進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-1906201315534100
論文名稱(中文) 人類膠質瘤細胞與秀麗隱桿線蟲中PI3K/Akt訊息傳遞路徑所扮演之角色
論文名稱(英文) Role of the PI3K/Akt signaling pathway in human glioma cells and Caenorhabditis elegans
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 2
出版年 102
研究生(中文) 楊亞倫
研究生(英文) Ya-Luen Yang
學號 S58931112
學位類別 博士
語文別 英文
論文頁數 103頁
口試委員 指導教授-陳昌熙
召集委員-張文粲
口試委員-何漣漪
口試委員-傅子芳
口試委員-洪瑞祥
口試委員-許鴻猷
中文關鍵字 端粒酶  組蛋白去乙醯酶  結晶毒素 
英文關鍵字 Telomerase  histone deacetylase  PI3K  Akt  Crystal toxin 
學科別分類
中文摘要 地球上各種生物體內囊括許多精密且複雜的訊息傳遞路徑,每個分子各司其職調控著細微的生理變化。然而在不同物種間,所存在相同的信息路徑也可能扮演著不同的角色。透過組蛋白去乙醯化酶異常活化的表觀遺傳調控,是一種導致癌症起始與促進的機制。組蛋白去乙醯化酶的活化能導致人類端粒酶反轉錄酵素的轉錄上調,並增加細胞永生不死能力及腫瘤化細胞中端粒酶的活性。然而,在不同的癌細胞中組蛋白去乙醯化酶抑制劑對人類端粒酶反轉錄酵素轉錄變化影響各異。在此,我們探討一種新型的組蛋白去乙醯化酶抑制劑,AR42,對剔除PTEN表現的U87MG膠質瘤細胞端粒酶活性的影響。AR42能增加U87MG膠質瘤細胞人類端粒酶反轉錄酵素訊息RNA表現,但在劑量依賴方式中使得端粒酶活性呈現梯度抑制的情形。在更進一步分析中証實AR42藉由Akt依賴機制降低人類端粒酶反轉錄酵素磷酸化作用。而抑制Akt磷酸化和端粒酶活性也在使用PI3K抑制劑LY294002後發生,因此更加以支持AR42所參與抑制端粒酶活性的作用是透過Akt傳遞路徑。另以構築持續活化態的Akt作用下,能恢復在AR42處裡過的細胞中端粒酶的活性,我們的結果證明了未知的組蛋白去乙醯化酶抑制劑AR42,能藉由抑制Akt調節人類端粒酶反轉錄酵素磷酸化,達到壓制端粒酶的活性,並指出此種組蛋白去乙醯化酶抑制劑AR42,在PI3K/Akt途徑中對於端粒酶活性反應所扮演的重要角色。另一方面,在線蟲體內,DAF-2類胰島素/IGF訊息傳導路徑為重要的內泌調節系統,此路徑能調節壽命、抵制壓力,同時也已知參與抗病原性細菌的能力。我們證實了一泛素化連結酶(E3)家族蛋白WWP-1,是一個存在於DAF-2類胰島素/IGF訊息傳導路徑下游PI3K/Akt傳訊網絡的未知訊息調節因子,並在線蟲裡參與內在的細胞防禦機制。我們提出WWP-1是一個可能與PDK-1產生交互作用的蛋白,是抵禦蘇力菌所產生的穿孔蛋白攻擊重要因子,當失去此蛋白時將導致蟲體對穿孔蛋白呈現高度感受性。總結而言,我們的研究成果證明了PI3K-Akt訊息傳遞路徑不止參與調控人類膠質瘤細胞的端粒酶活性,並且也在線蟲體內扮演著重要的細胞反應機制。
英文摘要 There are many subtle and complicated signal transduction pathways within every creature on the planet. Respectively, every molecule controls minute pathological changes. However, among different species, the same transduction pathways may play different roles. Epigenetic regulation via abnormal activation of histone deacetylases (HDACs) is a mechanism that leads to cancer initiation and promotion. Activation of HDACs results in transcriptional upregulation of human telomerase reverse transcriptase (hTERT) and increases telomerase activity during cellular immortalization and tumorigenesis. However, the effects of HDAC inhibitors on the transcription of hTERT vary in different cancer cells. Here, we studied the effects of a novel HDAC inhibitor, AR42, on telomerase activity in a PTEN-null U87MG glioma cell line. AR42 increased hTERT mRNA in U87MG glioma cells, but suppressed total telomerase activity in a dose-dependent manner. Further analyses suggested that AR42 decreases the phosphorylation of hTERT via an Akt-dependent mechanism. Suppression of Akt phosphorylation and telomerase activity was also observed with PI3K inhibitor LY294002, further supporting the hypothesis that Akt signaling is involved in suppression of AR42-induced inhibition of telomerase activity. Eectopic expression of a constitutive active form of Akt restored telomerase activity in AR42-treated cells. Our results demonstrated that the novel HDAC inhibitor AR42 can suppress telomerase activity by inhibiting Akt-mediated hTERT phosphorylation, indicating that the PI3K/Akt pathway plays an important role in the regulation of telomerase activity in response to this HDAC inhibitor. On the other hand, the DAF-2 insulin/insulin-like growth IGF-1 factor-1 signaling pathway, which regulates lifespan and stress resistance in Caenorhabditis elegans, is known to mutate to resistance to