跳到主要內容

臺灣博碩士論文加值系統

(18.207.132.116) 您好!臺灣時間:2021/07/29 19:22
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:許凱翔
研究生(外文):Hsu, Kaihsiang
論文名稱:蛋白質磷酸酶 PP1 參與在組蛋白去乙醯酶抑制劑 LBH589調控 MAP Kinase的活化
論文名稱(外文):PP1 Participated in HDACi LBH589 Induced MAP Kinase Activation
指導教授:查岱龍查岱龍引用關係
指導教授(外文):Cha, Tailung
口試委員:黃世明
口試委員(外文):Huang, Shihming
口試日期:2012-06-14
學位類別:碩士
校院名稱:國防醫學院
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:84
中文關鍵詞:蛋白質
外文關鍵詞:protein
相關次數:
  • 被引用被引用:0
  • 點閱點閱:86
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:0
組蛋白去乙醯酶(HDAC)對於組蛋白(Histone)去乙醯化的能力已廣泛的被研究,透過對組蛋白上離蛋白(Lysine)的乙醯基作去乙醯化作用,造成染
色體結構變緻密導致基因無法正常的被轉錄轉譯出來。在許多研究中 HDAC 的過度表現更在不同種類的腫瘤研究中被報導,但 HDAC 調控腫瘤細胞中訊息傳遞的機轉至今仍未釐清。在實驗室的研究中發現組蛋白去乙醯酶抑制劑 LBH589 主要抑制 HDAC 1、3、6,並造成MAP Kinase 下游 ERK 的活化以及使細胞週期停留在 G2/M arrest。實驗中更發現 HADC6 蛋白與磷酸化 ERK 間存在著彼此反向調控的關係。在過去的研究中指出,蛋白質磷酸酶 PP1α 和 PP2A 會移除磷酸根Ser259 使 C-Raf 的活性增加。在本篇研究中發現細胞經 LBH589 刺激後可觀察到 Ser259 的磷酸化表現下降,同時激活 MAP Kinase 下游 ERK。LBH589可以提高 PP1α 的活性,增加 PP1α 對磷酸根 Ser259 去磷酸化的能力進而活化 C-Raf 下游 ERK。相反的,LBH589 刺激下同時加入蛋白質磷酸酶 PP1抑制劑,發現 Ser259 磷酸化表現恢復以及 ERK 的活性被抑制的現象,證明PP1α 透過對 Ser259 去磷酸化參與在 LBH589 激活 ERK 的調控中。實驗中發現 LBH589 可打斷 HDAC6 和 PP1α 的鍵結,同時提升 PP1α和 C-Raf 的結合程度,增加對 Ser259 去磷酸化。14-3-3ζ 會與 Ser259 產生鍵結避免被 PP1α 去磷酸化,實驗中發現經 LBH589 後 14-3-3ζ 與 Ser259 之間結合降低使 Ser259 暴露出來,讓 PP1α 可順利結合上 Ser259。在本實驗研究中不僅發現 HDAC6 和磷酸化 ERK 之間存在著反向調控的關係,在組蛋白去乙醯酶抑制劑 LBH589 激活 ERK 的過程中發現經LBH589 刺激下 PP1α 與 Ser259 間的結合上升,同時 LBH589 亦使得 14-3-3ζ
乙醯化程度升高,造成 14-3-3ζ 和 Ser259 的結合降低。HDAC6、PP1α 以及14-3-3ζ 間存在著類似 Complex 的結構,在 LBH589 刺激下共同調控 C-Raf的活性,進而影響下游 ERK 的磷酸化程度。
12

Abstract

Histone Deacetylases (HDACs) have been extensively studied in
transcriptional regulation due to their deacetylation ability on histone
modification. By removing the acetyl group on the lysine residue of histone,
HDACs caused condense chromatin to prevent transcriptional factors binding on
chromatin, which lead to gene silencing.
In recent studies, HDACs have been shown to play an important role in
cancer initiation. Thought oerexpression of various HDACs have been found in
many types of cancer, the roles of HDACs participate in the regulation of
signaling pathway in cancer cells remain unknown. In our previous study, we
found an HDAC inhibitior, LBH589 majorly targeting HDAC1, 3, and 6.
