation: (Figure 4) 7
五、錯誤摺疊蛋白質降解 (Misfolded protein degradation) 7
1. ER-associated degradation (ERAD): (Figure 6) 7
2. ER-activated autophagy (ERAA): (Figure 7) 8
六、實驗目的: 9
第二章、實驗材料與方法
第一節、質體的構築 11
第二節、微量質體粗萃取 (LiCl-Phenol-Chloroform extraction method) 11
第三節、組套純化微量 (mini) 質體 12
第四節、組套純化中量 (midi) 質體 13
第五節、限制酶鑑定 (Restriction enzyme digestion) 14
第六節、瓊脂膠電泳 (Agarose gel electrophoresis) 15
第七節、透析膜中回收純化瓊脂膠內的DNA (DNA electro-elution) 16
第八節、接合反應 (Ligation) 17
第九節、氯化銣法 (Rubidium Chloride method) 製備勝任細胞 18
(Competent cell) 18
第十節、轉形作用 (Transformation) 19
第十一節、凍菌保存 21
第十二節、DNA 定序 21
第十三節、細胞培養 22
第十四節、細胞株的質體短暫轉染 (Transient transfection) 25
第十五節、細胞株的質體穩定轉染 (Stably transfection) 25
第十六節、挑選穩定表現之細胞株 (Establish stable cell lines) 26
第十七節、免疫螢光染色 (Immunostaining) 27
第十八節、四唑鹽分析方法 (MTT assay) 28
第十九節、細胞增生及細胞倍增實驗 (Doubling time) 29
第二十節、細胞株的蛋白質萃取 30
第二十一節、蛋白質定量 31
第二十二節、SDS-PAGE (SDS-polyacrylamide gel electrophoresis) 31
第二十三節、西方墨點分析法 (Western-blotting analysis) 33
第二十四節、Total RNA 萃取 36
第二十五節、反轉錄聚合連鎖反應 (Reverse transcription polymerase chain reaction) 36
第三章、實驗結果
一、利用西方點墨法以及 GFP 表現確認 HEK293 Tet-on 細胞株 39
二、短暫誘導大量 B2704 蛋白質表現對 HEK293 Tet-on 細胞株的內質網壓力反應 39
三、B2704 蛋白質在 HEK293 細胞株的表現位置 41
四、短暫過量表現 B2704 蛋白質造成 HEK293 細胞株的內質網壓力反應 42
五、短暫過量表現 B2704 蛋白質會造成 HeLa 細胞株的內質網壓力反應 43
六、短暫過量表現 B2704 蛋白質造成 293T 細胞株明顯的內質網壓力反應 44
七、建立穩定表現 B2704 蛋白質之細胞株 45
八、穩定表現 B2704 蛋白質之細胞株的內質網壓力反應 45
九、比較原本細胞株以及穩定表現 B2704 蛋白質之細胞株的細胞生理特性 46
十、穩定表現 B2704 蛋白質之細胞株有 B2704 蛋白質的降解現象 47
十一、HLA-B2706 對細胞株的影響 48
第四章、結論與討論
一、短暫促成 HLA-B2704 蛋白質大量表現對細胞株產生內質網壓力反應 51
二、穩定表現 HLA-B2704 蛋白質不會造成細胞內質網壓力 53
三、穩定表現 HLA-B2704 蛋白質的細胞株與原本細胞株的生理特性的差異 53
四、穩定表現 HLA-B2704 蛋白質的細胞株經 ERAD/ERAA pathway 降解 B2704 蛋白質以避免內質網壓力的傷害 54
五、HLA-B2706 對細胞株的影響 55
圖目錄
Figure 1: 錯誤摺疊學說 (The misfolding hypothesis) 57
Figure 2: 哺乳動物的內質網壓力反應 (The mammalian UPR pathways) 58
Figure 3: 內質網壓力反應和細胞凋亡之間的關聯 (Putative links between the UPR and apoptotic responses) 59
Figure 4: 受到內質網壓力反應調控之 JNK 和 NF-κB 的活化 (Proposed models for UPR-mediated JNK and NF-κB activation) 60
Figure 5: 和內質網相關之經由蛋白酶體和溶酶體降解錯誤摺疊蛋白的降解途徑 (The ER commands the degradation of misfolded proteins by the proteasome and autophagy) 61
Figure 6: 內質網相關降解途徑的逐步說明 (A step-by-step illustration of endoplasmic reticulum- associated degradation) 62
Figure 7: 巨型細胞自噬和伴護蛋白調節自噬之步驟 (Steps in macroautophagy and chaperone-mediated autophagy) 63
Figure 8: 四環素控制的表達系統 (The Tet-on system) 64
Figure 9: 利用西方點墨法以及 GFP 的表現確認 HEK293 Tet-on 細胞株 65
Figure 10: 短暫誘導大量 B2704 蛋白質表現的 HEK293 Tet-on 細胞株呈現 XBP-1 splicing 現象 67
Figure 11: 短暫誘導大量 B2704 蛋白質表現的 HEK293 Tet-on 細胞株呈現 GRP78 表現量增加 69
Figure 12: B2704 蛋白質表現在 HEK293 細胞的內質網 70
Figure 13: 短暫過量表現 B2704 蛋白質會造成 HEK293 細胞株的內質網壓力反應 71
Figure 14: 短暫過量表現 B2704 蛋白質會造成 HeLa 細胞株的內質網壓力反應 73
Figure 15: 短暫過量表現 B2704 蛋白質會造成 293T 細胞株明顯的內質網壓力反應 74
Figure 16: 建立穩定表現 B2704 蛋白質之細胞株 75
Figure 17: 穩定表現 B2704 蛋白質之細胞株的內質網壓力反應 77
Figure 18: 原本細胞株和能穩定表現 B2704 蛋白質之細胞株的型態 (Morphology) 比較 79
Figure 19: 原本細胞株和穩定表現 B2704 蛋白質之細胞株的生長速率 (Growing rate) 比較 82
Figure 20: 原本細胞株和穩定表現 B2704 蛋白質之細胞株對 thapsigargin 的敏感度 (Sensitivity) 比較 83
Figure 21: 穩定表現的 B2704 蛋白質可經由 ERAD 機制降解 85
Figure 22: 穩定表現的 B2704 由 ERAA 機制降解 87
Figure 23: pcDNA3.1-B2706-myc-His sequencing 88
Figure 24: B2706 蛋白質在 HEK293 和 HeLa 細胞株表現的分子量和 B2704 蛋白質相同 89
Figure 25: 建立穩定表現 B2706 蛋白質之細胞株 90
Figure 26: B2706 蛋白質是否對 293T 細胞株產生內質網壓力反應 91
Figure 27: B2706 蛋白質、B2704 蛋白質、Herp 以及 somatostatin receptor (SSTR) 在 293T 細胞株表現時對 GRP78 表現量的影響 92
表目錄
Table 1: HLA-B27 subtype frequencies (%) in different world populations 93
Table 2: HLA-B27 subtype amino acid sequence variations 94
Table 3: List of pimers used in this study 95
Table 4: Doubling time of HeLa or HEK293 cell lines and their stable cell lines 95
參考文獻 96
附錄
1. 利用西方點墨法以及 GFP 的表現確認 sstr1-EGFP、sstr2-EGFP 在 293T 細胞株的表現 (Figure 27的補充) 107
2. 在不同細胞株中 human β2-microglobulin 的 mRNA 表現量 107

