(3.236.228.250) 您好!臺灣時間:2021/04/20 00:25
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:::

我願授權國圖
: 
twitterline
研究生:鄔康邁
研究生(外文):Kang-mai Wu
論文名稱:在斑馬魚動物模式和細胞株中探討BRAM1在BMP訊息傳遞的角色
論文名稱(外文):Role of BRAM1 in BMP signaling examined in zebrafish model and cell lines
指導教授:張玉生張玉生引用關係
指導教授(外文):Yu-sun Chang
學位類別:博士
校院名稱:國立陽明大學
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:2006
畢業學年度:94
語文別:英文
論文頁數:116
中文關鍵詞:BMP接受器接合分子一號BMP斑馬魚心臟轉置不對稱基因中軸
外文關鍵詞:BRAM1BMPzebrafishheart loopingasymmetry genemidline
相關次數:
  • 被引用被引用:0
  • 點閱點閱:184
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:20
  • 收藏至我的研究室書目清單書目收藏:0
BRAM1(bone morphogenetic protein receptor associated molecule 1)是腫瘤抑制蛋白BS69的切割產物。它的C端和BS69C端片段有99%的相似度。BRAM1 由198 個胺基酸組成,C端具有一個MYND區域。它位於細胞質中藉由MYND 區域和Bmp接受器一號有結合的能力。由過去的實驗知道BRAM1在C.elegan的動物模式中,可能參與抑制TGFβ的訊息傳遞。但是真正的生物意義仍然未知。
為了探討BRAM1在生物中扮演的角色,我們利用斑馬魚當作動物模式,從EST資料庫分析以及5端和3端RACE的結果,選殖出斑馬魚BRAM1相關基因的cDNA。斑馬魚BRAM1同樣具有C端MYND區域,利用這段區域和斑馬魚Bmp接受器一號在生體內或生體外實驗皆證明有結合的能力。這樣結合的能力會干擾Bmp的訊息傳遞。從斑馬魚的體組織和胚胎發育的分析中顯示,斑馬魚BRAM1大量存在於母體的卵中以及胚胎初期。利用morpholinos抑制BRAM1的基因產物,導致斑馬魚胚胎在心臟和尾部的發育不正常。這樣的表現型和Bmp 變異種的表現型類似。同時注射活化Bmp接受器一號的mRNA和斑馬魚BRAM1mRNA到胚胎中,BRAM1基因產物可以抑制心臟位置從原本沒有轉置 (looping) 恢復到正常向右轉置 (D-looping)。心臟的轉置是呈現生物發育中左右不對稱基因表現的結果。所以我們利用左右不對稱基因cyclops, southpaw, lefty-1, lefty-2, 以及pitx2c。以原位雜交的方式證明這些原本分布在生物體中軸左側的基因產物, 因為BRAM1的表現降低,呈現隨意分布於中軸兩側。同時我們也分析了中軸的基因標的,發現flh和gsc的表現不正常。這些結果顯示斑馬魚BRAM1可能影響中軸的訊息傳遞進而影響左右不對稱基因的表現。
進一步在細胞株探討對BRAM1的生物機制發現,BRAM1會抑制Smad的訊息傳遞。而且從生體內實驗結果證明BRAM1和Smad1, 5, 4具有結合的能力。利用螢光染色法和共軛焦顯微鏡觀察發現BRAM1位於細胞質內,和Bmp接受器分布的位置有交集。經由Bmp ligand刺激,BRAM1會干擾Smad4和Smad5經由ligand的活化而轉移到細胞核。
從斑馬魚動物模式以及細胞株的實驗得知,BRAM1可能扮演一個負向調控Bmp生物訊息傳遞的角色。
BRAM1, bone morphogenetic protein receptor (BMPR) associated molecule 1, is a cytoplasmic protein consisting of 198 amino acids. BRAM1 shares 99% homology with the MYND domain-containing carboxy terminus of a tumor suppressor protein, BS69, which interacts with adenovirus E1A and Epstein-Barr virus-encoded nuclear protein EBNA2 through the MYND domain. Interaction of BS69 with E1A or EBNA2 inhibits viral oncoprotein-mediated transactivation. On the other hand, BRAM1 is a cytoplasmic protein and interacts with BMPR. To date, the biological role of BRAM1 remains unclear.
In this thesis work, we evaluate the physiological role of BRAM1 in zebrafish model system. zebrafish bram 1 cDNA was generated by bioinformatic search of zebrafish EST database, followed by 5’ and 3’ RACE analysis. We demonstrate that zebrafish BRAM1 associates with C-terminal region of zebrafish BMP receptor through MYND domain in vitro and in vivo. Interaction between zebrafish BRAM1 and zebrafish BMP receptor blocked BMP signaling pathway. In zebrafish, bram1 is a maternal factor and its expression profile is coordinated with bmp4 and bmp receptor in early developmental stage. bram1 was expressed throughout the embryos before blastula stage as examined by whole mount in-situ hybridization analysis, and was expressed ubiquitously in different tissues such as brain, heart, muscle, ovary, and especially ovary as examined by northern blot assay. Using antisense morpholinos to knock down BRAM1 resulted in defects in heart looping and curly tails. This phenotype of bram1 morphants was similar to phenotype of mutants involved in Bmp signaling. Injection of constitutively active bmp receptor mRNA resulted in defects in heart looping. Overexpression of BRAM1 reversed the heart position from no looping (N-looping) to rightward looping (D-looping). Further analysis of zebrafish left-right asymmetry genes incluidng cyclops, southpaw, lefty1, lefty2, and pitx2c demonstrate that BRAM1 affects the zebrafish left-right asymmetry. As zebarfish midline is critical for development of left-right asymmetry, we hypothesize that BRAM1 may have earlier effect in regulating midline. Indeed, we show that expression of flh and gsc in bram1 morphants is reduced. These findings indicate that BRAM1 may function as a negative regulator of Bmp signaling to participate in the midline development during early cell fate decision.