LBH589 treatment resulted in activation of MAPK pathway ERK
phosphorylation and causing G2/M cell-cycle arrest. In this study, we found that
there was an inverse correlation between HDAC6 protein levels and ERK
phosphorylation status.
As previous studies showed, protein phosphatase 1α and 2A (PP1α/PP2A)
would activate ERK by removing the phosphor site of serine 259 of C-Raf. In
LBH589 treatment, we found that the phosphorylation status was downregulated
and ERK was activated simultaneously. Furthermore, ERK activation was
turned down and Ser259 phosphorylation status was rescued while combined
phosphatase inhibitor with LBH589 treatment.
LBH589 also showed its ability to interrupt the binding between HDAC6
and PP1α, and increased the interaction of PP1α and Ser259, making Ser259 dephosphorylated by PP1α. Since 14-3-3ζ bound to Ser259 and cover this phosphor site in order to avoid Ser259 was dephosphorylated by PP1α. In LBH589 decreased Ser259 phosphorylation, we found that the interaction between 14-3-3ζ and Ser259 was doenregulated under LBH589 treatment, result in the exposal of Ser259, and PP1α would bind to Ser259 easily.In this study we not just found that the invert correlation of HDAC6 and pi-ERK, the interation of PP1α and Ser259 was increased under LBH589 treatment, also found that the acetylation status of 14-3-3ζ was increased,decreased the nteraction with Ser259. HDAC6, PP1α and 14-3-3ζ formed as a complex, regulated the activation of C-Raf in LBH589 treatment.
7

目錄

目錄……………………………………………………………………... ……...7
圖目錄…………………………………………………………………... ……...8
中文摘要………………………………………………………………... ……...9
英文摘要………………………………………………………………... …….11
第一章 前言…………………………………………………………... …….14
第一節 組蛋白去乙醯酶 HDACs…...………………………………. …14
第二節 組蛋白去乙醯酶與癌症生成……………………. ……………16
第三節 組蛋白去乙醯酶抑制劑 LBH589………………………………17
第四節 MAP Kinase 活化的調控…………………………………….....18
第五節 MAP Kinase 與蛋白質磷酸酶 (Protein Phosphatase)…………19
第六節 LBH589 與蛋白質磷酸酶(Protein Phosphatase).........................20
第七節 14-3-3 蛋白...................................................................................21
第八節 14-3-3s 蛋白與 MAP Kinase........................................................22
第九節 14-3-3 與組蛋白去乙醯酶(HDACs)..........................................22
第十節 研究動機......................................................................................23
第二章 材料與方法.........................................................................................26
第一節 細胞株…………………………………………………………..26
第二節 細胞培養………………………………………………………..27
第三節 藥品……………………………………………..........................28
第四節 西方墨點實驗(Western Blotting)………………………………28
第五節 聚合酶鏈式反應 (Polymerase chain reaction)…………………31
第六節 Small interference RNA(siRNA)之轉染(transfection)………32
第七節 免疫沉澱法 (Immuno-precipitation)…………………………...33
第三章 實驗結果.............................................................................................35
第一節 組蛋白去乙醯酶抑制劑 LBH589 激活 ERK 係經由其上游 Raf
的活化...…………………………………………………………35
第二節 LBH589 所造成 ERK 的活化在不同細胞中的結果不同……..36
第三節 HDAC6 和磷酸化 ERK 的反向調控 (Invert Correlation)……..36
第四節 PP1α 在藥物刺激和生理情況下的活化……………………….38
第五節 PP1α 參與 LBH589 對於 MAP Kinase 的調控………………..39
第六節 LBH589 刺激對 HDAC6 和 PP1α 間鍵結以及造成 PP1α 和其受
質間的影響….……………………………………………..……41 第七節 LBH589 降低 14-3-3ζ 與 Ser259 的鍵結並增加 14-3-3ζ 乙醯化程
度……………………….……………………………………..42
第四章 討論.....................................................................................................44
第五章 結論………………………………………………………………….50
第六章 參考文獻…………………………………………………………….51
51

第六章 參考文獻

[1] M. D. Shahbazian and M. Grunstein, "Functions of site-specific histone acetylation
and deacetylation," Annu Rev Biochem, vol. 76, pp. 75-100, 2007.
