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Title Page

ABSTRACT

Contents

ABBREVIATIONS 9

INTRODUCTION 10

MATERIALS AND METHODS 13

Cell culture and construction of stable cell lines 13

Yeast two-hybrid assay 13

Immunoprecipitation and GST pull-down assay 14

Immunoblotting, immunofluorescence and immunohistochemistry assay 14

Semi-quantitative RT-PCR assay 15

Expression plasmids, siRNA and transfection 15

Cell cycle, apoptosis and colony formation assay 16

Senescence associated-β-galactosidase activity assay 16

Ubiquitination assay 16

Animal studies 17

Statistical analysis 17

RESULTS 18

Identification of ZNF313 as a novel XAF1-binding protein 18

ZNF313 increases XAF1 protein stability 18

ZNF313 is a novel cell cycle activator with proapoptotic potential 19

ZNF313 is a negative regulator of cellular senescence 19

ZNF313 is a specific antagonist of the CIP/KIP family members of CDK inhibitors 20

ZNF313 promotes ubiquitination and degradation of p21 WAF1(이미지참조) 21

ZNF313 stimulates a G1 to S phase transition of the cell cycle 22

ZNF313 is reduced in differentiation process 23

ZNF313 is elevated in cancer cells 23

DISCUSSION 57

REFERENCES 61

ABSTRACT IN KOREAN 66

Figure 1. Identification of ZNF313 25

Figure 2. In vivo and in vitro protein binding between ZNF313 and XAF1 26

Figure 3. Characterization of XAF1-interacting region of ZNF313 27

Figure 4. ZNF313 up-regulates XAF1 28

Figure 5. Decreased polyubiquitination of XAF1 by ZNF313 29

Figure 6. ZNF313 stimulates apoptosis 30

Figure 7. ZNF313's effect on apoptosis and cell cycle arrest 31

Figure 8. ZNF313 effect on cellular response to genotoxic stresses 32

Figure 9. Effect of ZNF313 on tumor growth 33

Figure 10. ZNF313 is a negative regulator of cellular senescence 34

Figure 11. Downregulation of ZNF313 during replicative senescence 35

Figure 12. ZNF313 in premature senescence 36

Figure 13. XAF1-independency of ZNF313 regulation of cellular senescence 37

Figure 14. p53-independent induction of cellular senescence by ZNF313 depletion 38

Figure 15. ZNF313 destabilizes CIP/KIP proteins 39

Figure 16. ZNF313 blocks p21 WAF1-mediated cellular senescence(이미지참조) 40

Figure 17. No effect of ZNF313 on G1 cell cycle arrest in p21 WAF1-deficient cells(이미지참조) 41

Figure 18. p21 WAF1 dependent effect of ZNF313 on colony formation of tumor cells(이미지참조) 42

Figure 19. p53-independent regulation of p21 WAF1 by ZNF313(이미지참조) 43

Figure 20. No effect of ZNF313 depletion on SAHF formation 44

Figure 21. Elevation of p21 WAF1 protein stability by ZNF313-depletion(이미지참조) 45

Figure 22. Validation of the E3 ligase activity of ZNF313 46

Figure 23. RING on ZNF313 is responsible for p21 WAF1-degradation(이미지참조) 47

Figure 24. Cell cycle-associated regulation of ZNF313 expression 48

Figure 25. Expression kinetics of ZNF313 during the cell cycle 49

Figure 26. ZNF313 modulates G1 to S cell cycle transition 50

Figure 27. ZNF313 protein induction by growth factors 51

Figure 28. ZNF313 depletion inhibits p21 WAF1-dependent G1-S transition(이미지참조) 52

Figure 29. ZNF313 is decreased in differentiated cells 53

Figure 30. Expression of ZNF313 and p21 WAF1 in differentiating mouse brain(이미지참조) 54