pathogenic bacteria. We identified a ubiquitination ligase (E3)family protein, WWP-1, as a novel signal modulator of the DAF-2 insulin IGF-1- like pathway. This pathway is upstream of the PI3K/ Akt signaling network in the intrinsic cellular defenses of C. elegans. We suggest that WWP-1, a novel PDK-1 putative interacting protein, is functionally important for defense against Bacillus thuringiensis producing pore-forming toxin (PFT) attack since loss of this protein leads to animals hypersensitive to PFT. Taken together, our data suggest that the PI3K/Akt signaling pathway is not only involved in telomerase activity in human glioma cell but also take part in the fundamental cellular responses of C. elegans.
論文目次 Table of Contents
Abstract…………………………………………………………………………… I
Chinese abstract…………………………………………………........................ III
Acknowledgment……………………………………………………………..… V
Contents………………………………………………………………………... VII
1. Introduction………………………………………………………………… 1
1.1 Telomerase…………………………………………………………….. 1
1.2 Human Telomerase Reverse Transcriptase………………….……… 2
1.3 Histone-deacetylase and inhibitors….……………..………………..... 3
1.4 The phosphatidylinositol 3-kinase AKT pathway in human cancer.... 4
1.5 Protein phosphatase 1 (PP1) and 2A (PP2A)……………………….... 5
1.6 Caenorhabditis elegans is a simple and powerful animal model…..... 7
1.7 Bacillus thuringiensis and Crystal pore-forming toxin…………….. 8
1.8 The DAF-2 insulin/insulin-like growth factor 1 (IGF-1) receptor pathway………………………………………………………………... 10
1.9 The purpose and goals of this work……….……………………….... 12
2. Materials and Methods………………..…………………………………... 14
Part A……………………………………………………..…………………. 14
2.1 Cell culture and reagents…………………………………………….. 14
2.2 Immunoprecipitation and Immunoblotting ……………………….. 14
2.3 Ectopic expression of constitutively active Akt ..……………..…… 16
2.4 Telomerase activity assay…………….....……………..………….… 17
2.5 RNA preparation and RT-PCR…………………………….……….. 17
2.6 Data analysis……………………………………………………….… 18
Part B……………………………………………………..……….………... 18
2.7 C. elegans and Bacterial Strains……………………………..…..….. 18
2.8 Cry Toxins Toxicity Assays and Microscopy………….…………….. 19
2.9 RNA interference (RNAi)……………………………………………. 20
2.10 C. elegans lifespan assay……………………………………………. 22
2.11 Pseudomonas aeruginosa PA14 Killing Assay…………..……...….. 23
2.12 General Stressors Analysis…………………………………..……... 23
2.12.1 CuSO4 Assay………………………………….………..…….. 23
2.12.2 H2O2 Assay………………………………………………...…. 24
2.13 Data Analysis………………………………………….…..………… 24
III. Results………………………………………………………………...……… 25
3.1 Total telomerase activity is suppressed by AR42 in U87MG
glioma cells…………………………………………………………...… 25
3.2 AR42 up-regulates the transcriptional activity of hTERT in
U87MG cells…………………………………………………………… 25
3.3 AR42 downregulates hTERT phosphorylation via the PI3K
/Akt pathway………………………………………………………. 26
3.4 AR42-induced suppression of telomeraseactivity and phospho-
AKT can be restored by phosphatase inhibitors………………… 28
3.5 Reduction of the DAF-2 insulin-like receptor signal confers
resistance to Bt Cry PFTs in C. elegans…………………….…….. 29
3.6 Resistance of daf-2 mutant to Cry toxins is, in part,
through a daf-16 independent manner…………………………… 31
3.7 The resistance of Cry Toxins signal in DAF-2 signaling pathway
in part deviates from PDK-1…………………………………….... 32