[2] L. Chen, W. Fischle, E. Verdin, and W. C. Greene, "Duration of nuclear NF-kappaB
action regulated by reversible acetylation," Science, vol. 293, pp. 1653-7, Aug 31
2001.
[3] M. A. Glozak, N. Sengupta, X. Zhang, and E. Seto, "Acetylation and deacetylation of
non-histone proteins," Gene, vol. 363, pp. 15-23, Dec 19 2005.
[4] W. Gu and R. G. Roeder, "Activation of p53 sequence-specific DNA binding by
acetylation of the p53 C-terminal domain," Cell, vol. 90, pp. 595-606, Aug 22 1997.
[5] K. Ito, C. E. Charron, and I. M. Adcock, "Impact of protein acetylation in inflammatory
lung diseases," Pharmacol Ther, vol. 116, pp. 249-65, Nov 2007.
[6] L. Guarente, "Sirtuins as potential targets for metabolic syndrome," Nature, vol. 444,
pp. 868-74, Dec 14 2006.
[7] X. J. Yang and S. Gregoire, "Class II histone deacetylases: from sequence to function,
regulation, and clinical implication," Mol Cell Biol, vol. 25, pp. 2873-84, Apr 2005.
[8] S. K. Kurdistani and M. Grunstein, "Histone acetylation and deacetylation in yeast,"
Nat Rev Mol Cell Biol, vol. 4, pp. 276-84, Apr 2003.
[9] P. A. Marks, T. Miller, and V. M. Richon, "Histone deacetylases," Curr Opin Pharmacol,
vol. 3, pp. 344-51, Aug 2003.
[10] C. M. Grozinger, C. A. Hassig, and S. L. Schreiber, "Three proteins define a class of
human histone deacetylases related to yeast Hda1p," Proc Natl Acad Sci U S A, vol. 96,
pp. 4868-73, Apr 27 1999.
[11] A. Verdel, S. Curtet, M. P. Brocard, S. Rousseaux, C. Lemercier, M. Yoshida, and S.
Khochbin, "Active maintenance of mHDA2/mHDAC6 histone-deacetylase in the
cytoplasm," Curr Biol, vol. 10, pp. 747-9, Jun 15 2000.
[12] Y. Zhang, B. Gilquin, S. Khochbin, and P. Matthias, "Two catalytic domains are required
for protein deacetylation," J Biol Chem, vol. 281, pp. 2401-4, Feb 3 2006.
[13] W. Fischle, F. Dequiedt, M. J. Hendzel, M. G. Guenther, M. A. Lazar, W. Voelter, and E.
Verdin, "Enzymatic activity associated with class II HDACs is dependent on a
multiprotein complex containing HDAC3 and SMRT/N-CoR," Mol Cell, vol. 9, pp. 45-57,
Jan 2002.
[14] X. J. Yang and E. Seto, "The Rpd3/Hda1 family of lysine deacetylases: from bacteria
and yeast to mice and men," Nat Rev Mol Cell Biol, vol. 9, pp. 206-18, Mar 2008.
[15] J. Lu, T. A. McKinsey, R. L. Nicol, and E. N. Olson, "Signal-dependent activation of the 52

MEF2 transcription factor by dissociation from histone deacetylases," Proc Natl Acad
Sci U S A, vol. 97, pp. 4070-5, Apr 11 2000.
[16] J. Lu, T. A. McKinsey, C. L. Zhang, and E. N. Olson, "Regulation of skeletal myogenesis
by association of the MEF2 transcription factor with class II histone deacetylases,"
Mol Cell, vol. 6, pp. 233-44, Aug 2000.
[17] R. B. Vega, B. C. Harrison, E. Meadows, C. R. Roberts, P. J. Papst, E. N. Olson, and T. A.
McKinsey, "Protein kinases C and D mediate agonist-dependent cardiac hypertrophy
through nuclear export of histone deacetylase 5," Mol Cell Biol, vol. 24, pp. 8374-85,
Oct 2004.
[18] T. Watanabe, J. Noritake, and K. Kaibuchi, "Regulation of microtubules in cell
migration," Trends Cell Biol, vol. 15, pp. 76-83, Feb 2005.