Figure 31. Elevated ZNF313 level in cancer cells 55

Figure 32. Translocalization of ZNF313 during cancer progression 56

초록보기

 ZNF313 은 zinc 결합 단백질의 하나로서 염색체에서의 위치는 다양한 암에서 증폭되어 있는 것으로 보고되고 있는 20q13.13 부위에 위치해있으나, 생체내 기능은 거의 알려져 있지 않다. 본 논문은 ZNF313 이 새로운 ubiquitin E3 ligase 이며 세포주기의 진행, 분화와 세포노화에 중요한 역할을 함을 규명하고 있다. 본 논문에서 ZNF313 은 XAF1 과 결합하는 단백질로 동정하였으며, 이를 통해 XAF1 의 세포내 안정성을 증가시키고 세포사멸 효과를 증진함을 밝혔다. 또한 ZNF313 이 세포주기의 진행을 촉진시키고 세포노화를 저해함을 볼 수 있었는데, 이는 ZNF313 내의 RING 부위를 통한 p21WAF1 단백질의 억제 기능을 통한 것임을 확인하였다. ZNF313 은 p21WAF1 을 ubiquitin 化 시켰으며 CIP/KIP 단백질群에 속하는 다른 단백질인 p27KIP1 and p57KIP2도 억제하였다. 그러나 또 다른 CDK 억제 단백질群에 속하는 INK4 계열의 p16INK4A and p15INK4B 에는 영향을 끼치지 않았다. ZNF313 단백질의 발현은 양상은 세포주기와 밀접한 연관성을 보였다. 즉, G1 期의 후기에 발현이 증가하기 시작하였으며, G1-S 전환에 중요한 역할을 함을 확인 할 수 있었다. 세포분열 유도물질 또는 성장인자 등의 처리는 ZNF313 의 증가를 야기하였다. ZNF313 의 세포내 제거는 세포주기의 진행을 저해하고 p21WAF1 에 의한 세포노화가 촉진됨을 확인할 수 있었다. ZNF313 은 분열의 진행에 의한 세포노화와 스트레스에 의해 야기된 세포노화 모두에 관여되어 있었다. ZNF313 단백질의 양은 세포가 분화됨에 따라 감소하였으며 다양한 종류의 암세포에서 증가해 있음을 확인하였다. 또한, ZNF313 은 정상적인 표피세포에서는 핵과 세포질에 고루 분포함을 볼 수 있었으나 암환자의 상피암세포에서는 세포질에 과발현함을 확인 할 수 있었다. 결론적으로, ZNF313 은 p21WAF1 을 억제하는 새로운 ubiquitin E3 ligase 로서, 이 단백질의 생체내 異象은 암을 포함한 다양한 질환과 관련이 있을 것으로 여겨진다.

참고문헌 (49건) : 자료제공( 네이버학술정보 )