As Bmp signaling involves interaction of BMP and BMPR, and its downstream Smad mediators, BRAM1 may affect the BMP signaling by inhibiting Smad signaling. As tested in BALB/c3T3 and COS7 cells, mammalian BRAM1 (mBRAM1) inhibit Smad signalling pathway. mBRAM1 interacted with Bmp receptor type IA through MYND domain in the absence or presence of Bmp2 treatment. mBRAM1 interacted with Smads proteins, especially Smad4 and Smad5. Such interactions blocked the nuclear translocation of Smad4 or Smad5 in Bmp2-mediated manner. Thus, mBRAM1 inhibits Smad signaling through preventing Smad4 and Smad5 to translocate into nucleus.
In conclusion, these results suggest that BRAM1 may function as a negative regulator of BMP-mediated biological functions.
書名頁
中文摘要
英文摘要
目錄
Introduction...............................................9
I BMP signaling............................................9
I-1 BMP receptor associated protein 1 (BRAM1).............10
I-2 BMP...................................................12
I-3 BMP receptors.........................................12
I-4 BMP signaling pathways................................14
Smad signaling pathway....................................14
TAB1/TAK1/p38 MAP Kinase pathway..........................16
I-5 Negative regulations of BMP signaling pathway.........16
Inhibitory Smads (I-Smads.................................16
Receptor degradation......................................16
R-Smads degradation.......................................17
Growth factors............................................17
I-6 Significance of BMP signaling in developmental stages.17
II Zebrafish model system................................19
III Cardiac development in zebrafish.....................21
III-1 Left-right asymmetry................................22
III-2 The role of the midline barrier in L-R axis development...............................................24
Specific aims of thesis...................................26
Materials and methods.....................................27
Fish embryos..............................................27
Cell culture..............................................27
Preparation of total RNA..................................27
5'RACE and 3'RACE.........................................28
Morpholino and mRNA microinjections.......................29
Whole mount in situ hybridization.........................30
Northern blot.............................................31
Southern blot.............................................32
In vitro transcription/translation........................32
Purification of GST fusion proteins and GST pull-down assay.....................................................33
Western blot..............................................33
Knockdown assay...........................................34
Coimmunoprecipitation.....................................34
RT-PCR....................................................35
Real-time RT-PCR..........................................35
Luciferase reporter assay.................................36
Immunostaining............................................36
Yeast two-hybrid..........................................37
Results...................................................38
Part I Investigation of BRAM1 in zebrafish model
Isolation and characterization of zebrafish bram1 gene....38
Zebrafish BRAM1 interacts with zebrafish BMPR-IA in yeast.39
Zebrafish BRAM1 specifically interacts with zebrafish BMPR-IA in mammalian cells.....................................40
Zebrafish BRAM1 directly associates with zebrafish BMPR-IA........................................................41
Zebrafish BRAM1 represses the BMP signaling...............41
Temporal expression profiles of zebrafish bram1...........42
The expression pattern of zebrafish bram1.................43
Tissue distribution of zebrafish bram1....................43
Zebrafish bram1 was knocked down with antisense morpholinos in mammalian cells........................................44
Blockage of the endogenous BRAM1 results in defects of hearts and tails in zebrafish.............................44
Knockdown of BRAM1 interferes with the heart looping......45
Injections of bram1 MOs partially rescues the phenotype injecting active form BMP receptor........................46
Knockdown of BRAM1 leads to the randomization of heart jogging and heart looping.................................46
Expression of LR asymmetry genes is randomized in bram1 morphants.................................................48
BRAM1 is required for early midline development...........49
BRAM1 interferes with genes expression of midline mesoderm..................................................50
Part II Analysis of BRAM1-involved BMP signaling
mBRAM1 inhibits BMP signaling.............................50
mBRAM1 represses activity of active form BMP receptor type IA........................................................51
mBRAM1 supresses Smads signaling pathway..................51
mBRAM1 interacts with Smad4 and Smad5 and interacts with Smad1.....................................................52
Discussion................................................53
BRAM1 is a conserved protein among species................53
BRAM1 is involved in early embryonic development..........53
BRAM1 is a downstream molecule of Bmp signaling in zebrafish.................................................54
BRAM1 has a role in midline development...................55
BRAM1 functions before gastrulation stage.................56
BRAM1 inhibits BMP signaling by blocking Smads translocation.............................................56
BRAM1 may play a role in TAB1/TAK1/p38 MAP Kinase pathway.58
References................................................59
Tables....................................................71
Figures...................................................74
Appendix.................................................109
論文本文
參考文獻
Abdollah, S., Macias-Silva, M., Tsukazaki, T., Hayashi, H., Attisano, L., and Wrana, J. L. (1997). TbetaRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling. J Biol Chem 272, 27678-85.