3.8 WWP-1 is a novel PDK-1 interacting protein involved in
Cry5B defense……………………………………………………. 34
3.9 WWP-1 is also involved in innate immunity and aging
regulation………………………………………….…………….…. 36
3.10 WWP-1 works downstream of DAF-2 and in parallel to
DAF-16 in the DAF-2 insulin/IGF-1 signaling network……….... 38
IV. Discussion…………………………………………………………………. 40
4.1 HDAC inhibitors regulates hTERT transcription in cancer cells…………………………………………………………….…... 40
4.2 The functional role of AR42 in human glioma cancer cell……… 41
4.3 AR42 in telomerase activity and PI3K/Akt-dependent pathway.. 42
4.4 Characterization of AR42 in cancer therapy potiental…..……… 45
4.5 WWP-1 involved DAF-2 insulin/IGF-1 pathway and parallel to daf-16 in C.elegans.……………………………………………….... 45
4.6 The role of WWP-1 in PI3K(AGE-1)/AKT-1 signal pathway….. 47
IV. Conclusion……………………………………………………………….…… 50
V. References……………………………………………………………………... 52
Figures and Figure legends…………………………………………………. 71
Figure 1. AR42 reduces telomerase activity in U87MG glioblastoma cells………………………………………………………….. 71
Figure 2. AR42 increases hTERT mRNA and protein levels and decreases phosphorylation of Akt and hTERT in U87MG cells.ublications……………………………………………..... 72
Figure3. PP1 inhibitors reverse AR42-induced Akt
dephosphorylation and telomerase inhibition……………... 74
Figure 4. Validation of the role of Akt in AR42-induced telomerase inhibition…………………………………………….……… 75
Figure 5. Reduction of the DAF-2 insulin-like receptor signal
confers resistance to Cry toxins……………………….…. 76
Figure 6. The resistance to Cry toxin is only partly dependent
upon DAF-16 FOXO and forks at PDK-1 in the DAF-2 insulin-like network………………………………………. 78
Figure 7. WWP-1 is a novel PDK-1 interacting protein involved in Cry5B defense……………………………………….…….. 80
Figure 8. WWP-1 is involved in the innate immunity against
P. aeruginosa PA14…………………………………….…..... 82
Figure 9. WWP-1 is a positive regulator of lifespan in C. elegans..... 83
Figure10. WWP-1 is a downstream signal of DAF-2 and in parallel
to DAF-16 in response to Cry5B……………………..…… 85
Figure11. Schematic illustrating relationship between WWP-1 and DAF-2 insulin-like signal network………………………..…. 86
VII. Table………………………………………………..……………………….. 87 Table 1. Data analysis of the quantitative Crystal toxins lethal
concentration assays……..…………………………………. 87
Table 2. Data analysis of the toxins toxicity assays……………….... 89
Table 3. Data analysis of the lifespan and general stresses assays….. 90
參考文獻 References
1 Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345 (1990).
2 Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011-2015 (1994).
3 Meyerson, M. et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90, 785-795 (1997).
4 Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349-352 (1998).
5 Hahn, W. C. et al. Creation of human tumour cells with defined genetic elements. Nature 400, 464-468 (1999).
6 Inoue, H. et al. Histone deacetylase inhibitors sensitize human colonic adenocarcinoma cell lines to TNF-related apoptosis inducing ligand-mediated apoptosis. International journal of molecular medicine 9, 521-525 (2002).
7 Thiagalingam, S. et al. Histone deacetylases: unique players in shaping the epigenetic histone code. Annals of the New York Academy of Sciences 983, 84-100 (2003).
