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研究生:謝錫賢
研究生(外文):Hsi-Hsien Hsieh
論文名稱:探討SerpinB2在細胞老化中扮演的角色
論文名稱(外文):Investigating the role of SerpinB2 in cellular senescence
指導教授:林敬哲林敬哲引用關係
指導教授(外文):Jing-Jer Lin
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生物藥學研究所
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:2018
畢業學年度:106
語文別:英文
論文頁數:100
中文關鍵詞:細胞老化絲胺酸水解酶抑制蛋白
外文關鍵詞:Cellular senescenceSerpinB2
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細胞在遭受壓力時,會進入穩定且不可逆的細胞生長停滯狀態,這個狀態便稱為細胞老化。目前的研究已經發現,細胞老化在許多生理現象與疾病的發展中扮演非常重要的角色。除了染色體端粒縮短之外,也有其他的壓力會造成細胞老化,例如:致癌基因(oncogene)的活化、氧化壓力與DNA損傷等。雖然目前導致細胞老化的重要因子,例如p53、p21與p16已被人所熟知,但對於細胞老化的詳細機制,以及細胞是如何在細胞老化過程中維持穩定的生長停滯,仍然是需要繼續被探討的課題。在這個研究中,我們發現一種絲胺酸水解酶抑制蛋白SerpinB2,參與在細胞老化的維持。在老化過程中,SerpinB2的mRNA與蛋白質表現量都有上升,而我們也發現,SerpinB2的表現量提升會促進人類纖維母細胞進入細胞老化;相反地,SerpinB2表現量降低則會降低細胞老化的程度。由於p53的活化在細胞老化中扮演重要角色,故我們想進一步探討p53是否會參與調控SerpinB2在細胞老化過程的表現。由染色體免疫沉澱法(chromatin-immunoprecipitation)發現,在老化細胞中,p53會與SerpinB2 promoter結合,顯示在細胞老化的過程中,SerpinB2會受到p53的直接調控。而我們也發現,p21對於SerpinB2所參與的細胞老化是必要的,SerpinB2會與p21進行交互作用,並且增加p21蛋白質穩定性。除此之外,我們也發現SerpinB2可能會參與在溶體(lysosomes)的生成。TPPII (tripeptidyl peptidase II)是一種絲氨酸水解酶,參與細胞內多肽鏈(polypeptides)分解為三胜肽(tripeptides)過程,而目前已知TPPII的突變與細胞內溶體的生成有關。由此,本研究揭示了SerpinB2在細胞老化中至少扮演了兩個重要的調控角色。
Cellular senescence is a stable growth arrest and plays an important role in physiological and pathological activity. In addition to telomere shortening, many stressors like oncogene activation, oxidative stress and DNA damage are reported to induce cellular senescence. Although it is now well-described that the common senescence effectors including p53, p21 and p16 are involved in senescence progression, the detailed molecular mechanism about how the senescent cells maintain stable growth arrest state is still not clear. In this study, we find that SerpinB2, a serine protease inhibitor is involved in the maintenance of cellular senescence. During cellular senescence, the levels of SerpinB2 mRNA and proteins both elevated. We find that up-regulation of SerpinB2 is sufficient to induce cellular senescence in normal human diploid fibroblasts. On the other hand, down-regulation of SerpinB2 reduces the level of cellular senescence. Since activation of p53 is a critical procedure for cellular senescence, we investigate whether p53 can activate SerpinB2 expression. The chromatin-immunoprecipitation assay shows that p53 can directly bind to SerpinB2 promoter during senescence. It indicates that the elevated expression of SerpinB2 is directly regulated by the senescent effectors p53. Moreover, we find that SerpinB2-mediated senescence requires p21. We find that SerpinB2 can interact with p21 proteins and enhance p21 protein stability in a proteasome-independent manner. In addition to p21 stabilization, SerpinB2 might also mediate lysosome biogenesis. Tripeptidyl peptidase TPPII is a serine protease that digests polypeptides into tripeptides and mutation of TPPII is associated with lysosome biogenesis. Here, we find that SerpinB2 can interact with TPPII and inhibit the activity of TPPII in vitro. Thus, this study demonstrates that SerpinB2 plays at least two roles on senescence maintenance and regulation.