Attisano, L., and Wrana, J. L. (2002). Signal transduction by the TGF-beta superfamily. Science 296, 1646-7.
Bisgrove, B. W., Essner, J. J., and Yost, H. J. (2000). Multiple pathways in the midline regulate concordant brain, heart and gut left-right asymmetry. Development 127, 3567-79.
Burdine, R. D., and Schier, A. F. (2000). Conserved and divergent mechanisms in left-right axis formation. Genes Dev 14, 763-76.
Cai, Y., Maeda, Y., Cedzich, A., Torres, V. E., Wu, G., Hayashi, T., Mochizuki, T., Park, J. H., Witzgall, R., and Somlo, S. (1999). Identification and characterization of polycystin-2, the PKD2 gene product. J Biol Chem 274, 28557-65.
Calonge, M. J., and Massague, J. (1999). Smad4/DPC4 silencing and hyperactive Ras jointly disrupt transforming growth factor-beta antiproliferative responses in colon cancer cells. J Biol Chem 274, 33637-43.
Capdevila, J., Vogan, K. J., Tabin, C. J., and Izpisua Belmonte, J. C. (2000). Mechanisms of left-right determination in vertebrates. Cell 101, 9-21.
Chen, J. N., van Eeden, F. J., Warren, K. S., Chin, A., Nusslein-Volhard, C., Haffter, P., and Fishman, M. C. (1997). Left-right pattern of cardiac BMP4 may drive asymmetry of the heart in zebrafish. Development 124, 4373-82.
Chin, A. J., Tsang, M., and Weinberg, E. S. (2000). Heart and gut chiralities are controlled independently from initial heart position in the developing zebrafish. Dev Biol 227, 403-21.
Chung, P. J., Chang, Y. S., Liang, C. L., and Meng, C. L. (2002). Negative regulation of Epstein-Barr virus latent membrane protein 1-mediated functions by the bone morphogenetic protein receptor IA-binding protein, BRAM1. J Biol Chem 277, 39850-7.
Clarke, T. R., Hoshiya, Y., Yi, S. E., Liu, X., Lyons, K. M., and Donahoe, P. K. (2001). Mullerian inhibiting substance signaling uses a bone morphogenetic protein (BMP)-like pathway mediated by ALK2 and induces SMAD6 expression. Mol Endocrinol 15, 946-59.
Danos, M. C., and Yost, H. J. (1995). Linkage of cardiac left-right asymmetry and dorsal-anterior development in Xenopus. Development 121, 1467-74.
Dennler, S., Huet, S., and Gauthier, J. M. (1999). A short amino-acid sequence in MH1 domain is responsible for functional differences between Smad2 and Smad3. Oncogene 18, 1643-8.
Dennler, S., Itoh, S., Vivien, D., ten Dijke, P., Huet, S., and Gauthier, J. M. (1998). Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. Embo J 17, 3091-100.
Derynck, R., Zhang, Y., and Feng, X. H. (1998). Smads: transcriptional activators of TGF-beta responses. Cell 95, 737-40.
Dick, A., Hild, M., Bauer, H., Imai, Y., Maifeld, H., Schier, A. F., Talbot, W. S., Bouwmeester, T., and Hammerschmidt, M. (2000). Essential role of Bmp7 (snailhouse) and its prodomain in dorsoventral patterning of the zebrafish embryo. Development 127, 343-54.
Dick, A., Meier, A., and Hammerschmidt, M. (1999). Smad1 and Smad5 have distinct roles during dorsoventral patterning of the zebrafish embryo. Dev Dyn 216, 285-98.
Dosch, R., Gawantka, V., Delius, H., Blumenstock, C., and Niehrs, C. (1997). Bmp-4 acts as a morphogen in dorsoventral mesoderm patterning in Xenopus. Development 124, 2325-34.
Ebisawa, T., Fukuchi, M., Murakami, G., Chiba, T., Tanaka, K., Imamura, T., and Miyazono, K. (2001). Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem 276, 12477-80.
Ebisawa, T., Tada, K., Kitajima, I., Tojo, K., Sampath, T. K., Kawabata, M., Miyazono, K., and Imamura, T. (1999). Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation. J Cell Sci 112 ( Pt 20), 3519-27.
Eimon, P. M., and Harland, R. M. (1999). In Xenopus embryos, BMP heterodimers are not required for mesoderm induction, but BMP activity is necessary for dorsal/ventral patterning. Dev Biol 216, 29-40.
Eisenberg, L. M., and Markwald, R. R. (1995). Molecular regulation of atrioventricular valvuloseptal morphogenesis. Circ Res 77, 1-6.
Essner, J. J., Branford, W. W., Zhang, J., and Yost, H. J. (2000). Mesendoderm and left-right brain, heart and gut development are differentially regulated by pitx2 isoforms. Development 127, 1081-93.
Estevez, M., Attisano, L., Wrana, J. L., Albert, P. S., Massague, J., and Riddle, D. L. (1993). The daf-4 gene encodes a bone morphogenetic protein receptor controlling C. elegans dauer larva development. Nature 365, 644-9.
Fisher, S., Amacher, S. L., and Halpern, M. E. (1997). Loss of cerebum function ventralizes the zebrafish embryo. Development 124, 1301-11.