8 Hutchins, M. U. & Klionsky, D. J. Vacuolar localization of oligomeric alpha-mannosidase requires the cytoplasm to vacuole targeting and autophagy pathway components in Saccharomyces cerevisiae. The Journal of biological chemistry 276, 20491-20498 (2001).
9 McConkey, D. J., White, M. & Yan, W. HDAC inhibitor modulation of proteotoxicity as a therapeutic approach in cancer. Advances in cancer research 116, 131-163 (2012).
10 Bali, P. et al. Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clinical cancer research : an official journal of the American Association for Cancer Research 10, 4991-4997 (2004).
11 Alessi, D. R. et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Current biology : CB 7, 261-269 (1997).
12 Currie, R. A. et al. Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. The Biochemical journal 337 ( Pt 3), 575-583 (1999).
13 Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nature reviews. Cancer 2, 489-501 (2002).
14 Courtney, K. D., Corcoran, R. B. & Engelman, J. A. The PI3K pathway as drug target in human cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 28, 1075-1083 (2010).
15 Liu, J. P. Studies of the molecular mechanisms in the regulation of telomerase activity. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 13, 2091-2104 (1999).
16 Kulp, S. K., Chen, C. S., Wang, D. S. & Chen, C. Y. Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 12, 5199-5206 (2006).
17 Lu, Y. S. et al. Efficacy of a novel histone deacetylase inhibitor in murine models of hepatocellular carcinoma. Hepatology 46, 1119-1130 (2007).
18 Jacob, A. et al. Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas. The Laryngoscope 122, 174-189 (2012).
19 Tournebize, R. et al. Distinct roles of PP1 and PP2A-like phosphatases in control of microtubule dynamics during mitosis. The EMBO journal 16, 5537-5549 (1997).
20 Wang, B., Xie, X. & Wei, Q. [Advances of protein phosphatase-1--a review]. Wei sheng wu xue bao = Acta microbiologica Sinica 48, 269-273 (2008).
21 Goldberg, B. & Stricker, R. B. Apoptosis and HIV infection: T-cells fiddle while the immune system burns. Immunology letters 70, 5-8 (1999).
22 Zolnierowicz, S. Type 2A protein phosphatase, the complex regulator of numerous signaling pathways. Biochemical pharmacology 60, 1225-1235 (2000).
23 Xie, H. & Clarke, S. Protein phosphatase 2A is reversibly modified by methyl esterification at its C-terminal leucine residue in bovine brain. The Journal of biological chemistry 269, 1981-1984 (1994).
24 Bryant, J. C., Westphal, R. S. & Wadzinski, B. E. Methylated C-terminal leucine residue of PP2A catalytic subunit is important for binding of regulatory Balpha subunit. The Biochemical journal 339 ( Pt 2), 241-246 (1999).
25 Ogris, E., Gibson, D. M. & Pallas, D. C. Protein phosphatase 2A subunit assembly: the catalytic subunit carboxy terminus is important for binding cellular B subunit but not polyomavirus middle tumor antigen. Oncogene 15, 911-917 (1997).
26 Chen, J., Martin, B. L. & Brautigan, D. L. Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science 257, 1261-1264 (1992).
27 Tolstykh, T., Lee, J., Vafai, S. & Stock, J. B. Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits. The EMBO journal 19, 5682-5691 (2000).
28 Lee, J. & Stock, J. Protein phosphatase 2A catalytic subunit is methyl-esterified at its carboxyl terminus by a novel methyltransferase. The Journal of biological chemistry 268, 19192-19195 (1993).
29 Lee, J., Chen, Y., Tolstykh, T. & Stock, J. A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain. Proceedings of the National Academy of Sciences of the United States of America 93, 6043-6047 (1996).
30 Kowluru, A., Seavey, S. E., Rabaglia, M. E., Nesher, R. & Metz, S. A. Carboxylmethylation of the catalytic subunit of protein phosphatase 2A in insulin-secreting cells: evidence for functional consequences on enzyme activity and insulin secretion. Endocrinology 137, 2315-2323 (1996).
31 Kamibayashi, C. et al. Comparison of heterotrimeric protein phosphatase 2A containing different B subunits. The Journal of biological chemistry 269, 20139-20148 (1994).
