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研究生:林宏栯
研究生(外文):Hung-yu Lin
論文名稱:RHBDL2調控凝血酶調節素的切割及其在角質細胞遷移上所扮演的角色
論文名稱(外文):Regulation of RHBDL2-Mediated Thrombomodulin Shedding and Its Role on Keratinocyte Migration
指導教授:吳華林
指導教授(外文):Hua-lin Wu
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生物化學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:英文
論文頁數:70
中文關鍵詞:凝血酶調節素遷移切割絲胺酸蛋白水解酶
外文關鍵詞:migrationthrombomodulinsheddingRHBDL2
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凝血酶調節素(TM)是第一型穿膜蛋白。已知TM會大量表現在內皮細胞上,並執行其為人熟知的抗凝血功能。TM藉由與不同蛋白的交互作用參與了許多的生物功能,例如:抗凝血、發炎反應、細胞與細胞間的連結,以及血管新生等等。然而TM不僅表現在內皮細胞,也會表現於上皮的刺狀層(spinous layer),並且在受傷後的新生表皮會大量表現。在過去的研究中發現,利用重組的TM片段(TM位於細胞外的部分,TMD123)刺激角質細胞,可以加速細胞的遷移,並提供了TM可能在上皮細胞中扮演著某種角色。近來的報告指出哺乳動物的絲胺酸蛋白水解酶(稱為RHBDL2)能切割TM,切點位於細胞膜裡的位置,且不同於果蠅的絲胺酸蛋白水解酶對上皮生長因子(EGF)水解的專一性。這些現象顯示出,在某些生理情況下,TM可能是RHBDL2的受質。然而,在角質細胞中RHBDL2所誘導的TM切割,具有什麼生物功能則尚未被充分了解。在本實驗中,我們在人類上皮細胞株(HaCaT細胞)的培養液中發現了可溶性的TM片段(稱為sTM),並且此片段與TMD123大小相近。而sTM的量會受到腫瘤壞死因子(TNF alpha)以及EGF的刺激而增加;這個現象則可以被專一性的絲胺酸蛋白水解酶抑制劑(DCI)所抑制。另外一方面,將養滿的細胞做不同程度的刮傷,接著用西方點墨法(Western blot)或是酵素免疫分析法(ELISA)都可以偵測到TM被切割的情況;而這樣的現象則跟RHBDL2的訊息核醣核酸(mRNA)表現量無關,但卻可以被DCI所抑制。接著,我們成功建立了穩定表現RHBDL2或RHBDL2活性位置突變的HaCaT細胞。在RHBDL2穩定表現的HaCaT細胞中,TM被切割釋放的情形明顯增加,並且觀察到RHBDL2分布在細胞膜上。除此之外,在刮傷癒合分析(scratch wound healing assay)中,穩定表現RHBDL2的HaCaT細胞其癒合能力比綠螢光蛋白表現的HaCaT細胞來的好(爬行24小時後,癒合的百分比分別為69.6%與39.5%),並且排除了細胞生長複製可能帶來的影響。然而RHBDL2-及RHBDL2-SA-HaCaT細胞在培養48小時後,仍表現較高的生長速率。在細胞與基質的黏著實驗中(cell-matrix adhesion),RHBDL2-HaCaT細胞與膠原蛋白(type I collagen)間的黏著力較差。我們的結果顯示,在角質細胞中,可經由TNF alpha以及EGF調控RHBDL2的活性,增加RHBDL2調控的TM切割,並且能促進角質細胞的遷移。另外,這些結果也闡明了RHBDL2對TM切割與其在角質細胞移動及釋放TM所扮演的角色。
Thrombomodulin (TM) is a type I transmembrane protein constitutively expressed in endothelial cells, and acts as a cofactor in natural protein C anti-coagulant system. TM is involved in several biological processes, including anti-coagulation cascade, inflammatory response, cell-cell adhesion as well as angiogenesis through interaction with diverse proteins. TM expression is also observed in the spinous layer of epidermis and highly expressed in the neoepidermis of wounded skin tissue. In previous studies, we demonstrated that the treatment of recombinant TM extracellular fragment elevated keratinocyte migration, indicating that TM might participate in epithelial dynamics. Moreover, a recent report revealed that TM transmembrane domain was cleaved by mammalian rhomboid-like serine protease (RHBDL2) which did not shed other EGF-like ligands as Drosophila rhomboid did. These findings implied that TM could be a physiological substrate for RHBDL2. However, the significance of RHBDL2-mediated TM ectodomain shedding in keratinocytes remains elusive. In this study, we observed that soluble TM fragments (sTM) collected from the culture medium of TM-abundant human epithelium cell line HaCaT cells had almost the same size as recombinant human TM extracellular fragment (TMD123). The release of sTM increased upon the stimulation of tumor necrosis factor alpha (TNF alpha) and epidermal growth factor (EGF), and specifically inhibited by a serine protease inhibitor 3, 4-dichloroisocoumarin (DCI). Moreover, extensive wounding could initiate proteolytic processing of TM in either Western blot or ELISA assay. The TM cleavage was not corresponded with the RNA expression of RHBDL2, but was