참고문헌 목록에 대한 테이블로 번호, 참고문헌, 국회도서관 소장유무로 구성되어 있습니다.
번호 참고문헌 국회도서관 소장유무
1 p21 in cancer: intricate networks and multiple activities. 네이버 미소장
2 BMP-induced growth suppression in colon cancer cells is mediated by p21 WAF1 stabilization and modulated by RAS/ERK 네이버 미소장
3 Functional analysis of the RNF114 psoriasis susceptibility gene implicates innate immune responses to double-stranded RNA in disease pathogenesis 네이버 미소장
4 Deregulated degradation of the cdk inhibitor p27 and malignant transformation 네이버 미소장
5 Hypermethylation of XIAP-associated factor 1, a putative tumor suppressor gene from the 17p13.2 locus, in human gastric adenocarcinomas. 네이버 미소장
6 Cellular senescence: when bad things happen to good cells 네이버 미소장
7 Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene 네이버 미소장
8 Frequent Alteration of XAF1 in Human Colorectal Cancers: Implication for Tumor Cell Resistance to Apoptotic Stresses 네이버 미소장
9 Involvement of the INK4a/Arf gene locus in senescence 네이버 미소장
10 Integration of DNA Copy Number Alterations and Transcriptional Expression Analysis in Human Gastric Cancer 네이버 미소장
11 c-Jun NH2-terminal kinase decreases ubiquitination and promotes stabilization of p21(WAF1/CIP1) in K562 cell. 네이버 미소장
12 p21Waf1/Cip1/Sdi1 induces permanent growth arrest with markers of replicative senescence in human tumor cells lacking functional p53. 네이버 미소장
13 Identification of polyubiquitin binding proteins involved in NF-κB signaling using protein arrays 네이버 미소장
14 Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 네이버 미소장
15 Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. 네이버 미소장
16 T-cell regulator RNF125/TRAC-1 belongs to a novel family of ubiquitin ligases with zinc fingers and a ubiquitin-binding domain. 네이버 미소장
17 Transforming growth factor beta 1 increases the stability of p21/WAF1/CIP1 protein and inhibits CDK2 kinase activity in human colon carcinoma FET cells. 네이버 미소장
18 1965. The Limited in Vitro Lifetime of Human Diploid Cell Strains. Experimental Cell Research, 37: 614-636. 미소장
19 Regulation of p21(WAF1/CIP1) stability by WISp39, a Hsp90 binding TPR protein. 네이버 미소장
20 Global cancer statistics 네이버 미소장
21 Abrogation of apoptosis induced by DNA‐damaging agents in human bladder‐cancer cell lines with p21/WAF1/CIP1 and/or p53 gene alterations 네이버 미소장
22 Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. 네이버 미소장
23 The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing. 네이버 미소장
24 Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a). 네이버 미소장
25 Identification of X-linked inhibitor of apoptosis-associated factor-1 as an interferon-stimulated gene that augments TRAIL Apo2L-induced apoptosis. 네이버 미소장
26 Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies: implication for attenuated p53 response to apoptotic stresses. 네이버 미소장
27 Cloning and expression analysis of a novel mouse zinc finger protein gene Znf313 abundantly expressed in testis 소장
28 Identification of XAF1 as an antagonist of XIAP anti-Caspase activity 네이버 미소장
29 Degradation of activated protein kinases by ubiquitination. 네이버 미소장
30 Identification of a novel human zinc finger protein gene ZNF313. 네이버 미소장
31 To cycle or not to cycle: a critical decision in cancer. 네이버 미소장
32 1998. Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts. Current Biology, 8: 351-354. 미소장
33 Silencing of the XAF1 gene by promoter hypermethylation in cancer cells and reactivation to TRAIL-sensitization by IFN-β 네이버 미소장
34 Transcriptional role of p53 in interferon-mediated antiviral immunity. 네이버 미소장
35 Integrative genomic approaches in cervical cancer: implications for molecular pathogenesis. 네이버 미소장
36 A Novel Role for High-Mobility Group A Proteins in Cellular Senescence and Heterochromatin Formation 네이버 미소장
37 Oncogenic functions of tumour suppressor p21(Waf1/Cip1/Sdi1): association with cell senescence and tumour-promoting activities of stromal fibroblasts. 네이버 미소장
38 Amplification and over‐expression of the AIB1 nuclear receptor co‐activator gene in primary gastric cancers 네이버 미소장
39 CDK inhibitors: positive and negative regulators of G1-phase progression. 네이버 미소장
40 Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. 네이버 미소장
41 Genome-wide association analysis identifies three psoriasis susceptibility loci. 네이버 미소장
42 Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence. 네이버 미소장
43 Tumor suppressor XIAP‐Associated factor 1 (XAF1) cooperates with tumor necrosis factor‐related apoptosis‐inducing ligand to suppress colon cancer growth and trigger tumor regression 네이버 미소장
44 Involvement of elevated expression of multiple cell-cycle regulator, DTL/RAMP (denticleless/RA-regulated nuclear matrix associated protein), in the growth of breast cancer cells. 네이버 미소장
45 2006. Genomic array and expression analysis of frequent high-level amplifications in adenocarcinomas of the gastro-esophageal junction. Cancer Genetics and Cytogenetics, 166: 157-162. 미소장
46 p21 is necessary for the p53-mediated G1 arrest in human cancer cells. 네이버 미소장
47 TFDP1, CUL4A, and CDC16 identified as targets for amplification at 13q34 in hepatocellular carcinomas 네이버 미소장
48 Wnt5a-dopamine D2 receptor interactions regulate dopamine neuron development via extracellular signal-regulated kinase (ERK) activation. 네이버 미소장
49 XIAP-associated factor 1 (XAF1), a novel target of p53, enhances p53-mediated apoptosis via post-translational modification. 네이버 미소장

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