Franco, D., Lamers, W. H., and Moorman, A. F. (1998). Patterns of expression in the developing myocardium: towards a morphologically integrated transcriptional model. Cardiovasc Res 38, 25-53.
Georgi, L. L., Albert, P. S., and Riddle, D. L. (1990). daf-1, a C. elegans gene controlling dauer larva development, encodes a novel receptor protein kinase. Cell 61, 635-45.
Gilboa, L., Nohe, A., Geissendorfer, T., Sebald, W., Henis, Y. I., and Knaus, P. (2000). Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. Mol Biol Cell 11, 1023-35.
Gouedard, L., Chen, Y. G., Thevenet, L., Racine, C., Borie, S., Lamarre, I., Josso, N., Massague, J., and di Clemente, N. (2000). Engagement of bone morphogenetic protein type IB receptor and Smad1 signaling by anti-Mullerian hormone and its type II receptor. J Biol Chem 275, 27973-8.
Graf, D., Nethisinghe, S., Palmer, D. B., Fisher, A. G., and Merkenschlager, M. (2002). The developmentally regulated expression of Twisted gastrulation reveals a role for bone morphogenetic proteins in the control of T cell development. J Exp Med 196, 163-71.
Green, J. (2002). Morphogen gradients, positional information, and Xenopus: interplay of theory and experiment. Dev Dyn 225, 392-408.
Groppe, J., Greenwald, J., Wiater, E., Rodriguez-Leon, J., Economides, A. N., Kwiatkowski, W., Affolter, M., Vale, W. W., Belmonte, J. C., and Choe, S. (2002). Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420, 636-42.
Gurdon, J. B., and Bourillot, P. Y. (2001). Morphogen gradient interpretation. Nature 413, 797-803.
Hager-Theodorides, A. L., Outram, S. V., Shah, D. K., Sacedon, R., Shrimpton, R. E., Vicente, A., Varas, A., and Crompton, T. (2002). Bone morphogenetic protein 2/4 signaling regulates early thymocyte differentiation. J Immunol 169, 5496-504.
Halpern, M. E., Hatta, K., Amacher, S. L., Talbot, W. S., Yan, Y. L., Thisse, B., Thisse, C., Postlethwait, J. H., and Kimmel, C. B. (1997). Genetic interaction in zebrafish midline development. Dev Biol 187, 154-70.
Hammerschmidt, M., Pelegri, F., Mullins, M. C., Kane, D. A., van Eeden, F. J., Granato, M., Brand, M., Furutani-Seiki, M., Haffter, P., Heisenberg, C. P., Jiang, Y. J., Kelsh, R. N., Odenthal, J., Warga, R. M., and Nusslein-Volhard, C. (1996a). dino and mercedes, two genes regulating dorsal development in the zebrafish embryo. Development 123, 95-102.
Hammerschmidt, M., Serbedzija, G. N., and McMahon, A. P. (1996b). Genetic analysis of dorsoventral pattern formation in the zebrafish: requirement of a BMP-like ventralizing activity and its dorsal repressor. Genes Dev 10, 2452-61.
Hanyu, A., Ishidou, Y., Ebisawa, T., Shimanuki, T., Imamura, T., and Miyazono, K. (2001). The N domain of Smad7 is essential for specific inhibition of transforming growth factor-beta signaling. J Cell Biol 155, 1017-27.
Harvey, R. P. (1998). Links in the left/right axial pathway. Cell 94, 273-6.
Hata, A., Lagna, G., Massague, J., and Hemmati-Brivanlou, A. (1998). Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev 12, 186-97.
Hata, A., Seoane, J., Lagna, G., Montalvo, E., Hemmati-Brivanlou, A., and Massague, J. (2000). OAZ uses distinct DNA- and protein-binding zinc fingers in separate BMP-Smad and Olf signaling pathways. Cell 100, 229-40.
Hateboer, G., Gennissen, A., Ramos, Y. F., Kerkhoven, R. M., Sonntag-Buck, V., Stunnenberg, H. G., and Bernards, R. (1995). BS69, a novel adenovirus E1A-associated protein that inhibits E1A transactivation. Embo J 14, 3159-69.
Hayashi, H., Abdollah, S., Qiu, Y., Cai, J., Xu, Y. Y., Grinnell, B. W., Richardson, M. A., Topper, J. N., Gimbrone, M. A., Jr., Wrana, J. L., and Falb, D. (1997). The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell 89, 1165-73.
Heldin, C. H., Miyazono, K., and ten Dijke, P. (1997). TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465-71.
Hild, M., Dick, A., Rauch, G. J., Meier, A., Bouwmeester, T., Haffter, P., and Hammerschmidt, M. (1999). The smad5 mutation somitabun blocks Bmp2b signaling during early dorsoventral patterning of the zebrafish embryo. Development 126, 2149-59.
Hogan, B. L. (1996). Bone morphogenetic proteins in development. Curr Opin Genet Dev 6, 432-8.
Hoodless, P. A., Haerry, T., Abdollah, S., Stapleton, M., O'Connor, M. B., Attisano, L., and Wrana, J. L. (1996). MADR1, a MAD-related protein that functions in BMP2 signaling pathways. Cell 85, 489-500.
Hu, N., Sedmera, D., Yost, H. J., and Clark, E. B. (2000). Structure and function of the developing zebrafish heart. Anat Rec 260, 148-57.