susceptible to DCI treatment. Besides, we established RHBDL2- or active-site mutated RHBDL2 (RHBDL2-SA) stably expressed HaCaT cells. Substantially increased TM ectodomain shedding of RHBDL2-HaCaT cells was observed as determined by Western blot assay. The localization of RHBDL2 in HaCaT cells was found in cell membrane. RHBDL2-HaCaT cells displayed higher wound-closure percentage in comparison with corresponding controls (69.6 and 39.5% 24 hr after wounding), and this higher migratory ability was independent of cell proliferation during first 24 hours. However, higher proliferation rate was also observed in either RHBDL2- or RHBDL2-SA-HaCaT cells after 48 hr. In cell-matrix adhesion assay, RHBDL2- HaCaT cells also possessed less ability to adhere to type I collagen. In conclusion, we propose that TM shedding mediated by RHBDL2 is regulated by TNF alpha and EGF, and plays an important role in facilitating keratinocyte migration. These results shed light on the interplay between TM ectodomain shedding and biological functions of keratinocytes, and further investigation is warranted.
中文摘要..................................................1
ABSTRACT..................................................3
ACKNOWLEGEMENT............................................5
CONTENTS..................................................6
CONTENTS OF FIGURES.......................................8
ABBREVIATION..............................................9
REAGENTS.................................................10
INTRODUCTION.............................................13
SPECIFIC AIMS............................................20
MATERIALS AND METHODS....................................21
CULTURE AND SUBCULTURE OF HACAT CELLS....................21
CRYOPRESERVATION OF HACAT CELLS..........................22
RETRIEVAL OF HACAT CELLS FROM FROZEN STORAGE.............22
SDS-POLYACRYLAMIDE GEL ELECTROPHORESIS...................23
WESTERN BLOT.............................................24
REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION..........25
I.TOTAL RNA EXTRACTION (VIOGENE MINIPREP SYSTEM).........25
II.REMOVAL OF GENOMIC DNA IN ELUTED TOTAL RNA............26
III.REVERSE TRANSCRIPTION................................27
IV.POLYMERASE CHAIN REACTION.............................28
PLASMID DNA EXTRACTION (GENEAID PLASMID MINI KIT)........28
VALIDATION OF PLASMID DNA................................30
AGAROSE GEL ELECTROPHORESIS..............................30
RHBDL2 TRANSFECTION INTO HACAT CELLS.....................31
SITE-DIRECT MUTAGENESIS OF RHBDL2 PLASMID................32
PROTEIN C ACTIVATION ASSAY...............................32
SCRATCH WOUND HEALING ASSAY..............................33
CELL PROLIFERATION ASSAY.................................34
ADHESION ASSAY...........................................34
SPREADING ASSAY..........................................35
RESULTS..................................................36
DISCCUSSION..............................................42
REFERENCES...............................................48
FIGURES..................................................54
APPENDIX.................................................69
RESUME...................................................70
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