Allen RL, O'Callaghan CA, McMichael AJ, Bowness P (1999) Cutting edge: HLA-B27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure. J Immunol 162: 5045-5048

Ball EJ, Khan MA (2001) HLA-B27 polymorphism. Joint Bone Spine 68: 378-382

Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2: 326-332

Beukelman CJ, Van Leeuwen A (1990) Guilt by association: HLA-B27 and ankylosing spondylitis. Immunol Today 11: 270

Bird LA, Peh CA, Kollnberger S, Elliott T, McMichael AJ, Bowness P (2003) Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling. Eur J Immunol 33: 748-759

Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, Stenmark H, Johansen T (2005) p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171: 603-614

Braun J, Baraliakos X (2011) Imaging of axial spondyloarthritis including ankylosing spondylitis. Ann Rheum Dis 70 Suppl 1: i97-103

Brewerton DA, Hart FD, Nicholls A, Caffrey M, James DC, Sturrock RD (1973) Ankylosing spondylitis and HL-A 27. Lancet 1: 904-907

Brodsky JL, McCracken AA (1999) ER protein quality control and proteasome-mediated protein degradation. Semin Cell Dev Biol 10: 507-513

Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415: 92-96

Carlson EJ, Pitonzo D, Skach WR (2006) p97 functions as an auxiliary factor to facilitate TM domain extraction during CFTR ER-associated degradation. EMBO J 25: 4557-4566

Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354: 610-621

Chatzikyriakidou A, Voulgari PV, Drosos AA (2011) What is the role of HLA-B27 in spondyloarthropathies? Autoimmun Rev

Chiang HL, Dice JF (1988) Peptide sequences that target proteins for enhanced degradation during serum withdrawal. J Biol Chem 263: 6797-6805

Colbert RA, DeLay ML, Klenk EI, Layh-Schmitt G (2010) From HLA-B27 to spondyloarthritis: a journey through the ER. Immunol Rev 233: 181-202

Colbert RA, DeLay ML, Layh-Schmitt G, Sowders DP (2009) HLA-B27 misfolding and spondyloarthropathies. Prion 3: 15-26

Cox JS, Shamu CE, Walter P (1993) Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 73: 1197-1206

Credle JJ, Finer-Moore JS, Papa FR, Stroud RM, Walter P (2005) On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc Natl Acad Sci U S A 102: 18773-18784

Dakwar E, Reddy J, Vale FL, Uribe JS (2008) A review of the pathogenesis of ankylosing spondylitis. Neurosurg Focus 24: E2

Dangoria NS, DeLay ML, Kingsbury DJ, Mear JP, Uchanska-Ziegler B, Ziegler A, Colbert RA (2002) HLA-B27 misfolding is associated with aberrant intermolecular disulfide bond formation (dimerization) in the endoplasmic reticulum. J Biol Chem 277: 23459-23468

de Vlam K (2010) Soluble and tissue biomarkers in ankylosing spondylitis. Best Pract Res Clin Rheumatol 24: 671-682

Deng J, Lu PD, Zhang Y, Scheuner D, Kaufman RJ, Sonenberg N, Harding HP, Ron D (2004) Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Mol Cell Biol 24: 10161-10168

Dice JF (2007) Chaperone-mediated autophagy. Autophagy 3: 295-299

Ding WX, Ni HM, Gao W, Yoshimori T, Stolz DB, Ron D, Yin XM (2007) Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 171: 513-524

Ding WX, Yin XM (2008) Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy 4: 141-150

Han D, Lerner AG, Vande Walle L, Upton JP, Xu W, Hagen A, Backes BJ, Oakes SA, Papa FR (2009) IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138: 562-575

Harding HP, Calfon M, Urano F, Novoa I, Ron D (2002) Transcriptional and translational control in the Mammalian unfolded protein response. Annu Rev Cell Dev Biol 18: 575-599

Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000a) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6: 1099-1108

Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000b) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5: 897-904

Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397: 271-274

Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11: 619-633

Haze K, Yoshida H, Yanagi H, Yura T, Mori K (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10: 3787-3799

Helfgott SM, Kieval RI, Breedveld FC, Brahn E, Young CT, Dynesius-Trentham R, Trentham DE (1988) Detection of arthritogenic factor in adjuvant arthritis. J Immunol 140: 1838-1843

Hillen W, Berens C (1994) Mechanisms underlying expression of Tn10 encoded tetracycline resistance. Annu Rev Microbiol 48: 345-369

Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444: 860-867

Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH (2006) Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol 26: 3071-3084

Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, Zhai B, Wan L, Gutierrez A, Lau AW, Xiao Y, Christie AL, Aster J, Settleman J, Gygi SP, Kung AL, Look T, Nakayama KI, DePinho RA, Wei W (2011) SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471: 104-109

Jaeger PA, Wyss-Coray T (2009) All-you-can-eat: autophagy in neurodegeneration and neuroprotection. Mol Neurodegener 4: 16

Jarosch E, Taxis C, Volkwein C, Bordallo J, Finley D, Wolf DH, Sommer T (2002) Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat Cell Biol 4: 134-139

Jia L, Yu G, Zhang Y, Wang MM (2009) Lysosome-dependent degradation of Notch3. Int J Biochem Cell Biol 41: 2594-2598

Kabuta T, Suzuki Y, Wada K (2006) Degradation of amyotrophic lateral sclerosis-linked mutant Cu,Zn-superoxide dismutase proteins by macroautophagy and the proteasome. J Biol Chem 281: 30524-30533

Kamimoto T, Shoji S, Hidvegi T, Mizushima N, Umebayashi K, Perlmutter DH, Yoshimori T (2006) Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity. J Biol Chem 281: 4467-4476

Kaufman RJ (1999) Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13: 1211-1233

