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 U0026-1308201321583800
論文名稱(中文) 探討PKA亞型抑制核內有絲分裂之機制
論文名稱(英文) The mechanism of endomitosis inhibited by PKA isoforms
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 101
學期 2
出版年 102
研究生(中文) 曾馨柔
研究生(英文) Hsin-Jou Tseng
學號 s26991055
學位類別 碩士
語文別 中文
論文頁數 90頁
口試委員 指導教授-簡偉明
口試委員-錢偉鈞
口試委員-陳清玉
中文關鍵字 核內有絲分裂  細胞週期  環磷酸腺苷  蛋白激酶A 
英文關鍵字 endomitosis  cell cycle  cAMP  PKA 
學科別分類
中文摘要 多倍化,是指一個細胞擁有超過兩套以上的染色體,這個現象在人體的巨核細胞、肝細胞及肌肉細胞中皆可發現。多倍化現象可藉由核內有絲分裂機制形成,包含細胞分裂的阻斷及染色體的再複製,而巨核細胞便是仰賴這個機制協助產生大量的血小板。當核內有絲分裂產生異常,會導致血小板數量或功能異常。過去研究指出,巨核細胞分化過程中,cyclin B1及CDK1被發現與正常細胞分裂的消失有關,而cyclin D與cyclin E會促使細胞再次進入染色體複製期,提高染色體套數。最近研究更發現環磷酸腺苷-蛋白激酶A(cAMP-PKA)這條訊息路徑會對核內有絲分裂產生抑制作用,然而目前對於cAMP如何抑制核內有絲分裂及影響不同細胞週期階段中的調控分子仍不清楚。因此,本研究利用HEL細胞株作為實驗模型,利用流式細胞儀(Acurri C6)進行觀察,欲了解提高細胞內cAMP濃度會如何影響PMA所誘發的核內有絲分裂及相關調控分子的變化。實驗結果顯示利用腺苷酸環化酶活化劑forskolin提高細胞cAMP濃度確實可以抑制PMA誘發的核內有絲分裂,包含細胞體積及染色體套數下降。接著也發現PMA可以誘發p21表現量增加,且提高cAMP可抑制p21表現量的增加。由於p21可影響細胞週期分子的變化,因此先觀察細胞分裂相關的因子是否受到影響,結果發現處於G2/M期且表現cyclin B1的細胞數有明顯的下降,但cAMP的提高並不影響PMA誘發的效果。進一步觀察細胞中cyclin B1表現量的變化,發現cAMP會抑制該分子晚期表現量的增加。此外,在PMA處理後,cdc2Y15的磷酸化程度會逐漸下降,但cAMP的提高並不會影響PMA誘發的變化。另外,在促進細胞進入染色體複製期分子的部分,發現cyclin D3的表現量在PMA誘發的早期有顯著的增加,而cAMP提高可抑制該分子早期表現量的增加。另外,cyclin E1的表現量在PMA投與後確實會提高,但該提高的表現量並不被cAMP所抑制。故由以上結果推論p21及cyclin D3為主要參與在cAMP造成核內有絲分裂抑制作用的分子。過去研究發現PKA亞型在細胞中的功能不同,因此利用shRNA的方式抑制特定PKA亞型的基因表現,進一步確認cAMP下游的作用分子。結果顯示當完全抑制PKAIIA的表現時,會阻斷cAMP的抑制效果,而部分抑制PKAIIA的表現時,則仍可觀察到cAMP的抑制效果,而抑制PKAIA的表現並不影響cAMP的抑制效果,故可知cAMP是藉由PKAIIA抑制PMA誘發的核內有絲分裂。
核內有絲分裂會影響血小板的生成,若了解cAMP抑制核內有絲分裂的作用機制及下游訊息傳遞路徑的作用分子,對於未來藥物設計的方向及作用奠定基礎,以便運用於血小板疾病及相關疾病的治療。
英文摘要 Ployploidy, a cell containing more than two paired set of chromosome, can be observed in megakaryocytes, hepatocytes and muscular cells of human. The phenomenon of polyploidy, also known as endomitosis, is composed of interruption of cytokinesis and re-synthesis of DNA. The abnormality of endomitosis in megakarypoiesis can cause the platelet disorder. In megakarypoiesis, it is reported that cyclin B1 and CDK1 are correlated to interruption of cytokinesis. Cyclin D and cyclin E promote the entrance of S phase and DNA re-synthesis. It’s recently found that cAMP-PKA signaling can inhibit endomitosis through E2A-p21 axis. However, the alternation of those factors at different cell cycle stage in endomitotic cells and the specific mechanism of cAMP inhibition are not completely known. In this study, we observed alternation of cyclins and related factors in PMA-induced endomitosis with and without forskolin-mediated inhibition in HEL cells through Acurri C6 flow cytometry. The results showed that elevation of cAMP levels by forskolin indeed inhibits PMA-induced endomitosis, including the decrease of cell size and cell ploidy. In cytokinesis-related factors, we found number of cyclin B1-expressed-cells at G2/M phase has similar change under PMA treatment and PMA/forskolin co-treatment. However, cAMP can inhibit PMA-induced cyclin B1 expression in these cells at late stage. Furthermore, cdc2Y15 levels have no significantly difference between two groups. In factors related to S-phase entry, cyclin D3 levels are incresed after PMA treatment, but the increase can be inhibited by pre-treatment of cAMP. Moreover, cyclin E is significantly increased after PMA treatment, but forskolin had no effect on the expression induced by PMA. The results showed that cyclin D3 and p21 may be the determinant factors in forskolin-mediated inhibition. Recent studies revealed that cAMP inhibited endomitosis through PKA. To uncover the downstream PKA isoforms of cAMP, we reduced the expression of PKA isoforms with shRNA. The results showed that complete knockdown of PKAIIA can abolish the inhibition on PMA-induced endomitosis by forskolin. However, partial knockdown of PKAIIA can not reverse cAMP-mediated inhibition. Knockdown of PKAIA is not able to withstand the inhibitory effect of cAMP. Therefore, PKAIIA is the downstream factor of cAMP during the inhibition.
Endomitosis is related to the production of functional platelet in human. Knowing the specific mechanisms and the downstream factors may contribute to the treatment strategy and drug design in the future.
論文目次 口試合格證明 I
中文摘要 II
英文摘要 IV
誌謝 VI
目錄 VII
圖表目錄 IX
縮寫表 X
第一章 緒論 1
1.1 核內有絲分裂及巨核細胞分化 1
1.2 巨核細胞作為研究核內有絲分裂的模型 2
1.3 正常細胞週期及其調控因子 3
1.4 核內有絲分裂及細胞週期調控因子之關係 5
1.4.1 p21在巨核細胞之核內有絲分裂的角色 5
1.4.2 cyclin B1與CDK1在巨核細胞之核內有絲分裂的角色 6
1.4.3 cyclin D3在巨核細胞之核內有絲分裂的角色 8
1.4.4 cyclin E在巨核細胞之核內有絲分裂的角色 9
1.5 cAMP及PKA分子和巨核細胞中核內有絲分裂之關係 10
1.6 PKA的結構及功能 11
1.7 PKA和細胞週期調控因子的關係 12
1.8 研究背景 14
1.9 實驗設計 14
第二章 材料及方法 16
2.1 材料 16
2.2 方法 24
第三章 實驗結果 29
3.1 提高cAMP可抑制核內有絲分裂的發生 29
3.2 細胞內cAMP或PKA的提高皆可以抑制核內有絲分裂 29
3.3 p21的表現確實受到cAMP的調控 30
3.4 cAMP可抑制cyclin B1在後期的表現但不影響CDK1活性 30
3.5 cAMP可以調控核內有絲分裂過程中cyclin D3的表現 32
3.6 cAMP並不影響Cyclin E的表現 32
3.7 PKA參與在核內有絲分裂的過程當中 33
3.8 PKA2α參與在核內有絲分裂的過程當中 33
第四章 討論 35
4.1實驗設計及分析 35
4.2 cAMP藉由下游分子PKA抑制巨核細胞分化 36
4.3 Forskolin對於細胞週期分子的影響 37
4.3.1 cAMP對於p21之影響 37
4.3.2 cAMP對調控細胞分裂分子之影響 38
4.3.3 cAMP對cyclin D3之影響 38
4.3.4 cAMP對cyclin E1之影響 39
4.4 PKA與核內有絲分裂之關係 39
4.5 未來展望 40
第五章 結論 42
參考文獻 43
附錄 58

















參考文獻 Afdhal N, McHutchison J, Brown R, Jacobson I, Manns M, Poordad F, et al. Thrombocytopenia associated with chronic liver disease. Journal of Hepatology 48(6):1000-7 (2008)

Aleem E, Kiyokawa H, Kaldis P. Cdc2-cyclin E complexes regulate the G1/S phase transition. Nature cell biology 7(8):831-6 (2005)

Ando K, Ajchenbaum-Cymbalista F, Griffin JD. Regulation of G1/S transition by cyclins D2 and D3 in hematopoietic cells. PNAS 90(20):9571-5 (1993)

Baccini V, Roy L, Vitrat N, Chagraoui H, Sabri S, Le Couedic JP, et al. Role of p21(Cip1/Waf1) in cell-cycle exit of endomitotic megakaryocytes. Blood 98(12):3274-82 (2001)

Ballen KK, Ritchie AJ, Murphy C, Handin RI, Ewenstein BM. Expression and activation of protein kinase C isoforms in a human megakaryocytic cell line. Experimental Hematology 24(13):1501-8 (1996)

Bartkova J, Lukas J, Strauss M, Bartek J. Cyclin D3: requirement for G1/S transition and high abundance in quiescent tissues suggest a dual role in proliferation and differentiation. Oncogene 17(8):1027-37 (1998)

Bastians H, Müller R.(2008), Encyclopedia of Molecular Pharmacology: Cell-cycle Control(2nd ed.), New York: Springer.

Begonja AJ, Gambaryan S, Schulze H, Patel-Hett S, Italiano JE, Jr., Hartwig JH, et al. Differential roles of cAMP and cGMP in megakaryocyte maturation and platelet biogenesis. Experimental hematology 41(1):91-101 e4 (2013)

Bos JL. Epac: a new cAMP target and new avenues in cAMP research. Nature Reviews Molecular Cell Biology 4(9):733-8 (2003)

Blomhoff HK, Gützkow KB, Låhne HU, Ryves JW, Harwood AJ, Naderi S. PKA-mediated regulation of cyclin D3 stability through its phosphorylation by GSK-3ß on T283. Proc Amer Assoc Cancer Res 45 (2004)

Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA. Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma-irradiation. PNAS 96(3):1002-7 (1999)

Cazzalini O, Scovassi AI, Savio M, Stivala LA, Prosperi E. Multiple roles of the cell cycle inhibitor p21(CDKN1A) in the DNA damage response. Mutation Research 704(1-3):12-20 (2010)

Charrier-Savournin FB, Chateau MT, Gire V, Sedivy J, Piette J, Dulic V. p21-Mediated nuclear retention of cyclin B1-Cdk1 in response to genotoxic stress. Molecular Biology of the Cell 15(9):3965-76 (2004)

Cho-Chung YS, Nesterova M, Pepe S, Lee GR, Noguchi K, Srivastava RK, et al. Antisense DNA-targeting protein kinase A-RIA subunit: a novel approach to cancer treatment. Frontiers in Bioscience 4:D898-907 (1999)

Chotinantakul K, Leeanansaksiri W. Hematopoietic stem cell development, niches, and signaling pathways. Bone Marrow Research 2012:270425 (2012)

Ciemerych MA, Kenney AM, Sicinska E, Kalaszczynska I, Bronson RT, Rowitch DH, et al. Development of mice expressing a single D-type cyclin. Genes & development 16(24):3277-89 (2002)

Das R, Esposito V, Abu-Abed M, Anand GS, Taylor SS, Melacini G. cAMP activation of PKA defines an ancient signaling mechanism. Proc Natl Acad Sci US A 104(1):93-8 (2007)

Davoli T, de Lange T. The causes and consequences of polyploidy in normal development and cancer. Annual Review of Cell and Developmental Biology 27:585-610 (2011)

Datta NS, Williams JL, Caldwell J, Curry AM, Ashcraft EK, Long MW. Novel alterations in CDK1/cyclin B1 kinase complex formation occur during the acquisition of a polyploid DNA content. Molecular Biology of the Cell 7(2):209-23 (1996)

den Dekker E, Gorter G, Heemskerk JW, Akkerman JW. Development of platelet inhibition by cAMP during megakaryocytopoiesis. The Journal of Biological Chemistry 277(32):29321-9 (2002-1)

den Dekker E, Heemskerk JW, Gorter G, van der Vuurst H, Donath J, Kroner C et al. Cyclic AMP Raises Intracellular Ca2+ in Human Megakaryocytes Independent of Protein. Arteriosclerosis, Thrombosis, and Vascular Biology 22:179-86 (2002-2)

di Benedetto G, Zoccarato A, Lissandron V, Terrin A, Li X, Houslay MD, et al. Protein kinase A type I and type II define distinct intracellular signaling compartments. Circulation Research 103(8):836-44 (2008)

Dulic V, Kaufmann WK, Wilson SJ, Tlsty TD, Lees E, Harper JW, et al. p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell 76(6):1013-23 (1994)

Eid M, Kayed H, El-Bassyouni HT. Polyploidy in chronic lymphocytic leukemia with p53 deletion detected by fish: a case report. Cases Journal 2:8872 (2009)

Eliades A, Papadantonakis N, Ravid K. New roles for cyclin E in megakaryocytic polyploidization. The Journal of Biological Chemistry 285(24):18909-17 (2010)

Feijge MA, Ansink K, Vanschoonbeek K, Heemskerk JW. Control of platelet activation by cyclic AMP turnover and cyclic nucleotide phosphodiesterase type-3. Biochemical Pharmacology 67(8):1559-67 (2004)

Ferrandiz N, Caraballo JM, Garcia-Gutierrez L, Devgan V, Rodriguez-Paredes M, Lafita MC, et al. p21 as a transcriptional co-repressor of S-phase and mitotic control genes. PloS one 7(5):e37759 (2012)

Freson K, Peeters K, De Vos R, Wittevrongel C, Thys C, Hoylaerts MF, et al. PACAP and its receptor VPAC1 regulate megakaryocyte maturation: therapeutic implications. Blood 111(4):1885-93 (2008)

Furukawa Y, Kikuchi J, Nakamura M, Iwase S, Yamada H, Matsuda M. Lineage-specific regulation of cell cycle control gene expression during haematopoietic cell differentiation. British Journal of Haematology 110(3):663-73 (2000)

Gao Y, Smith E, Ker E, Campbell P, Cheng EC, Zou S, et al. Role of RhoA-specific guanine exchange factors in regulation of endomitosis in megakaryocytes. Developmental Cell 22(3):573-84 (2012)

Garcia P, Cales C. Endoreplication in megakaryoblastic cell lines is accompanied by sustained expression of G1/S cyclins and downregulation of cdc25C. Oncogene 13(4):695-703 (1996)

Garcia P, Frampton J, Ballester A, Cales C. Ectopic expression of cyclin E allows non-endomitotic megakaryoblastic K562 cells to establish re-replication cycles. Oncogene 19(14):1820-33 (2000)

Geddis AE. Shedding light on endomitosis. Blood 116(13):2202-3 (2010)

Geng Y, Yu Q, Sicinska E, Das M, Schneider JE, Bhattacharya S, et al. Cyclin E ablation in the mouse. Cell 114(4):431-43 (2003)

Ghosh PM, Moyer ML, Mott GE, Kreisberg JI. Effect of cyclin E overexpression on lovastatin-induced G1 arrest and RhoA inactivation in NIH3T3 cells. Journal of Cellular Biochemistry 74(4):532-43 (1999)

Goel G, Makkar HP, Francis G, Becker K. Phorbol esters: structure, biological activity, and toxicity in animals. International Journal of Toxicology 26(4):279-88 (2007)

Grieco D, Avvedimento EV, Gottesman ME. A role for cAMP-dependent protein kinase in early embryonic divisions. PNAS 91(21):9896-900 (1994)

Gui CY, Jiang C, Xie HY, Qian RL. The apoptosis of HEL cells induced by hydroxyurea. Cell Research 7(1):91-7 (1997)

Han SJ, Conti M. New pathways from PKA to the Cdc2/cyclin B complex in oocytes: Wee1B as a potential PKA substrate. Cell Cycle 5(3):227-31 (2006)

Herzinger T, Reed SI. Cyclin D3 is rate-limiting for the G1/S phase transition in fibroblasts. The Journal of Biological Chemistry 273(24):14958-61 (1998)

Kato JY, Sherr CJ. Inhibition of granulocyte differentiation by G1 cyclins D2 and D3 but not D1. PNAS 90(24):11513-7 (1993)

Kostyak JC, Naik UP. Megakaryopoiesis: transcriptional insights into megakaryocyte maturation. Frontiers in Bioscience 12:2050-62 (2007)

Kurokawa K, Kato J. Cyclic AMP delays G2 progression and prevents efficient accumulation of cyclin B1 proteins in mouse macrophage cells. Cell Structure and Function 23(6):357-65 (1998)

Landsverk HB, Carlson CR, Steen RL, Vossebein L, Herberg FW, Tasken K, et al. Regulation of anchoring of the RIIalpha regulatory subunit of PKA to AKAP95 by threonine phosphorylation of RIIalpha: implications for chromosome dynamics at mitosis. Journal of Cell Science 114(Pt 18):3255-64 (2001)

Lee HO, Davidson JM, Duronio RJ. Endoreplication: polyploidy with purpose. Genes & Development 23(21):2461-77 (2009-1)

Lee J, Kim JA, Barbier V, Fotedar A, Fotedar R. DNA damage triggers p21WAF1-dependent Emi1 down-regulation that maintains G2 arrest. Molecular Biology of the Cell 20(7):1891-902 (2009-2)

Long MW, Heffner CH, Williams JL, Peters C, Prochownik EV. Regulation of megakaryocyte phenotype in human erythroleukemia cells. The Journal of Clinical Investigation 85(4):1072-84 (1990)
Lordier L, Chang Y, Jalil A, Aurade F, Garcon L, Lecluse Y, et al. Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process. Blood 116(13):2345-55 (2010)

Lordier L, Bluteau D, Jalil A, Legrand C, Pan J, Rameau P, et al. RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization. Nature Communications 3:717 (2012)

Lorenowicz MJ, Fernandez-Borja M, Hordijk PL. cAMP signaling in leukocyte transendothelial migration. Arteriosclerosis, Thrombosis, and Vascular Biology 27(5):1014-22 (2007)

Mantel C, Braun SE, Reid S, Henegariu O, Liu L, Hangoc G, et al. p21(cip-1/waf-1) deficiency causes deformed nuclear architecture, centriole overduplication, polyploidy, and relaxed microtubule damage checkpoints in human hematopoietic cells. Blood 93(4):1390-8 (1999)

Matsouka P, Sambani C, Giannakoulas N, Symeonidis A, Zoumbos N. Polyploidy in acute promyelocytic leukemia without the 15:17 translocation. Haematologica 86(12):1312-3 (2001)

Matyakhina L, Lenherr SM, Stratakis CA. Protein kinase A and chromosomal stability. Annals of the New York Academy of Sciences 968:148-57 (2002)

Møller MB, Nielsen O, Pedersen NT. Cyclin D3 expression in non-Hodgkin lymphoma. Correlation with other cell cycle regulators and clinical features. American Journal of Clinical Pathology 115(3):404-12 (2001)

Mosieniak G, Sikora E. Polyploidy: the link between senescence and cancer. Current Pharmaceutical Design 16(6):734-40 (2010)

Nesterova M, Noguchi K, Park YG, Lee YN, Cho-Chung YS. Compensatory stabilization of RIIbeta protein, cell cycle deregulation, and growth arrest in colon and prostate carcinoma cells by antisense-directed down-regulation of protein kinase A RIalpha protein. Clinical Cancer Research 6(9):3434-41 (2000)

Nesterova M, Cho-Chung YS. A single-injection protein kinase A-directed antisense treatment to inhibit tumour growth. Nature Medicine 1(6):528-33 (1995)

Nurden AT. Qualitative disorders of platelets and megakaryocytes. Journal of Thrombosis and Haemostasis 3(8):1773-82 (2005)

Ono Y, Fujii T, Igarashi K, Kuno T, Tanaka C, Kikkawa U, et al. Phorbol ester binding to protein kinase C requires a cysteine-rich zinc-finger-like sequence. PNAS 86(13):4868-71 (1989)

Peeters K, Stassen JM, Collen D, Van Geet C, Freson K. Emerging treatments for thrombocytopenia: increasing platelet production. Drug Discovery Today 13(17-18):798-806 (2008)

Porter AC. Preventing DNA over-replication: a Cdk perspective. Cell Division 3:3 (2008)

Raslova H, Baccini V, Loussaief L, Comba B, Larghero J, Debili N, et al. Mammalian target of rapamycin (mTOR) regulates both proliferation of megakaryocyte progenitors and late stages of megakaryocyte differentiation. Blood 107(6):2303-10 (2006)

Ravid K, Lu J, Zimmet JM, Jones MR. Roads to polyploidy: the megakaryocyte example. Journal of Cellular Physiology 190(1):7-20 (2002)

Renner D, Queisser W. Megakaryocyte polyploidy and maturation in chronic granulocytic leukemia. Acta Haematologica 80(2):74-8 (1988)

Robb L. Cytokine receptors and hematopoietic differentiation. Oncogene 26(47):6715-23 (2007)

Rubinstein JD, Elagib KE, Goldfarb AN. Cyclic AMP signaling inhibits megakaryocytic differentiation by targeting transcription factor 3 (E2A) cyclin-dependent kinase inhibitor 1A (CDKN1A) transcriptional axis. The Journal of Biological Chemistry 287(23):19207-15 (2012)

Russell A, Hendley J, Germain D. Inhibitory effect of p21 in MCF-7 cells is overcome by its coordinated stabilization with D-type cyclins. Oncogene 18(47):6454-9 (1999)
Sassone-Corsi P. The cyclic AMP pathway. Cold Spring Harbor Perspectives in Biology 4(12) (2012)

Sauer M, Tausch S, Zieger M, Zintl F, Nowak G, Kaufmann R. Evidence for a novel thrombopoietin signalling event: activation of protein kinase A in human megakaryoblastic CMK cells. Cytokine 15(2):75-9 (2001)

Shen HW, Chen YL, Chern CY, Kan WM. The effect of prostacyclin agonists on the differentiation of phorbol ester treated human erythroleukemia cells. Prostaglandins & Other Lipid Mediators 83(3):231-6 (2007)

Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes & Development 13(12):1501-12 (1999)

Sherr CJ, Roberts JM. Living with or without cyclins and cyclin-dependent kinases. Genes & Development 18(22):2699-711 (2004)

Shibuya EK. G2 cell cycle arrest--a direct link between PKA and Cdc25C. Cell Cycle 2(1):39-41 (2003)

Skalhegg BS, Tasken K. Specificity in the cAMP/PKA signaling pathway. Differential expression,regulation, and subcellular localization of subunits of PKA. Frontiers in Bioscience 5:D678-93 (2000)

Song S, Cooperman J, Letting DL, Blobel GA, Choi JK. Identification of cyclin D3 as a direct target of E2A using DamID. Molecular and Cellular Biology 24(19):8790-802 (2004)

Taniguchi T, Endo H, Chikatsu N, Uchimaru K, Asano S, Fujita T, et al. Expression of p21(Cip1/Waf1/Sdi1) and p27(Kip1) cyclin-dependent kinase inhibitors during human hematopoiesis. Blood 93(12):4167-78 (1999)

Taylor SS, Kim C, Vigil D, Haste NM, Yang J, Wu J, et al. Dynamics of signaling by PKA. Biochimica et Biophysica Acta 1754(1-2):25-37 (2005)

Taylor SS, Ilouz R, Zhang P, Kornev AP. Assembly of allosteric macromolecular switches: lessons from PKA. Nature Reviews Molecular Cell Biology 13(10):646-58 (2012)

Terrin A, Monterisi S, Stangherlin A, Zoccarato A, Koschinski A, Surdo NC, et al. PKA and PDE4D3 anchoring to AKAP9 provides distinct regulation of cAMP signals at the centrosome. The Journal of Cell Biology 198(4):607-21 (2012)

Tomer A, Friese P, Conklin R, Bales W, Archer L, Harker LA, et al. Flow cytometric analysis of megakaryocytes from patients with abnormal platelet counts. Blood 74(2):594-601 (1989)

Tortora G, Caputo R, Damiano V, Bianco R, Pepe S, Bianco AR, et al. Synergistic inhibition of human cancer cell growth by cytotoxic drugs and mixed backbone antisense oligonucleotide targeting protein kinase A. Proc Natl Acad Sci USA 94(23):12586-91 (1997)

Tortora G, Ciardiello F. Protein kinase A type I: a target for cancer therapy. Clinical Cancer Research 8(2):303-4 (2002)

Tortora G, Ciardiello F. Antisense targeting protein kinase A type I as a drug for integrated strategies of cancer therapy. Annals of the New York Academy of Sciences 1002:236-43 (2003)

Unhavaithaya Y, Orr-Weaver TL. Polyploidization of glia in neural development links tissue growth to blood-brain barrier integrity. Genes & Development 26(1):31-6 (2012)

van Oirschot BA, Stahl M, Lens SM, Medema RH. Protein kinase A regulates expression of p27(kip1) and cyclin D3 to suppress proliferation of leukemic T cell lines. The Journal of Biological Chemistry 276(36):33854-60 (2001)

Vitrat N, Cohen-Solal K, Pique C, Le Couedic JP, Norol F, Larsen AK, et al. Endomitosis of human megakaryocytes are due to abortive mitosis. Blood 91(10):3711-23 (1998)

Wang Z, Zhang Y, Kamen D, Lees E, Ravid K. Cyclin D3 is essential for megakaryocytopoiesis. Blood 86(10):3783-8 (1995)

Wickrema A, Crispino JD. Erythroid and megakaryocytic transformation. Oncogene 26(47):6803-15 (2007)

Wu YM, Zhang YX, Shi J, Liu SL, Liu YX, Zheng DX. Molecular mechanism of hydroxyurea enhances K562 cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 34(2):146-52 (2012)

Yamane A, Nakamura T, Suzuki H, Ito M, Ohnishi Y, Ikeda Y, et al. Interferon-alpha 2b-induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes. Blood 112(3):542-50 (2008)

Yang J, Ikezoe T, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, et al. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood 110(6):2034-40 (2007)

Yu B, Wang Y, Liu Y, Liu Y, Li X, Wu D, et al. Protein kinase A regulates cell cycle progression of mouse fertilized eggs by means of MPF. Developmental Dynamics 232(1):98-105 (2005)

Zhao W, He H, Ren K, Li B, Zhang H, Lin Y, et al. MR-1 blocks the megakaryocytic differentiation and transition of CML from chronic phase to blast crisis through MEK dephosphorylation. Blood Cancer Journal 3:e107 (2013)
Zauli G, Bassini A, Catani L, Gibellini D, Celeghini C, Borgatti P, et al. PMA-induced megakaryocytic differentiation of HEL cells is accompanied by striking modifications of protein kinase C catalytic activity and isoform composition at the nuclear level. British Journal of Haematology 92(3):530-6 (1996)

Zhang Y, Wang Z, Liu DX, Pagano M, Ravid K. Ubiquitin-dependent degradation of cyclin B is accelerated in polyploid megakaryocytes. The Journal of Biological Chemistry 273(3):1387-92 (1998)

Zimmet JM, Toselli P, Ravid K. Cyclin D3 and megakaryocyte development: exploration of a transgenic phenotype. Stem Cells 16 Suppl 2:97-106 (1998)
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2018-08-28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