Hu, N., Yost, H. J., and Clark, E. B. (2001). Cardiac morphology and blood pressure in the adult zebrafish. Anat Rec 264, 1-12.
Hyatt, B. A., and Yost, H. J. (1998). The left-right coordinator: the role of Vg1 in organizing left-right axis formation. Cell 93, 37-46.
Imamura, T., Takase, M., Nishihara, A., Oeda, E., Hanai, J., Kawabata, M., and Miyazono, K. (1997). Smad6 inhibits signalling by the TGF-beta superfamily. Nature 389, 622-6.
Inoue, H., Imamura, T., Ishidou, Y., Takase, M., Udagawa, Y., Oka, Y., Tsuneizumi, K., Tabata, T., Miyazono, K., and Kawabata, M. (1998). Interplay of signal mediators of decapentaplegic (Dpp): molecular characterization of mothers against dpp, Medea, and daughters against dpp. Mol Biol Cell 9, 2145-56.
Inoue, T., and Thomas, J. H. (2000). Targets of TGF-beta signaling in Caenorhabditis elegans dauer formation. Dev Biol 217, 192-204.
Isaac, A., Sargent, M. G., and Cooke, J. (1997). Control of vertebrate left-right asymmetry by a snail-related zinc finger gene. Science 275, 1301-4.
Jamin, S. P., Arango, N. A., Mishina, Y., Hanks, M. C., and Behringer, R. R. (2002). Requirement of Bmpr1a for Mullerian duct regression during male sexual development. Nat Genet 32, 408-10.
Janknecht, R., Wells, N. J., and Hunter, T. (1998). TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300. Genes Dev 12, 2114-9.
Janowski, B. A., Willy, P. J., Devi, T. R., Falck, J. R., and Mangelsdorf, D. J. (1996). An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383, 728-31.
Jonk, L. J., Itoh, S., Heldin, C. H., ten Dijke, P., and Kruijer, W. (1998). Identification and functional characterization of a Smad binding element (SBE) in the JunB promoter that acts as a transforming growth factor-beta, activin, and bone morphogenetic protein-inducible enhancer. J Biol Chem 273, 21145-52.
Kavsak, P., Rasmussen, R. K., Causing, C. G., Bonni, S., Zhu, H., Thomsen, G. H., and Wrana, J. L. (2000). Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell 6, 1365-75.
Kimmel, C. B., Ballard, W. W., Kimmel, S. R., Ullmann, B., and Schilling, T. F. (1995). Stages of embryonic development of the zebrafish. Dev Dyn 203, 253-310.
Kimura, N., Matsuo, R., Shibuya, H., Nakashima, K., and Taga, T. (2000). BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem 275, 17647-52.
Kirsch, T., Sebald, W., and Dreyer, M. K. (2000). Crystal structure of the BMP-2-BRIA ectodomain complex. Nat Struct Biol 7, 492-6.
Kishimoto, Y., Lee, K. H., Zon, L., Hammerschmidt, M., and Schulte-Merker, S. (1997). The molecular nature of zebrafish swirl: BMP2 function is essential during early dorsoventral patterning. Development 124, 4457-66.
Koenig, B. B., Cook, J. S., Wolsing, D. H., Ting, J., Tiesman, J. P., Correa, P. E., Olson, C. A., Pecquet, A. L., Ventura, F., Grant, R. A., and et al. (1994). Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. Mol Cell Biol 14, 5961-74.
Koulen, P., Cai, Y., Geng, L., Maeda, Y., Nishimura, S., Witzgall, R., Ehrlich, B. E., and Somlo, S. (2002). Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol 4, 191-7.
Kretzschmar, M., Doody, J., and Massague, J. (1997a). Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature 389, 618-22.
Kretzschmar, M., Doody, J., Timokhina, I., and Massague, J. (1999). A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. Genes Dev 13, 804-16.
Kretzschmar, M., Liu, F., Hata, A., Doody, J., and Massague, J. (1997b). The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase. Genes Dev 11, 984-95.
Krishna, S., Maduzia, L. L., and Padgett, R. W. (1999). Specificity of TGFbeta signaling is conferred by distinct type I receptors and their associated SMAD proteins in Caenorhabditis elegans. Development 126, 251-60.
Kurozumi, K., Nishita, M., Yamaguchi, K., Fujita, T., Ueno, N., and Shibuya, H. (1998). BRAM1, a BMP receptor-associated molecule involved in BMP signalling. Genes Cells 3, 257-64.
Lagna, G., Hata, A., Hemmati-Brivanlou, A., and Massague, J. (1996). Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways. Nature 383, 832-6.
Lawrence, P. A. (2001). Morphogens: how big is the big picture? Nat Cell Biol 3, E151-4.
Levin, M., Johnson, R. L., Stern, C. D., Kuehn, M., and Tabin, C. (1995). A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell 82, 803-14.
Levin, M., and Mercola, M. (1998). Evolutionary conservation of mechanisms upstream of asymmetric Nodal expression: reconciling chick and Xenopus. Dev Genet 23, 185-93.
Lin, X., Liang, M., and Feng, X. H. (2000). Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. J Biol Chem 275, 36818-22.
Liu, F., Ventura, F., Doody, J., and Massague, J. (1995). Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs. Mol Cell Biol 15, 3479-86.