Keller JN, Dimayuga E, Chen Q, Thorpe J, Gee J, Ding Q (2004) Autophagy, proteasomes, lipofuscin, and oxidative stress in the aging brain. Int J Biochem Cell Biol 36: 2376-2391

Knittler MR, Dirks S, Haas IG (1995) Molecular chaperones involved in protein degradation in the endoplasmic reticulum: quantitative interaction of the heat shock cognate protein BiP with partially folded immunoglobulin light chains that are degraded in the endoplasmic reticulum. Proc Natl Acad Sci U S A 92: 1764-1768

Kostova Z, Tsai YC, Weissman AM (2007) Ubiquitin ligases, critical mediators of endoplasmic reticulum-associated degradation. Semin Cell Dev Biol 18: 770-779

Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, Ogawa S, Kaufman RJ, Kominami E, Momoi T (2007) ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ 14: 230-239

Kruse KB, Dear A, Kaltenbrun ER, Crum BE, George PM, Brennan SO, McCracken AA (2006) Mutant fibrinogen cleared from the endoplasmic reticulum via endoplasmic reticulum-associated protein degradation and autophagy: an explanation for liver disease. Am J Pathol 168: 1299-1308; quiz 1404-1295

Lai E, Teodoro T, Volchuk A (2007) Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology (Bethesda) 22: 193-201

Laval SH, Timms A, Edwards S, Bradbury L, Brophy S, Milicic A, Rubin L, Siminovitch KA, Weeks DE, Calin A, Wordsworth BP, Brown MA (2001) Whole-genome screening in ankylosing spondylitis: evidence of non-MHC genetic-susceptibility loci. Am J Hum Genet 68: 918-926

Lawless MW, Mankan AK, White M, O'Dwyer MJ, Norris S (2007) Expression of hereditary hemochromatosis C282Y HFE protein in HEK293 cells activates specific endoplasmic reticulum stress responses. BMC Cell Biol 8: 30

Lee KP, Dey M, Neculai D, Cao C, Dever TE, Sicheri F (2008) Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing. Cell 132: 89-100

Li H, Korennykh AV, Behrman SL, Walter P (2010) Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering. Proc Natl Acad Sci U S A 107: 16113-16118

Liu CY, Schroder M, Kaufman RJ (2000) Ligand-independent dimerization activates the stress response kinases IRE1 and PERK in the lumen of the endoplasmic reticulum. J Biol Chem 275: 24881-24885

Lu PD, Harding HP, Ron D (2004) Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J Cell Biol 167: 27-33

Ma Y, Hendershot LM (2004) The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 4: 966-977

Madden DR, Gorga JC, Strominger JL, Wiley DC (1991) The structure of HLA-B27 reveals nonamer self-peptides bound in an extended conformation. Nature 353: 321-325

Majeski AE, Dice JF (2004) Mechanisms of chaperone-mediated autophagy. Int J Biochem Cell Biol 36: 2435-2444

Martin TM, Smith JR, Rosenbaum JT (2002) Anterior uveitis: current concepts of pathogenesis and interactions with the spondyloarthropathies. Curr Opin Rheumatol 14: 337-341

McGonagle D, Gibbon W, Emery P (1998) Classification of inflammatory arthritis by enthesitis. Lancet 352: 1137-1140

Merksamer PI, Papa FR (2010) The UPR and cell fate at a glance. J Cell Sci 123: 1003-1006

Meusser B, Hirsch C, Jarosch E, Sommer T (2005) ERAD: the long road to destruction. Nat Cell Biol 7: 766-772

Ni M, Lee AS (2007) ER chaperones in mammalian development and human diseases. FEBS Lett 581: 3641-3651

Ni M, Zhou H, Wey S, Baumeister P, Lee AS (2009) Regulation of PERK signaling and leukemic cell survival by a novel cytosolic isoform of the UPR regulator GRP78/BiP. PLoS One 4: e6868

Nishikawa SI, Fewell SW, Kato Y, Brodsky JL, Endo T (2001) Molecular chaperones in the yeast endoplasmic reticulum maintain the solubility of proteins for retrotranslocation and degradation. J Cell Biol 153: 1061-1070

Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26: 9220-9231

Orenstein SJ, Cuervo AM (2010) Chaperone-mediated autophagy: molecular mechanisms and physiological relevance. Semin Cell Dev Biol 21: 719-726

Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, Overvatn A, Bjorkoy G, Johansen T (2007) p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem 282: 24131-24145

Park SH, Bolender N, Eisele F, Kostova Z, Takeuchi J, Coffino P, Wolf DH (2007) The cytoplasmic Hsp70 chaperone machinery subjects misfolded and endoplasmic reticulum import-incompetent proteins to degradation via the ubiquitin-proteasome system. Mol Biol Cell 18: 153-165

Perlmutter DH (1999) Misfolded proteins in the endoplasmic reticulum. Lab Invest 79: 623-638

Prostko CR, Brostrom MA, Brostrom CO (1993) Reversible phosphorylation of eukaryotic initiation factor 2 alpha in response to endoplasmic reticular signaling. Mol Cell Biochem 127-128: 255-265

Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, Gotoh T, Akira S, Bouillet P, Strasser A (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129: 1337-1349

Reveille JD (2011) The genetic basis of spondyloarthritis. Ann Rheum Dis 70 Suppl 1: i44-50

Reveille JD, Maganti RM (2009) Subtypes of HLA-B27: history and implications in the pathogenesis of ankylosing spondylitis. Adv Exp Med Biol 649: 159-176

Reveille JD, Sims AM, Danoy P, Evans DM, Leo P, Pointon JJ, Jin R, Zhou X, Bradbury LA, Appleton LH, Davis JC, Diekman L, Doan T, Dowling A, Duan R, Duncan EL, Farrar C, Hadler J, Harvey D, Karaderi T, Mogg R, Pomeroy E, Pryce K, Taylor J, Savage L, Deloukas P, Kumanduri V, Peltonen L, Ring SM, Whittaker P, Glazov E, Thomas GP, Maksymowych WP, Inman RD, Ward MM, Stone MA, Weisman MH, Wordsworth BP, Brown MA (2010) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 42: 123-127

Rideout HJ, Lang-Rollin I, Stefanis L (2004) Involvement of macroautophagy in the dissolution of neuronal inclusions. Int J Biochem Cell Biol 36: 2551-2562

Ron D (2002) Translational control in the endoplasmic reticulum stress response. J Clin Invest 110: 1383-1388

Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8: 519-529

Rutkowski DT, Kaufman RJ (2004) A trip to the ER: coping with stress. Trends Cell Biol 14: 20-28

Sant SM, O'Connell D (1995) Cauda equina syndrome in ankylosing spondylitis: a case report and review of the literature. Clin Rheumatol 14: 224-226

Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74: 739-789

Shamu CE, Walter P (1996) Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J 15: 3028-3039

Sheehan NJ (2010) HLA-B27: what's new? Rheumatology (Oxford) 49: 621-631

Shen J, Prywes R (2004) Dependence of site-2 protease cleavage of ATF6 on prior site-1 protease digestion is determined by the size of the luminal domain of ATF6. J Biol Chem 279: 43046-43051

Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, Wek RC (1998) Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol 18: 7499-7509

Smith JA, Marker-Hermann E, Colbert RA (2006) Pathogenesis of ankylosing spondylitis: current concepts. Best Pract Res Clin Rheumatol 20: 571-591

Smith JA, Turner MJ, DeLay ML, Klenk EI, Sowders DP, Colbert RA (2008) Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-beta induction via X-box binding protein 1. Eur J Immunol 38: 1194-1203

Sun S, Han J, Ralph WM, Jr., Chandrasekaran A, Liu K, Auborn KJ, Carter TH (2004) Endoplasmic reticulum stress as a correlate of cytotoxicity in human tumor cells exposed to diindolylmethane in vitro. Cell Stress Chaperones 9: 76-87

Tirasophon W, Welihinda AA, Kaufman RJ (1998) A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 12: 1812-1824

Tsang KY, Chan D, Bateman JF, Cheah KS (2010) In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences. J Cell Sci 123: 2145-2154

Tsao WC, Wu HM, Chi KH, Chang YH, Lin WW (2005) Proteasome inhibitors induce peroxisome proliferator-activated receptor transactivation through RXR accumulation and a protein kinase C-dependent pathway. Exp Cell Res 304: 234-243

Turner MJ, Delay ML, Bai S, Klenk E, Colbert RA (2007) HLA-B27 up-regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: Implications for the pathogenesis of spondylarthritis-like disease. Arthritis Rheum 56: 215-223

Turner MJ, Sowders DP, DeLay ML, Mohapatra R, Bai S, Smith JA, Brandewie JR, Taurog JD, Colbert RA (2005) HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol 175: 2438-2448

Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287: 664-666

Vadlamudi RK, Joung I, Strominger JL, Shin J (1996) p62, a phosphotyrosine-independent ligand of the SH2 domain of p56lck, belongs to a new class of ubiquitin-binding proteins. J Biol Chem 271: 20235-20237

Vembar SS, Brodsky JL (2008) One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 9: 944-957

Wang XZ, Harding HP, Zhang Y, Jolicoeur EM, Kuroda M, Ron D (1998) Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J 17: 5708-5717

Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC (2003) Alpha-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 278: 25009-25013

Welihinda AA, Kaufman RJ (1996) The unfolded protein response pathway in Saccharomyces cerevisiae. Oligomerization and trans-phosphorylation of Ire1p (Ern1p) are required for kinase activation. J Biol Chem 271: 18181-18187

Wu J, Rutkowski DT, Dubois M, Swathirajan J, Saunders T, Wang J, Song B, Yau GD, Kaufman RJ (2007) ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell 13: 351-364

Yamamoto K, Sato T, Matsui T, Sato M, Okada T, Yoshida H, Harada A, Mori K (2007) Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev Cell 13: 365-376

Yaman I, Fernandez J, Liu H, Caprara M, Komar AA, Koromilas AE, Zhou L, Snider MD, Scheuner D, Kaufman RJ, Hatzoglou M (2003) The zipper model of translational control: a small upstream ORF is the switch that controls structural remodeling of an mRNA leader. Cell 113: 519-531

Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6: 1355-1364

Yoshida H, Haze K, Yanagi H, Yura T, Mori K (1998) Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem 273: 33741-33749

Zhang K, Kaufman RJ (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454: 455-462

Zhang LH, Zhang X (2010) Roles of GRP78 in physiology and cancer. J Cell Biochem 110: 1299-1305

Zhou J, Liu CY, Back SH, Clark RL, Peisach D, Xu Z, Kaufman RJ (2006) The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response. Proc Natl Acad Sci U S A 103: 14343-14348

Ziegler A, Loll B, Misselwitz R, Uchanska-Ziegler B (2009) Implications of structural and thermodynamic studies of HLA-B27 subtypes exhibiting differential association with ankylosing spondylitis. Adv Exp Med Biol 649: 177-195
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1. 37. 楊儒賓:〈羅欽順與貝原益軒--東亞近世儒常詮釋傳統中的氣論問題〉,《漢學研究》,第23卷第1期,2005.06,頁261-290。
2. 2. 丁為祥:〈明代氣學析辨-兼論張載與氣學的關係〉,《中國文化月刊》,2000年第8期。
3. 9. 何佳駿:〈羅欽順與王門書信往來探析--以其中所涉格物致知思想為論述焦點〉,《鵝湖月刊》,第30卷第2期。
4. 33. 陳榮捷:〈宋明理學中的「太極」觀念〉,《思與言》,第二十卷第三期,1982.09。
5. 32. 陳榮捷:〈早期明代之程朱學派〉,《中國文化月刊》,第十七卷,1981.03。
6. 15. 林繼平:〈明代理學之前驅:曹月川、薛敬軒、吳康齋哲學詣境的探索〉,《中華文化復興月刊》,第十八卷第五期,1985。
7. 16. 施輝煌:〈從王學興起看羅欽順的成學經過及其思想屬性〉,《東方人文學誌》,第五卷第四期,2006.12,頁103-125。
8. 42. 鄧克銘:〈良知與實體--明中葉羅欽順與歐陽崇一之論爭的意義〉,《鵝湖學誌》,第37卷,2006.12,頁1-34。
9. 44. 鍾彩鈞:〈上海復旦大學藏《整菴續稿》及其價值〉,《中國文哲研究通訊》,第五卷第三期,台北:中研院,中國文哲研究所,1995.09,頁137-141。
10. 46. 鍾彩鈞:〈上海復旦大學藏《整菴續稿》及其價值〉,《中國文哲研究通訊》,第5卷第3期,。
11. 47. 鄧克銘:〈羅欽順「理氣為一物」說之理論效果〉,《漢學研究》,第19卷第2期,2001.12,頁33-57。
12. 48. 楊儒賓:〈檢證氣學—理學史脈絡下的觀點〉,《漢學研究》,第25卷第1期,2007.06,頁247-281。
13. 19.蔡渭水、蔡新豐 (1998),「集團企業赴大陸之經營模式與其影響因素之研究」,中原學報,第26 卷第4 期,頁35–52。