[19] J. R. Cabrero, J. M. Serrador, O. Barreiro, M. Mittelbrunn, S. Naranjo-Suarez, N.
Martin-Cofreces, M. Vicente-Manzanares, R. Mazitschek, J. E. Bradner, J. Avila, A.
Valenzuela-Fernandez, and F. Sanchez-Madrid, "Lymphocyte chemotaxis is regulated
by histone deacetylase 6, independently of its deacetylase activity," Mol Biol Cell, vol.
17, pp. 3435-45, Aug 2006.
[20] Y. S. Gao, C. C. Hubbert, J. Lu, Y. S. Lee, J. Y. Lee, and T. P. Yao, "Histone deacetylase 6
regulates growth factor-induced actin remodeling and endocytosis," Mol Cell Biol, vol.
27, pp. 8637-47, Dec 2007.
[21] A. R. Prescott, M. Vestberg, and R. M. Warn, "Microtubules rich in modified
alpha-tubulin characterize the tail processes of motile fibroblasts," J Cell Sci, vol. 94
( Pt 2), pp. 227-36, Oct 1989.
[22] N. Yoshida, Y. Omoto, A. Inoue, H. Eguchi, Y. Kobayashi, M. Kurosumi, S. Saji, K.
Suemasu, T. Okazaki, K. Nakachi, T. Fujita, and S. Hayashi, "Prediction of prognosis of
estrogen receptor-positive breast cancer with combination of selected
estrogen-regulated genes," Cancer Sci, vol. 95, pp. 496-502, Jun 2004.
[23] D. R. Hurst, A. Mehta, B. P. Moore, P. A. Phadke, W. J. Meehan, M. A. Accavitti, L. A.
Shevde, J. E. Hopper, Y. Xie, D. R. Welch, and R. S. Samant, "Breast cancer metastasis
suppressor 1 (BRMS1) is stabilized by the Hsp90 chaperone," Biochem Biophys Res
Commun, vol. 348, pp. 1429-35, Oct 6 2006.
[24] W. Glenisson, V. Castronovo, and D. Waltregny, "Histone deacetylase 4 is required for
TGFbeta1-induced myofibroblastic differentiation," Biochim Biophys Acta, vol. 1773,
pp. 1572-82, Oct 2007.
[25] D. Z. Qian, S. K. Kachhap, S. J. Collis, H. M. Verheul, M. A. Carducci, P. Atadja, and R.
Pili, "Class II histone deacetylases are associated with VHL-independent regulation of
hypoxia-inducible factor 1 alpha," Cancer Res, vol. 66, pp. 8814-21, Sep 1 2006.
[26] P. Bali, M. Pranpat, J. Bradner, M. Balasis, W. Fiskus, F. Guo, K. Rocha, S. Kumaraswamy,
S. Boyapalle, P. Atadja, E. Seto, and K. Bhalla, "Inhibition of histone deacetylase 6 53

acetylates and disrupts the chaperone function of heat shock protein 90: a novel
basis for antileukemia activity of histone deacetylase inhibitors," J Biol Chem, vol. 280,
pp. 26729-34, Jul 22 2005.
[27] L. Peng and E. Seto, "Deacetylation of nonhistone proteins by HDACs and the
implications in cancer," Handb Exp Pharmacol, vol. 206, pp. 39-56, 2011.
[28] M. F. Fraga, E. Ballestar, A. Villar-Garea, M. Boix-Chornet, J. Espada, G. Schotta, T.
Bonaldi, C. Haydon, S. Ropero, K. Petrie, N. G. Iyer, A. Perez-Rosado, E. Calvo, J. A.
Lopez, A. Cano, M. J. Calasanz, D. Colomer, M. A. Piris, N. Ahn, A. Imhof, C. Caldas, T.
Jenuwein, and M. Esteller, "Loss of acetylation at Lys16 and trimethylation at Lys20 of
histone H4 is a common hallmark of human cancer," Nat Genet, vol. 37, pp. 391-400,
Apr 2005.
[29] W. Yasui, N. Oue, S. Ono, Y. Mitani, R. Ito, and H. Nakayama, "Histone acetylation and
gastrointestinal carcinogenesis," Ann N Y Acad Sci, vol. 983, pp. 220-31, Mar 2003.
[30] M. A. Glozak and E. Seto, "Histone deacetylases and cancer," Oncogene, vol. 26, pp.
5420-32, Aug 13 2007.
[31] J. H. Choi, H. J. Kwon, B. I. Yoon, J. H. Kim, S. U. Han, H. J. Joo, and D. Y. Kim,
"Expression profile of histone deacetylase 1 in gastric cancer tissues," Jpn J Cancer
Res, vol. 92, pp. 1300-4, Dec 2001.
[32] K. Halkidou, L. Gaughan, S. Cook, H. Y. Leung, D. E. Neal, and C. N. Robson,
"Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate
cancer," Prostate, vol. 59, pp. 177-89, May 1 2004.
[33] Z. Zhang, H. Yamashita, T. Toyama, H. Sugiura, Y. Ando, K. Mita, M. Hamaguchi, Y. Hara,
S. Kobayashi, and H. Iwase, "Quantitation of HDAC1 mRNA expression in invasive
carcinoma of the breast*," Breast Cancer Res Treat, vol. 94, pp. 11-6, Nov 2005.
[34] B. H. Huang, M. Laban, C. H. Leung, L. Lee, C. K. Lee, M. Salto-Tellez, G. C. Raju, and S.
C. Hooi, "Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1
expression, independent of histone deacetylase 1," Cell Death Differ, vol. 12, pp.
395-404, Apr 2005.
[35] J. Song, J. H. Noh, J. H. Lee, J. W. Eun, Y. M. Ahn, S. Y. Kim, S. H. Lee, W. S. Park, N. J.
Yoo, J. Y. Lee, and S. W. Nam, "Increased expression of histone deacetylase 2 is found
in human gastric cancer," APMIS, vol. 113, pp. 264-8, Apr 2005.
[36] A. J. Wilson, D. S. Byun, N. Popova, L. B. Murray, K. L'Italien, Y. Sowa, D. Arango, A.
Velcich, L. H. Augenlicht, and J. M. Mariadason, "Histone deacetylase 3 (HDAC3) and
other class I HDACs regulate colon cell maturation and p21 expression and are
deregulated in human colon cancer," J Biol Chem, vol. 281, pp. 13548-58, May 12
2006.
[37] Z. Zhang, H. Yamashita, T. Toyama, H. Sugiura, Y. Omoto, Y. Ando, K. Mita, M.
Hamaguchi, S. Hayashi, and H. Iwase, "HDAC6 expression is correlated with better 54

survival in breast cancer," Clin Cancer Res, vol. 10, pp. 6962-8, Oct 15 2004.
[38] C. Y. Gui, L. Ngo, W. S. Xu, V. M. Richon, and P. A. Marks, "Histone deacetylase (HDAC)
inhibitor activation of p21WAF1 involves changes in promoter-associated proteins,
including HDAC1," Proc Natl Acad Sci U S A, vol. 101, pp. 1241-6, Feb 3 2004.
[39] J. Luo, F. Su, D. Chen, A. Shiloh, and W. Gu, "Deacetylation of p53 modulates its effect
on cell growth and apoptosis," Nature, vol. 408, pp. 377-81, Nov 16 2000.
[40] J. E. Bolden, M. J. Peart, and R. W. Johnstone, "Anticancer activities of histone
deacetylase inhibitors," Nat Rev Drug Discov, vol. 5, pp. 769-84, Sep 2006.
[41] W. K. Rasheed, R. W. Johnstone, and H. M. Prince, "Histone deacetylase inhibitors in
cancer therapy," Expert Opin Investig Drugs, vol. 16, pp. 659-78, May 2007.
[42] M. Gottlicher, S. Minucci, P. Zhu, O. H. Kramer, A. Schimpf, S. Giavara, J. P. Sleeman, F.
Lo Coco, C. Nervi, P. G. Pelicci, and T. Heinzel, "Valproic acid defines a novel class of
HDAC inhibitors inducing differentiation of transformed cells," EMBO J, vol. 20, pp.
6969-78, Dec 17 2001.
[43] S. Chen, J. Ye, I. Kijima, and D. Evans, "The HDAC inhibitor LBH589 (panobinostat) is an
inhibitory modulator of aromatase gene expression," Proc Natl Acad Sci U S A, vol.
107, pp. 11032-7, Jun 15 2010.
[44] L. Ellis, M. Bots, R. K. Lindemann, J. E. Bolden, A. Newbold, L. A. Cluse, C. L. Scott, A.
Strasser, P. Atadja, S. W. Lowe, and R. W. Johnstone, "The histone deacetylase
inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional
apoptosome to mediate tumor cell death or therapeutic efficacy," Blood, vol. 114, pp.
380-93, Jul 9 2009.
[45] W. Fiskus, Y. Ren, A. Mohapatra, P. Bali, A. Mandawat, R. Rao, B. Herger, Y. Yang, P.
Atadja, J. Wu, and K. Bhalla, "Hydroxamic acid analogue histone deacetylase inhibitors
attenuate estrogen receptor-alpha levels and transcriptional activity: a result of
hyperacetylation and inhibition of chaperone function of heat shock protein 90," Clin
Cancer Res, vol. 13, pp. 4882-90, Aug 15 2007.
[46] T. L. Cha, M. J. Chuang, S. T. Wu, G. H. Sun, S. Y. Chang, D. S. Yu, S. M. Huang, S. K.
Huan, T. C. Cheng, T. T. Chen, P. L. Fan, and P. W. Hsiao, "Dual degradation of aurora A
and B kinases by the histone deacetylase inhibitor LBH589 induces G2-M arrest and
apoptosis of renal cancer cells," Clin Cancer Res, vol. 15, pp. 840-50, Feb 1 2009.
[47] T. Bluethner, M. Niederhagen, K. Caca, F. Serr, H. Witzigmann, C. Moebius, J. Mossner,
and M. Wiedmann, "Inhibition of histone deacetylase for the treatment of biliary
tract cancer: a new effective pharmacological approach," World J Gastroenterol, vol.
13, pp. 4761-70, Sep 21 2007.
[48] D. Z. Qian, Y. Kato, S. Shabbeer, Y. Wei, H. M. Verheul, B. Salumbides, T. Sanni, P.
Atadja, and R. Pili, "Targeting tumor angiogenesis with histone deacetylase inhibitors:
the hydroxamic acid derivative LBH589," Clin Cancer Res, vol. 12, pp. 634-42, Jan 15 55

2006.
[49] A. Ullrich and J. Schlessinger, "Signal transduction by receptors with tyrosine kinase
activity," Cell, vol. 61, pp. 203-12, Apr 20 1990.
[50] D. Hoeller, S. Volarevic, and I. Dikic, "Compartmentalization of growth factor receptor
signalling," Curr Opin Cell Biol, vol. 17, pp. 107-11, Apr 2005.
[51] J. N. Lavoie, G. L'Allemain, A. Brunet, R. Muller, and J. Pouyssegur, "Cyclin D1
expression is regulated positively by the p42/p44MAPK and negatively by the
p38/HOGMAPK pathway," J Biol Chem, vol. 271, pp. 20608-16, Aug 23 1996.
[52] R. Wang, G. He, M. Nelman-Gonzalez, C. L. Ashorn, G. E. Gallick, P. T. Stukenberg, M.
W. Kirschner, and J. Kuang, "Regulation of Cdc25C by ERK-MAP kinases during the
G2/M transition," Cell, vol. 128, pp. 1119-32, Mar 23 2007.
[53] H. S. Kim, M. C. Song, I. H. Kwak, T. J. Park, and I. K. Lim, "Constitutive induction of
p-Erk1/2 accompanied by reduced activities of protein phosphatases 1 and 2A and
MKP3 due to reactive oxygen species during cellular senescence," J Biol Chem, vol.
278, pp. 37497-510, Sep 26 2003.
[54] T. Ozben, "Oxidative stress and apoptosis: impact on cancer therapy," J Pharm Sci, vol.
96, pp. 2181-96, Sep 2007.
[55] R. Marais and C. J. Marshall, "Control of the ERK MAP kinase cascade by Ras and Raf,"
Cancer Surv, vol. 27, pp. 101-25, 1996.
[56] C. J. Marshall, "Specificity of receptor tyrosine kinase signaling: transient versus
sustained extracellular signal-regulated kinase activation," Cell, vol. 80, pp. 179-85,
Jan 27 1995.
[57] D. K. Morrison and R. E. Cutler, "The complexity of Raf-1 regulation," Curr Opin Cell
Biol, vol. 9, pp. 174-9, Apr 1997.
[58] M. Marshall, "Interactions between Ras and Raf: key regulatory proteins in cellular
transformation," Mol Reprod Dev, vol. 42, pp. 493-9, Dec 1995.
[59] D. Woods, D. Parry, H. Cherwinski, E. Bosch, E. Lees, and M. McMahon, "Raf-induced
proliferation or cell cycle arrest is determined by the level of Raf activity with arrest
mediated by p21Cip1," Mol Cell Biol, vol. 17, pp. 5598-611, Sep 1997.
[60] J. Zhu, D. Woods, M. McMahon, and J. M. Bishop, "Senescence of human fibroblasts
induced by oncogenic Raf," Genes Dev, vol. 12, pp. 2997-3007, Oct 1 1998.
[61] Y. Shi, "Serine/threonine phosphatases: mechanism through structure," Cell, vol. 139,
pp. 468-84, Oct 30 2009.
[62] M. H. Brush, A. Guardiola, J. H. Connor, T. P. Yao, and S. Shenolikar, "Deactylase
inhibitors disrupt cellular complexes containing protein phosphatases and
deacetylases," J Biol Chem, vol. 279, pp. 7685-91, Feb 27 2004.
[63] M. Gupta, S. M. Ansell, A. J. Novak, S. Kumar, S. H. Kaufmann, and T. E. Witzig,
"Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2," Blood, vol.
114, pp. 2926-35, Oct 1 2009.
[64] P. Boston and P. Jackson, "Purification and properties of a brain-specific protein,
human 14-3-3 protein," Biochem Soc Trans, vol. 8, pp. 617-8, Oct 1980.
[65] G. Tzivion, Z. Luo, and J. Avruch, "A dimeric 14-3-3 protein is an essential cofactor for
Raf kinase activity," Nature, vol. 394, pp. 88-92, Jul 2 1998.
[66] M. L. Henriksson, M. S. Francis, A. Peden, M. Aili, K. Stefansson, R. Palmer, A. Aitken,
and B. Hallberg, "A nonphosphorylated 14-3-3 binding motif on exoenzyme S that is
functional in vivo," Eur J Biochem, vol. 269, pp. 4921-9, Oct 2002.
[67] N. Meiri, "14-3-3epsilon Expression is induced during the critical period of thermal
control establishment," Dev Neurobiol, vol. 68, pp. 62-72, Jan 2008.
[68] M. J. van Hemert, H. Y. Steensma, and G. P. van Heusden, "14-3-3 proteins: key
regulators of cell division, signalling and apoptosis," Bioessays, vol. 23, pp. 936-46,
Oct 2001.
[69] P. Dent, T. Jelinek, D. K. Morrison, M. J. Weber, and T. W. Sturgill, "Reversal of Raf-1
activation by purified and membrane-associated protein phosphatases," Science, vol.
268, pp. 1902-6, Jun 30 1995.
[70] S. Roy, R. A. McPherson, A. Apolloni, J. Yan, A. Lane, J. Clyde-Smith, and J. F. Hancock,
"14-3-3 facilitates Ras-dependent Raf-1 activation in vitro and in vivo," Mol Cell Biol,
vol. 18, pp. 3947-55, Jul 1998.
[71] K. Ozaki, A. Minoda, F. Kishikawa, and M. Kohno, "Blockade of the ERK pathway
markedly sensitizes tumor cells to HDAC inhibitor-induced cell death," Biochem
Biophys Res Commun, vol. 339, pp. 1171-7, Jan 27 2006.
[72] X. Y. Pei, Y. Dai, and S. Grant, "Synergistic induction of oxidative injury and apoptosis
in human multiple myeloma cells by the proteasome inhibitor bortezomib and
histone deacetylase inhibitors," Clin Cancer Res, vol. 10, pp. 3839-52, Jun 1 2004.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top