32 Zhao, Y., Boguslawski, G., Zitomer, R. S. & DePaoli-Roach, A. A. Saccharomyces cerevisiae homologs of mammalian B and B' subunits of protein phosphatase 2A direct the enzyme to distinct cellular functions. The Journal of biological chemistry 272, 8256-8262 (1997).
33 Waterfield, N. R., Wren, B. W. & Ffrench-Constant, R. H. Invertebrates as a source of emerging human pathogens. Nature reviews. Microbiology 2, 833-841 (2004).
34 Powell, J. R. & Ausubel, F. M. Models of Caenorhabditis elegans infection by bacterial and fungal pathogens. Methods Mol Biol 415, 403-427 (2008).
35 Croll, N. A., Smith, J. M. & Zuckerman, B. M. The aging process of the nematode Caenorhabditis elegans in bacterial and axenic culture. Experimental aging research 3, 175-189 (1977).
36 Hosono, R., Sato, Y., Aizawa, S. I. & Mitsui, Y. Age-dependent changes in mobility and separation of the nematode Caenorhabditis elegans. Experimental gerontology 15, 285-289 (1980).
37 Herndon, L. A. et al. Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419, 808-814 (2002).
38 Huang, C., Xiong, C. & Kornfeld, K. Measurements of age-related changes of physiological processes that predict lifespan of Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 101, 8084-8089 (2004).
39 Hsu, A. L., Feng, Z., Hsieh, M. Y. & Xu, X. Z. Identification by machine vision of the rate of motor activity decline as a lifespan predictor in C. elegans. Neurobiology of aging 30, 1498-1503 (2009).
40 Murakami, S. & Murakami, H. The effects of aging and oxidative stress on learning behavior in C. elegans. Neurobiology of aging 26, 899-905 (2005).
41 Hughes, S. E., Evason, K., Xiong, C. & Kornfeld, K. Genetic and pharmacological factors that influence reproductive aging in nematodes. PLoS genetics 3 (2007).
42 Garigan, D. et al. Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161, 1101-1112 (2002).
43 Garsin, D. A. et al. Long-lived C. elegans daf-2 mutants are resistant to bacterial pathogens. Science 300, 1921 (2003).
44 Casadevall, A. Evolution of intracellular pathogens. Annual review of microbiology 62, 19-33 (2008).
45 Aronson, A. Sporulation and delta-endotoxin synthesis by Bacillus thuringiensis. Cellular and molecular life sciences : CMLS 59, 417-425 (2002).
46 Alouf, J. E. Molecular features of the cytolytic pore-forming bacterial protein toxins. Folia Microbiol (Praha) 48, 5-16 (2003).
47 Parker, M. W. & Feil, S. C. Pore-forming protein toxins: from structure to function. Prog Biophys Mol Biol 88, 91-142 (2005).
48 Iacovache, I., van der Goot, F. G. & Pernot, L. Pore formation: an ancient yet complex form of attack. Biochim Biophys Acta 1778, 1611-1623 (2008).
49 Kirouac, M. et al. Amino acid and divalent ion permeability of the pores formed by the Bacillus thuringiensis toxins Cry1Aa and Cry1Ac in insect midgut brush border membrane vesicles. Biochimica et biophysica acta 1561, 171-179 (2002).
50 de Maagd, R. A., Bravo, A., Berry, C., Crickmore, N. & Schnepf, H. E. Structure, diversity, and evolution of protein toxins from spore-forming entomopathogenic bacteria. Annu Rev Genet 37, 409-433 (2003).
51 Guerchicoff, A., Delecluse, A. & Rubinstein, C. P. The Bacillus thuringiensis cyt genes for hemolytic endotoxins constitute a gene family. Applied and environmental microbiology 67, 1090-1096 (2001).
52 Marroquin, L. D., Elyassnia, D., Griffitts, J. S., Feitelson, J. S. & Aroian, R. V. Bacillus thuringiensis (Bt) toxin susceptibility and isolation of resistance mutants in the nematode Caenorhabditis elegans. Genetics 155, 1693-1699 (2000).
53 Wei, J. Z. et al. Bacillus thuringiensis crystal proteins that target nematodes. Proceedings of the National Academy of Sciences of the United States of America 100, 2760-2765 (2003).