Lohr, J. L., Danos, M. C., Groth, T. W., and Yost, H. J. (1998). Maintenance of asymmetric nodal expression in Xenopus laevis. Dev Genet 23, 194-202.
Macias-Silva, M., Abdollah, S., Hoodless, P. A., Pirone, R., Attisano, L., and Wrana, J. L. (1996). MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling. Cell 87, 1215-24.
Macias-Silva, M., Hoodless, P. A., Tang, S. J., Buchwald, M., and Wrana, J. L. (1998). Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. J Biol Chem 273, 25628-36.
Massague, J. (1990). The transforming growth factor-beta family. Annu Rev Cell Biol 6, 597-641.
Massague, J. (1998). TGF-beta signal transduction. Annu Rev Biochem 67, 753-91.
Massague, J. (2000). How cells read TGF-beta signals. Nat Rev Mol Cell Biol 1, 169-78.
McDonald, V. L., Dick, K. O., Malik, N., and Shoyab, M. (1993). Selection and characterization of a variant of human melanoma cell line, A375 resistant to growth inhibitory effects of oncostatin M (OM): coresistant to interleukin 6 (IL-6). Growth Factors 9, 167-75.
Melloy, P. G., Ewart, J. L., Cohen, M. F., Desmond, M. E., Kuehn, M. R., and Lo, C. W. (1998). No turning, a mouse mutation causing left-right and axial patterning defects. Dev Biol 193, 77-89.
Morita, K., Shimizu, M., Shibuya, H., and Ueno, N. (2001). A DAF-1-binding protein BRA-1 is a negative regulator of DAF-7 TGF-beta signaling. Proc Natl Acad Sci U S A 98, 6284-8.
Mullins, M. C., Hammerschmidt, M., Kane, D. A., Odenthal, J., Brand, M., van Eeden, F. J., Furutani-Seiki, M., Granato, M., Haffter, P., Heisenberg, C. P., Jiang, Y. J., Kelsh, R. N., and Nusslein-Volhard, C. (1996). Genes establishing dorsoventral pattern formation in the zebrafish embryo: the ventral specifying genes. Development 123, 81-93.
Nakao, A., Afrakhte, M., Moren, A., Nakayama, T., Christian, J. L., Heuchel, R., Itoh, S., Kawabata, M., Heldin, N. E., Heldin, C. H., and ten Dijke, P. (1997a). Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature 389, 631-5.
Nakao, A., Imamura, T., Souchelnytskyi, S., Kawabata, M., Ishisaki, A., Oeda, E., Tamaki, K., Hanai, J., Heldin, C. H., Miyazono, K., and ten Dijke, P. (1997b). TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4. Embo J 16, 5353-62.
Nikaido, M., Tada, M., Saji, T., and Ueno, N. (1997). Conservation of BMP signalling in zebrafish mesoderm patterning. Mech Dev 61, 75-88.
Nguyen, V. H., Schmid, B., Trout, J., Connors, S. A., Ekker, M., and Mullins, M. C. (1998). Ventral and lateral regions of the zebrafish gastrula, including the neural crest progenitors, are established by a bmp2b/swirl pathway of genes. Dev Biol 199, 93-110.
Nohe, A., Hassel, S., Ehrlich, M., Neubauer, F., Sebald, W., Henis, Y. I., and Knaus, P. (2002). The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem 277, 5330-8.
Nonaka, S., Tanaka, Y., Okada, Y., Takeda, S., Harada, A., Kanai, Y., Kido, M., and Hirokawa, N. (1998). Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95, 829-37.
Onichtchouk, D., Chen, Y. G., Dosch, R., Gawantka, V., Delius, H., Massague, J., and Niehrs, C. (1999). Silencing of TGF-beta signalling by the pseudoreceptor BAMBI. Nature 401, 480-5.
Pagan-Westphal, S. M., and Tabin, C. J. (1998). The transfer of left-right positional information during chick embryogenesis. Cell 93, 25-35.
Payne, T. L., Postlethwait, J. H., and Yelick, P. C. (2001). Functional characterization and genetic mapping of alk8. Mech Dev 100, 275-89.
Pennekamp, P., Karcher, C., Fischer, A., Schweickert, A., Skryabin, B., Horst, J., Blum, M., and Dworniczak, B. (2002). The ion channel polycystin-2 is required for left-right axis determination in mice. Curr Biol 12, 938-43.
Ramsdell, A. F., and Yost, H. J. (1998). Molecular mechanisms of vertebrate left-right development. Trends Genet 14, 459-65.
Reddi, H. (1995). Bone morphogenetic proteins. Adv Dent Res 9, 13.
Ren, P., Lim, C. S., Johnsen, R., Albert, P. S., Pilgrim, D., and Riddle, D. L. (1996). Control of C. elegans larval development by neuronal expression of a TGF-beta homolog. Science 274, 1389-91.
Rodriguez Esteban, C., Capdevila, J., Economides, A. N., Pascual, J., Ortiz, A., and Izpisua Belmonte, J. C. (1999). The novel Cer-like protein Caronte mediates the establishment of embryonic left-right asymmetry. Nature 401, 243-51.
Rosenzweig, B. L., Imamura, T., Okadome, T., Cox, G. N., Yamashita, H., ten Dijke, P., Heldin, C. H., and Miyazono, K. (1995). Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci U S A 92, 7632-6.
Sasai, Y. (1998). Identifying the missing links: genes that connect neural induction and primary neurogenesis in vertebrate embryos. Neuron 21, 455-8.
Scheufler, C., Sebald, W., and Hulsmeyer, M. (1999). Crystal structure of human bone morphogenetic protein-2 at 2.7 A resolution. J Mol Biol 287, 103-15.
Schier, A. F., and Talbot, W. S. (1998). The zebrafish organizer. Curr Opin Genet Dev 8, 464-71.
Schmid, B., Furthauer, M., Connors, S. A., Trout, J., Thisse, B., Thisse, C., and Mullins, M. C. (2000). Equivalent genetic roles for bmp7/snailhouse and bmp2b/swirl in dorsoventral pattern formation. Development 127, 957-67.
Schroepfer, G. J., Jr. (2000). Oxysterols: modulators of cholesterol metabolism and other processes. Physiol Rev 80, 361-554.
Schulte-Merker, S., Lee, K. J., McMahon, A. P., and Hammerschmidt, M. (1997). The zebrafish organizer requires chordino. Nature 387, 862-3.
Schweickert, A., Campione, M., Steinbeisser, H., and Blum, M. (2000). Pitx2 isoforms: involvement of Pitx2c but not Pitx2a or Pitx2b in vertebrate left-right asymmetry. Mech Dev 90, 41-51.
Shi, Y., Wang, Y. F., Jayaraman, L., Yang, H., Massague, J., and Pavletich, N. P. (1998). Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell 94, 585-94.
Shibuya, H., Iwata, H., Masuyama, N., Gotoh, Y., Yamaguchi, K., Irie, K., Matsumoto, K., Nishida, E., and Ueno, N. (1998). Role of TAK1 and TAB1 in BMP signaling in early Xenopus development. Embo J 17, 1019-28.
Shirakabe, K., Yamaguchi, K., Shibuya, H., Irie, K., Matsuda, S., Moriguchi, T., Gotoh, Y., Matsumoto, K., and Nishida, E. (1997). TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem 272, 8141-4.
Smith, W. C., and Harland, R. M. (1992). Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos. Cell 70, 829-40.
Solnica-Krezel, L., Stemple, D. L., Mountcastle-Shah, E., Rangini, Z., Neuhauss, S. C., Malicki, J., Schier, A. F., Stainier, D. Y., Zwartkruis, F., Abdelilah, S., and Driever, W. (1996). Mutations affecting cell fates and cellular rearrangements during gastrulation in zebrafish. Development 123, 67-80.
Souchelnytskyi, S., Nakayama, T., Nakao, A., Moren, A., Heldin, C. H., Christian, J. L., and ten Dijke, P. (1998). Physical and functional interaction of murine and Xenopus Smad7 with bone morphogenetic protein receptors and transforming growth factor-beta receptors. J Biol Chem 273, 25364-70.
Souchelnytskyi, S., Tamaki, K., Engstrom, U., Wernstedt, C., ten Dijke, P., and Heldin, C. H. (1997). Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling. J Biol Chem 272, 28107-15.
Stainier, D. Y., and Fishman, M. C. (1992). Patterning the zebrafish heart tube: acquisition of anteroposterior polarity. Dev Biol 153, 91-101.
Stainier, D. Y., Lee, R. K., and Fishman, M. C. (1993). Cardiovascular development in the zebrafish. I. Myocardial fate map and heart tube formation. Development 119, 31-40.
Sugawara, K., Morita, K., Ueno, N., and Shibuya, H. (2001). BIP, a BRAM-interacting protein involved in TGF-beta signalling, regulates body length in Caenorhabditis elegans. Genes Cells 6, 599-606.
Talbot, W. S., Trevarrow, B., Halpern, M. E., Melby, A. E., Farr, G., Postlethwait, J. H., Jowett, T., Kimmel, C. B., Kimelman, D. (1995). A homeobox gene essential for zebrafish notochord development. Nature 378, 150-7.
Takaesu, G., Kishida, S., Hiyama, A., Yamaguchi, K., Shibuya, H., Irie, K., Ninomiya-Tsuji, J., and Matsumoto, K. (2000). TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway. Mol Cell 5, 649-58.
ten Dijke, P., Yamashita, H., Ichijo, H., Franzen, P., Laiho, M., Miyazono, K., and Heldin, C. H. (1994a). Characterization of type I receptors for transforming growth factor-beta and activin. Science 264, 101-4.
ten Dijke, P., Yamashita, H., Sampath, T. K., Reddi, A. H., Estevez, M., Riddle, D. L., Ichijo, H., Heldin, C. H., and Miyazono, K. (1994b). Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem 269, 16985-8.
Thisse, C., Thisse, B., Halpern, M. E., Postlethwait, J. H. (1994). Goosecoid expression in neurectoderm and mesendoderm is disrupted in zebrafish cyclops gastrulas. Dev Biol 164, 420-9.
Visser, J. A., Olaso, R., Verhoef-Post, M., Kramer, P., Themmen, A. P., and Ingraham, H. A. (2001). The serine/threonine transmembrane receptor ALK2 mediates Mullerian inhibiting substance signaling. Mol Endocrinol 15, 936-45.
Waite, K. A., and Eng, C. (2003). From developmental disorder to heritable cancer: it's all in the BMP/TGF-beta family. Nat Rev Genet 4, 763-73.
Warga, R. M., and Kimmel, C. B. (1990). Cell movements during epiboly and gastrulation in zebrafish. Development 108, 569-80.
Warga, R. M., and Nusslein-Volhard, C. (1999). Origin and development of the zebrafish endoderm. Development 126, 827-38.
Weinberg, E. S., Allende, M. L., Kelly, C. S., Abdelhamid, A., Murakami, T., Andermann, P., Doerre, O. G., Grunwald, D. J., and Riggleman, B. (1996). Developmental regulation of zebrafish MyoD in wild-type, no tail and spadetail embryos. Development 122, 271-80.
Wilson, P. A., Lagna, G., Suzuki, A., and Hemmati-Brivanlou, A. (1997). Concentration-dependent patterning of the Xenopus ectoderm by BMP4 and its signal transducer Smad1. Development 124, 3177-84.
Wolpert, L. (1996). One hundred years of positional information. Trends Genet 12, 359-64.
Wozney, J. M. (2002). Overview of bone morphogenetic proteins. Spine 27, S2-8.
Wozney, J. M., Rosen, V., Byrne, M., Celeste, A. J., Moutsatsos, I., and Wang, E. A. (1990). Growth factors influencing bone development. J Cell Sci Suppl 13, 149-56.
Wrana, J. L., Attisano, L., Wieser, R., Ventura, F., and Massague, J. (1994). Mechanism of activation of the TGF-beta receptor. Nature 370, 341-7.
Wu, R. Y., Zhang, Y., Feng, X. H., and Derynck, R. (1997). Heteromeric and homomeric interactions correlate with signaling activity and functional cooperativity of Smad3 and Smad4/DPC4. Mol Cell Biol 17, 2521-8.
Yagi, K., Goto, D., Hamamoto, T., Takenoshita, S., Kato, M., and Miyazono, K. (1999). Alternatively spliced variant of Smad2 lacking exon 3. Comparison with wild-type Smad2 and Smad3. J Biol Chem 274, 703-9.
Yamaguchi, K., Nagai, S., Ninomiya-T suji, J., Nishita, M., Tamai, K., Irie, K., Ueno, N., Nishida, E., Shibuya, H., Matsumoto, K. (1999). XIAP, a cellular member of the inhibitor of apoptosis protein family, link the receptors to TAB1-TAK1 in the BMP signaling pathway. EMBO J. 18, 179-87.
Yamaguchi, K., Shirakabe, K., Shibuya, H., Irie, K., Oishi, I., Ueno, N., Taniguchi, T., Nishida, E., and Matsumoto, K. (1995). Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science 270, 2008-11.
Yamashita, H., ten Dijke, P., Huylebroeck, D., Sampath, T. K., Andries, M., Smith, J. C., Heldin, C. H., and Miyazono, K. (1995). Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects. J Cell Biol 130, 217-26.
Yelon, D., Horne, S. A., and Stainier, D. Y. (1999). Restricted expression of cardiac myosin genes reveals regulated aspects of heart tube assembly in zebrafish. Dev Biol 214, 23-37.
Ying, Y., Liu, X. M., Marble, A., Lawson, K. A., and Zhao, G. Q. (2000). Requirement of Bmp8b for the generation of primordial germ cells in the mouse. Mol Endocrinol 14, 1053-63.
Yingling, J. M., Datto, M. B., Wong, C., Frederick, J. P., Liberati, N. T., and Wang, X. F. (1997). Tumor suppressor Smad4 is a transforming growth factor beta-inducible DNA binding protein. Mol Cell Biol 17, 7019-28.
Yokouchi, Y., Vogan, K. J., Pearse, R. V., 2nd, and Tabin, C. J. (1999). Antagonistic signaling by Caronte, a novel Cerberus-related gene, establishes left-right asymmetric gene expression. Cell 98, 573-83.
Yost, H. J. (1999). Diverse initiation in a conserved left-right pathway? Curr Opin Genet Dev 9, 422-6.
Zawel, L., Dai, J. L., Buckhaults, P., Zhou, S., Kinzler, K. W., Vogelstein, B., and Kern, S. E. (1998). Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1, 611-7.
Zhang, Y., Chang, C., Gehling, D. J., Hemmati-Brivanlou, A., and Derynck, R. (2001). Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci U S A 98, 974-9.
Zhang, Y., and Derynck, R. (1999). Regulation of Smad signalling by protein associations and signalling crosstalk. Trends Cell Biol 9, 274-9.
Zhang, Y., Feng, X., We, R., and Derynck, R. (1996). Receptor-associated Mad homologues synergize as effectors of the TGF-beta response. Nature 383, 168-72.
Zhao, G. Q. (2003). Consequences of knocking out BMP signaling in the mouse. Genesis 35, 43-56.
Zhu, H., Kavsak, P., Abdollah, S., Wrana, J. L., and Thomsen, G. H. (1999a). A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature 400, 687-93.
Zhu, L., Marvin, M. J., Gardiner, A., Lassar, A. B., Mercola, M., Stern, C. D., and Levin, M. (1999b). Cerberus regulates left-right asymmetry of the embryonic head and heart. Curr Biol 9, 931-8.
Zimmerman, L. B., De Jesus-Escobar, J. M., and Harland, R. M. (1996). The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 86, 599-606.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
系統版面圖檔 系統版面圖檔