Contents
致謝----i
摘要----iii
Abstract----iv
Contents----v
List of Figures----vii
Chapter 1. Introduction----1
1.1 The physiological role of cellular senescence----1
1.1.1 The overview of cellular senescence----1
1.1.2 The role of cellular senescence in disease progression----3
1.2 The physiological role of SerpinB2----8
1.3 The regulatory mechanism of p21 level----12
Chapter 2. Materials and Methods----14
Chapter 3. Results----20
3.1 SerpinB2 induces cellular senescence in normal fibroblasts----20
3.2 Telomerase does not rescue SerpinB2-induced senescence----21
3.3 Extracellular function of SerpinB2 is not related to cellular senescence----21
3.4 Expression of SerpinB2 is up-regulated by p53 in cellular senescence----23
3.5 SerpinB2-mediated senescence requires p21----24
3.6 SerpinB2 elevates p21 protein stability through a proteasome-independent
manner----25
3.7 The X factor is involved in SerpinB2-mediated senescence and p21 protein
stabilization----26
3.8 A tripeptidyl peptidase TPPII is a target of SerpinB2----29
Chapter 4. Discussion----31
4.1 The regulation of SerpinB2 expression during cellular senescence----33
4.2 The interaction between SerpinB2 and p21 proteins----35
4.3 The up-regulation of p53 proteins in SerpinB2-mediated senescence----36
4.4 The role of PTEN in SerpinB2-mediated senescence----37
4.5 The proteases involved in SerpinB2-mediated senescence----38
4.6 SerpinB2 might regulate lysosomal activity----41
4.7 The remaining questions----43
Reference----44
Figure----58


List of figures
Figure 1. Upregulation of SerpinB2 mRNA and proteins in senescent cells.
Figure 2. SerpinB2 induces growth arrest in young IMR90 cells.
Figure 3. SerpinB2 increases senescence phenotypes in young IMR90 cells.
Figure 4. SerpinB2 increases the expression of senescence-associated secretory
phenotypes (SASPs) in young IMR90 cells.
Figure 5. SerpinB2 increases senescent effectors p53 and p21 in young IMR90 cells.
Figure 6. Reduction of SA-b-gal (+) cells by knocking down SerpinB2.
Figure 7. Telomerase cannot rescue SerpinB2-induced senescence.
Figure 8. SerpinB2 induces senescence in the lung cancer cell line H1299.
Figure 9. Inhibition of the secretion of SerpinB2 does not affect erpinB2-induced
growth arrest.
Figure 10. Exogenous SerpinB2 does not inhibit cell growth.
Figure 11. SerpinB2 and uPA interaction is not involved in SerpinB2-mediated
senescence.
Figure 12. The interaction between SerpinB2 and uPA is not involved in
SerpinB2-meditaed senescence.
Figure 13. The expression of SerpinB2 is dependent on p53 under doxorubicin
treatment.
Figure 14. The promoter activity of SerpinB2 can be regulated by p53.
Figure 15. The promoter activity of SerpinB2 can be regulated by p53 in senescent
cells.
Figure 16. Different p53 activators can increase SerpinB2 mRNA level.
Figure 17. Downregulation of p53 does not affect SerpinB2-induced senescence.
Figure 18. p21 is required for SerpinB2-induced senescence.
Figure 19. SerpinB2-mediated senescence requires p21 in the human colorectal
cancer cell line HCT116.
Figure 20. SerpinB2 transiently elevates p21 mRNA level.
Figure 21. SerpinB2 interacts with p21 proteins.
Figure 22. SerpinB2 increases p21 protein stability.
Figure 23. SerpinB2 increases p21 protein stability through a
proteasome-independent manner.
Figure 24. Downregulation of SerpinB2 reduces p21 protein stability.
Figure 25. Downregrulation of X factor rescues SerpinB2-induced growth defect.
Figure 26. SerpinB2 interacts with X factor.
Figure 27. X factor is required for SerpinB2-mediated senescence.
Figure 28. X factor is involved in p21 protein stabilization.
Figure 29. The activity of X factor is increased in senescent cells.
Figure 30. SerpinB2 and X factor are required for the elevated activity of the X
factor.
Figure 31. The activity of X factor is increased in senescent cells.
Figure 32. Inhibition of X factor activity reduces p21 protein stability.
Figure 33. Inhibition of X factor activity delay growth arrest in normal human
fibroblasts.
Figure 34. Compound A has low toxicity on IMR90 cells and has no effect on
telomere length.
Figure 35. Inhibition of X factor represses SASP expression in senescent IMR90.
Figure 36. SerpinB2 inhibits TPPII activity.
Supplementary Figure 1. SerpinB2 proteins in medium.
Supplementary Figure 2. Down-regulation of Serpinb2 reduces the level of p21
proteins in doxorubicin-treated HCT116 p53-/- cells.
Supplementary Figure 3. The phosphatase treatment cannot reduce the band-shift of
p21 proteins.
Supplementary Figure 4. SerpinB2 does not affect the level of MDM2 proteins.
Supplementary Figure 5. The level of PTEN is dependent on different cell context.
Supplementary Figure 6. SerpinB2 R380A mutant can interact with the X factor.
Supplementary Figure 7. The cellular localization of SerpinB2.
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