54 Cappello, M. et al. A purified Bacillus thuringiensis crystal protein with therapeutic activity against the hookworm parasite Ancylostoma ceylanicum. Proc Natl Acad Sci U S A 103, 15154-15159 (2006).
55 Huffman, D. L., Bischof, L. J., Griffitts, J. S. & Aroian, R. V. Pore worms: using Caenorhabditis elegans to study how bacterial toxins interact with their target host. International journal of medical microbiology : IJMM 293, 599-607 (2004).
56 Huffman, D. L. et al. Mitogen-activated protein kinase pathways defend against bacterial pore-forming toxins. Proc Natl Acad Sci U S A 101, 10995-11000 (2004).
57 Bischof, L. J. et al. Activation of the unfolded protein response is required for defenses against bacterial pore-forming toxin in vivo. PLoS pathogens 4, e1000176 (2008).
58 Bellier, A., Chen, C. S., Kao, C. Y., Cinar, H. N. & Aroian, R. V. Hypoxia and the hypoxic response pathway protect against pore-forming toxins in C. elegans. PLoS pathogens 5, e1000689 (2009).
59 Finch, C. E. & Ruvkun, G. The genetics of aging. Annu Rev Genomics Hum Genet 2, 435-462 (2001).
60 Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449-460 (2005).
61 Baumeister, R., Schaffitzel, E. & Hertweck, M. Endocrine signaling in Caenorhabditis elegans controls stress response and longevity. J Endocrinol 190, 191-202 (2006).
62 Kurz, C. L. & Tan, M. W. Regulation of aging and innate immunity in C. elegans. Aging cell 3, 185-193 (2004).
63 Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nature reviews. Molecular cell biology 7, 85-96 (2006).
64 Hertweck, M., Gobel, C. & Baumeister, R. C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. Developmental cell 6, 577-588 (2004).
65 Paradis, S. & Ruvkun, G. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes & development 12, 2488-2498 (1998).
66 Paradis, S., Ailion, M., Toker, A., Thomas, J. H. & Ruvkun, G. A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes & development 13, 1438-1452 (1999).
67 Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655-1657 (2002).
68 Wong, K. K., Engelman, J. A. & Cantley, L. C. Targeting the PI3K signaling pathway in cancer. Current opinion in genetics & development 20, 87-90 (2010).
69 Kim, D. et al. AKT/PKB signaling mechanisms in cancer and chemoresistance. Frontiers in bioscience : a journal and virtual library 10, 975-987 (2005).
70 Engelman, J. A., Luo, J. & Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nature reviews. Genetics 7, 606-619 (2006).
71 Greer, E. L. & Brunet, A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24, 7410-7425 (2005).
72 Zhang, W. et al. FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. The Journal of biological chemistry 281, 10105-10117 (2006).
73 Chen, C. S., Weng, S. C., Tseng, P. H. & Lin, H. P. Histone acetylation-independent effect of histone deacetylase inhibitors on Akt through the reshuffling of protein phosphatase 1 complexes. The Journal of biological chemistry 280, 38879-38887 (2005).
74 Kulp, S. K. et al. 3-phosphoinositide-dependent protein kinase-1/Akt signaling represents a major cyclooxygenase-2-independent target for celecoxib in prostate cancer cells. Cancer Res 64, 1444-1451 (2004).
75 Suenaga, M. et al. Histone deacetylase inhibitors suppress telomerase reverse transcriptase mRNA expression in prostate cancer cells. International journal of cancer. Journal international du cancer 97, 621-625 (2002).
76 Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71-94 (1974).
77 Dillin, A., Crawford, D. K. & Kenyon, C. Timing requirements for insulin/IGF-1 signaling in C. elegans. Science 298, 830-834 (2002).
78 Bischof, L. J., Huffman, D. L. & Aroian, R. V. Assays for toxicity studies in C. elegans with Bt crystal proteins. Methods Mol Biol 351, 139-154 (2006).
80 Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A C. elegans mutant that lives twice as long as wild type. Nature 366, 461-464 (1993).
81 Zarse, K., Schulz, T. J., Birringer, M. & Ristow, M. Impaired respiration is positively correlated with decreased life span in Caenorhabditis elegans models of Friedreich Ataxia. FASEB J 21, 1271-1275 (2007).
82 Tan, M. W., Rahme, L. G., Sternberg, J. A., Tompkins, R. G. & Ausubel, F. M. Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors. Proceedings of the National Academy of Sciences of the United States of America 96, 2408-2413 (1999).
83 Chen, C. S. et al. WWP-1 is a novel modulator of the DAF-2 insulin-like signaling network involved in pore-forming toxin cellular defenses in Caenorhabditis elegans. PloS one 5, e9494 (2010).
84 Finney, D. J. Probit analysis. 3rd edn, (Cambridge University Press, 1980).
85 Chen, C. S. et al. Histone deacetylase inhibitors sensitize prostate cancer cells to agents that produce DNA double-strand breaks by targeting Ku70 acetylation. Cancer research 67, 5318-5327 (2007).
86 Liu, Y. L. et al. Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma. Autophagy 6, 1057-1065 (2010).
87 Kulp, S. K., Chen, C. S., Wang, D. S., Chen, C. Y. & Chen, C. S. Antitumor effects of a novel phenylbutyrate-based histone deacetylase inhibitor, (S)-HDAC-42, in prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 12, 5199-5206 (2006).
88 Bellon, M. & Nicot, C. Central role of PI3K in transcriptional activation of hTERT in HTLV-I-infected cells. Blood 112, 2946-2955 (2008).
89 Lin, K., Hsin, H., Libina, N. & Kenyon, C. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 28, 139-145 (2001).
90 Kerry, S., TeKippe, M., Gaddis, N. C. & Aballay, A. GATA transcription factor required for immunity to bacterial and fungal pathogens. PLoS One 1, e77 (2006).
91 Singh, V. & Aballay, A. Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity. Proc Natl Acad Sci U S A 103, 13092-13097 (2006).
92 Singh, V. & Aballay, A. Regulation of DAF-16-mediated Innate Immunity in Caenorhabditis elegans. J Biol Chem 284, 35580-35587 (2009).
93 Lin, K., Dorman, J. B., Rodan, A. & Kenyon, C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278, 1319-1322 (1997).
94 Mukhopadhyay, A. & Tissenbaum, H. A. Reproduction and longevity: secrets revealed by C. elegans. Trends Cell Biol 17, 65-71 (2007).
95 Evans, E. A., Chen, W. C. & Tan, M. W. The DAF-2 insulin-like signaling pathway independently regulates aging and immunity in C. elegans. Aging Cell 7, 879-893 (2008).
96 Li, S. et al. A map of the interactome network of the metazoan C. elegans. Science 303, 540-543 (2004).
97 Huang, K. et al. A HECT domain ubiquitin ligase closely related to the mammalian protein WWP1 is essential for Caenorhabditis elegans embryogenesis. Gene 252, 137-145 (2000).
98 Kagan, R. M. & Clarke, S. Protein L-isoaspartyl methyltransferase from the nematode Caenorhabditis elegans: genomic structure and substrate specificity. Biochemistry 34, 10794-10806 (1995).
99 Kamath, R. S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231-237 (2003).
100 Woo, H. J., Lee, S. J., Choi, B. T., Park, Y. M. & Choi, Y. H. Induction of apoptosis and inhibition of telomerase activity by trichostatin A, a histone deacetylase inhibitor, in human leukemic U937 cells. Experimental and molecular pathology 82, 77-84 (2007).
101 Takakura, M. et al. Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer research 59, 551-557 (1999).
102 Mukhopadhyay, N. K. et al. Histone deacetylation is directly involved in desilencing the expression of the catalytic subunit of telomerase in normal lung fibroblast. Journal of cellular and molecular medicine 9, 662-669 (2005).
103 Huang, P. H. et al. Histone deacetylase inhibitors stimulate histone H3 lysine 4 methylation in part via transcriptional repression of histone H3 lysine 4 demethylases. Molecular pharmacology 79, 197-206 (2011).
104 Nimmanapalli, R., Fuino, L., Stobaugh, C., Richon, V. & Bhalla, K. Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood 101, 3236-3239 (2003).
105 Kodani, M. et al. Suppression of phosphatidylinositol 3-kinase/Akt signaling pathway is a determinant of the sensitivity to a novel histone deacetylase inhibitor, FK228, in lung adenocarcinoma cells. Oncology reports 13, 477-483 (2005).
106 Marrazzo, A. et al. Antiproliferative activity of phenylbutyrate ester of haloperidol metabolite II [(+/-)-MRJF4] in prostate cancer cells. European journal of medicinal chemistry 46, 433-438 (2011).
107 Woo, H. J., Lee, S. J., Choi, B. T., Park, Y. M. & Choi, Y. H. Induction of apoptosis and inhibition of telomerase activity by trichostatin A, a histone deacetylase inhibitor, in human leukemic U937 cells. Exp Mol Pathol (2006).
108 Nakamura, M. et al. Reduction of telomerase activity in human liver cancer cells by a histone deacetylase inhibitor. J Cell Physiol 187, 392-401 (2001).
109 Minucci, S. & Pelicci, P. G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6, 38-51 (2006).
110 Lin, H. Y., Chen, C. S., Lin, S. P., Weng, J. R. & Chen, C. S. Targeting histone deacetylase in cancer therapy. Medicinal research reviews 26, 397-413 (2006).
111 Chen, C. S. et al. Histone deacetylase inhibitors sensitize prostate cancer cells to agents that produce DNA double-strand breaks by targeting Ku70 acetylation. Cancer Res 67, 5318-5327 (2007).
112 Hou, M. et al. The histone deacetylase inhibitor trichostatin A derepresses the telomerase reverse transcriptase (hTERT) gene in human cells. Experimental cell research 274, 25-34 (2002).
113 Wojtyla, A., Gladych, M. & Rubis, B. Human telomerase activity regulation. Molecular biology reports 38, 3339-3349 (2011).
114 Breitschopf, K., Zeiher, A. M. & Dimmeler, S. Pro-atherogenic factors induce telomerase inactivation in endothelial cells through an Akt-dependent mechanism. FEBS Lett 493, 21-25 (2001).
115 Seimiya, H. et al. Hypoxia up-regulates telomerase activity via mitogen-activated protein kinase signaling in human solid tumor cells. Biochem Biophys Res Commun 260, 365-370 (1999).
116 Kharbanda, S. et al. Regulation of the hTERT telomerase catalytic subunit by the c-Abl tyrosine kinase. Curr Biol 10, 568-575 (2000).
117 Li, H., Zhao, L., Yang, Z., Funder, J. W. & Liu, J. P. Telomerase is controlled by protein kinase Calpha in human breast cancer cells. J Biol Chem 273, 33436-33442 (1998).
118 Gami, M. S. & Wolkow, C. A. Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan. Aging cell 5, 31-37 (2006).
119 Wiles, T. J., Dhakal, B. K., Eto, D. S. & Mulvey, M. A. Inactivation of host Akt/protein kinase B signaling by bacterial pore-forming toxins. Mol Biol Cell 19, 1427-1438 (2008).
120 Babar, P., Adamson, C., Walker, G. A., Walker, D. W. & Lithgow, G. J. P13-kinase inhibition induces dauer formation, thermotolerance and longevity in C. elegans. Neurobiology of aging 20, 513-519 (1999).
121 Hu, P. J., Xu, J. & Ruvkun, G. Two membrane-associated tyrosine phosphatase homologs potentiate C. elegans AKT-1/PKB signaling. PLoS Genet 2, e99 (2006).
122 Zhang, Y. et al. Caenorhabditis elegans EAK-3 inhibits dauer arrest via nonautonomous regulation of nuclear DAF-16/FoxO activity. Dev Biol 315, 290-302 (2008).
123 Gami, M. S., Iser, W. B., Hanselman, K. B. & Wolkow, C. A. Activated AKT/PKB signaling in C. elegans uncouples temporally distinct outputs of DAF-2/insulin-like signaling. BMC Dev Biol 6, 45 (2006).
124 Gomez, T. A., Banfield, K. L., Trogler, D. M. & Clarke, S. G. The L-isoaspartyl-O-methyltransferase in Caenorhabditis elegans larval longevity and autophagy. Dev Biol 303, 493-500 (2007).
125 Banfield, K. L., Gomez, T. A., Lee, W., Clarke, S. & Larsen, P. L. Protein-repair and hormone-signaling pathways specify dauer and adult longevity and dauer development in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci 63, 798-808 (2008)
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2013-07-10起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw