Fused小鼠自然突变体Axin~（Fu-NT）影响野生型Axin功能的分子机理
摘要
Axin是一个多结构域的构架蛋白，它能通过与不同蛋白的相互作用调节不同的信号通路，其中包括Axin能通过促进β-catenin的降解下调Wnt信号；同源二聚化的Axin能通过MEKK1或MEKK4激活JNK磷酸化；Axin也能通过HIPK2激活p53第46位丝氨酸的磷酸化；最近的研究发现Axin还能通过Arkadia增加Smad7的降解增强TGF-β信号等。Axin通过对不同信号的调节参与调控生物个体发育、抑制肿瘤发生、参与细胞骨架重排等过程。鼠源Axin是由鼠的Fused(Fu)基因编码；Axin~(Fu)等位基因是由转座子IAP的插入产生的。Axin~(Fu/Fu)小鼠会出现胚胎致死、神经管分叉和不同程度尾巴卷曲等各种表型。目前的研究在Axin~(Fu)小鼠体内检测到了截短的Axin mRNA，但并没有相关突变蛋白的报道。Axin~(Fu)小鼠体内是不是真实存在Axin的突变蛋白，Axin~(Fu)小鼠的的表型是不是由于Axin突变的蛋白的存在引起的，如果是，又是通过怎样的途径引起的，这些问题目前还不清楚。本论文通过生物化学和分子生物学的方法，系统地阐明了Axin突变蛋白的存在及其在生物体内的重要功能。本论文首先用免疫沉淀的方法证明Axin~(Fu)小鼠体内确实存在Axin截短的突变体。该突变体只包含Axin第1-596个氨基酸，将其命名为Axin~(Fu-NT)。实验的研究发现Axin~(Fu-NT)能够像野生型Axin一样下调LEF-1和TOPFLASH的转录活性；与Wnt信号的主要调节因子的免疫共沉淀实验显示，Axin~(Fu-NT)能有效形成β-catenin的降解复合体；通过Axin和Axin~(Fu-NT)mRNA的斑马鱼胚胎注射实验也观察到β-catenin的靶向基因boz和tbx6都受到了类似程度的下调。这些说明Axin~(Fu-NT)对Wnt信号的调节与Axin没有明显的差异。本论文在研究过程中还发现Axin~(Fu-NT)不但不能激活JNK(这可能与Axin~(Fu-NT)缺失了Axin的C端有关)，还能强烈抑制Axin激活JNK。进一步的研究发现Axin~(Fu-NT)存在形成同源二聚化的结构域，Axin~(Fu-NT)通过该结构域能破坏Axin形成同源二聚体，从而起到抑制Axin激活JNK的作用；而且Axin~(Fu-NT)能竞争Axin与MEKK1或MEKK4结合，这可能是Axin~(Fu-NT)抑制Axin激活JNK的另一分子机制。在斑马鱼体内检测Axin~(Fu-NT)的生物学功能的实验也证明了Axin~(Fu-NT)能抑制β-catenin和JNK信号，从而获得了腹部化的表型。本论文还检测了Axin~(Fu-NT)对p53磷酸化的影响。实验的研究发现Axin~(Fu-NT)不影响p53-luc的转录活性但能强烈抑制Axin增强的p53-luc的转录活性；p53磷酸化的实验也证明了Axin~(Fu-NT)不能增强p53第46位丝氨酸的磷酸化(这可能与Axin~(Fu-NT)缺失了HIPK2的结合域有关)但能强烈抑制Axin促进p53第46位丝氨酸的磷酸化。Axin~(Fu-NT)缺失p53结合区域的突变体Axin~(Fu-NT)ΔMID不干扰Axin促进p53第46位丝氨酸的磷酸化作用。因此，Axin~(Fu-NT)不能与HIPK2相互作用但能竞争Axin与p53结合可能是Axin~(Fu-NT)抑制Axin促进p53第46位丝氨酸的磷酸化作用的分子机制。与此相一致的是，Axin~(Fu-NT)能抑制Axin通过促进p53磷酸化引起的细胞凋亡。总之，Axin~(Fu-NT)影响了Axin在多条信号通路中的重要调节作用，Axin~(Fu)小鼠的表型可能是Axin对多条信号通路调节受到影响的共同作用结果。
Axin is a multidomian scaffold protein, regulating many signaling pathwaysthrough interacting with different regulators. Axin can promote degradation ofβ-catenin to down-regualte Wnt signaling; homodimeric Axin can induce JNKactivation through MEKK1 or MEKK4; Axin can also up-regulate HIPK2-mediatedphosphorylation of p53 at Ser46. Through regulating multiple signaling pathways,Axin plays important roles in development, suppression of tumorgenesis, cytoskeletonrearrangement and so on. Axin was originally identified from the characterization ofthe mouse Fused (Fu) locus; the Axin~(Fu) allele is caused by the insertion of an IAPtransposon. Axin~(Fu/Fu) mice display varying phenotypes ranging from embryoniclethality to relatively normal adulthood with kinky tails. Aberrant mRNA species ofAxin from Axin~(Fu) mouse was previously identified; however, the mutant proteinproduct(s) had not been characterized. In particular, it was unclear how thephenotypes of Axin~(Fu) mouse are caused by the mutant protein products. In this thesis,the Axin mutant protein was identified by immunoprecipitation using brain extractsfrom Axin~(Fu) mice with specific antibodies. The mutant protein is a truncated Axincontaining amino acids 1-596, which is designated as Axin~(Fu-NT). When tested forfunction, Axin~(Fu-NT) exhibits no difference in the inhibition of Wnt signaling comparedwith wild type Axin as determined by LEF or TOPFLASH reporter gene assay,interaction with key Wnt regulators or detection ofβ-catenin target genes inzebrafish embryos. However, Axin~(Fu-NT) was found to abolish Axin-mediatedactivation of JNK, which plays a critical role in dorsoventral patterning. Together withGST pull-down assay, it was found that Axin~(Fu-NT) contains a previouslyuncharacterized dimerization domain and can form a heterodimeric interaction withwildtype Axin; it was also found that Axin~(Fu-NT) can compete with Axin in binding toMEKK1 or MEKK4. Consistently, Axin~(Fu-NT) can ventralize zebrafish embryos byantagonizing JNK activation. In the same study, it was found that Axin~(Fu-NT), whichcan interact with p53 but not HIPK2, can inhibit Axin-induced phoshorylation of p53at Ser46, but Axin~(Fu-NT)△MID, which was deleted of its p53 binding domain, has no effect on Axin-induced phoshorylation of p53 Ser46. It's suggested that Axin ~(Fu-NT) canattenuate p53 activation by sequestering p53. Consistently, Axin~(Fu-NT) can abolishAxin-mediated cell apoptosis. In summary, Axin~(Fu-NT) can dominant negatively affectthe function of Axin in many signaling pathways, and the phenotypes of Axin~(Fu) micemay be caused by perturbation of more than one signaling pathway.
Axin is a multidomian scaffold protein, regulating many signaling pathwaysthrough interacting with different regulators. Axin can promote degradation ofβ-catenin to down-regualte Wnt signaling; homodimeric Axin can induce JNKactivation through MEKK1 or MEKK4; Axin can also up-regulate HIPK2-mediatedphosphorylation of p53 at Ser46. Through regulating multiple signaling pathways,Axin plays important roles in development, suppression of tumorgenesis, cytoskeletonrearrangement and so on. Axin was originally identified from the characterization ofthe mouse Fused (Fu) locus; the Axin~(Fu) allele is caused by the insertion of an IAPtransposon. Axin~(Fu/Fu) mice display varying phenotypes ranging from embryoniclethality to relatively normal adulthood with kinky tails. Aberrant mRNA species ofAxin from Axin~(Fu) mouse was previously identified; however, the mutant proteinproduct(s) had not been characterized. In particular, it was unclear how thephenotypes of Axin~(Fu) mouse are caused by the mutant protein products. In this thesis,the Axin mutant protein was identified by immunoprecipitation using brain extractsfrom Axin~(Fu) mice with specific antibodies. The mutant protein is a truncated Axincontaining amino acids 1-596, which is designated as Axin~(Fu-NT). When tested forfunction, Axin~(Fu-NT) exhibits no difference in the inhibition of Wnt signaling comparedwith wild type Axin as determined by LEF or TOPFLASH reporter gene assay,interaction with key Wnt regulators or detection ofβ-catenin target genes inzebrafish embryos. However, Axin~(Fu-NT) was found to abolish Axin-mediatedactivation of JNK, which plays a critical role in dorsoventral patterning. Together withGST pull-down assay, it was found that Axin~(Fu-NT) contains a previouslyuncharacterized dimerization domain and can form a heterodimeric interaction withwildtype Axin; it was also found that Axin~(Fu-NT) can compete with Axin in binding toMEKK1 or MEKK4. Consistently, Axin~(Fu-NT) can ventralize zebrafish embryos byantagonizing JNK activation. In the same study, it was found that Axin~(Fu-NT), whichcan interact with p53 but not HIPK2, can inhibit Axin-induced phoshorylation of p53at Ser46, but Axin~(Fu-NT)△MID, which was deleted of its p53 binding domain, has no effect on Axin-induced phoshorylation of p53 Ser46. It's suggested that Axin ~(Fu-NT) canattenuate p53 activation by sequestering p53. Consistently, Axin~(Fu-NT) can abolishAxin-mediated cell apoptosis. In summary, Axin~(Fu-NT) can dominant negatively affectthe function of Axin in many signaling pathways, and the phenotypes of Axin~(Fu) micemay be caused by perturbation of more than one signaling pathway.
引文
[27] Stoothoff W H, Bailey C D, Mi K, et al. Axin negatively affects tau phosphorylation by glycogen synthase kinase 3beta [J]. J Neurochem, 2002, 83: 904-913.
[28] Gumbiner B M: Signal transduction of betacatenin [J]. Curr Opin Cell Biol, 1995, 7: 634-640.
[29] Willert K, Shibamoto S, Nusse R. Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex [J]. Genes Dev, 1999, 13: 1768-1773.
[30] Cong F, Varmus H. Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of beta-catenin [J]. Proc Natl Acad Sci USA, 2004, 101: 2882-2887.
[31] Wiechens N, Heinle K, Englmeier L, et al. Nucleo-cytoplasmic shuttling of Axin, a negative regulator of the Wnt-beta-catenin pathway [J]. J Biol Chem, 2004, 279: 5263-5267.
[32] Yamamoto H, Kishida S, Kishida M, et al. Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3β regulates its stability [J]. J Biol Chem, 1999, 274: 10681-10684.
[33] Cliffe A, Hamada F, Bienz M. A role of Dishevelled in relocating Axin to the plasma membrane during wingless signaling [J]. Curr Biol, 2003, 13: 960-966.
[34] Choi J, Park S Y, Costantini F, et al. Adenomatous polyposis coliis down-ergulated by the ubiquitin-proteasome pathway in a process facilitated by Axin [J]. J Biol Chem, 2004, 279: 49188-49198.
[35] Behrens J, Jerchow B A, Wurtele M, et al. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta [J]. Science, 1998, 280: 596-599.
[36] Nakamura Y, Nishisho I, Kinzler K W, et al. Mutations of the APC (adenomatous polyposis coli) gene in FAP (familial polyposis coli) patients and in sporadic colorectal tumors [J]. Tohoku J Exp Med, 1992, 168: 141-147.
[37] Rubinfeld B, Albert I, Porfiri E, et al. Loss of beta-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene [J]. Cancer Res, 1997, 57: 4624-4630.
[38] Rosin-Arbesfeld R, Cliffe A, Brabletz T, et al. Nuclear export of the APC tumor suppressor controls beta-catenin function in transcription [J]. EMBO J, 2003, 22: 1101-1113.
[39] Henderson B R, Fagotto F: The ins and outs of APC and beta-catenin nuclear transport [J]. EMBO Rep, 2002, 3: 834-839.
[40] Ahmed Y, Hayashi S, Levine A, Wieschaus E: Regulation of armadillo by a Drosophila APC inhibits neuronal apoptosis during retinal development [J]. Cell, 1998, 93:1171-1182.
[41] Hinoi T, Yamamoto H, Kishida M, et al. Complex formation of adenomatous polyposis coli gene product and axin facilitates glycogen synthase kinase-3beta dependent phosphorylation of beta-catenin and down-regulates beta-catenin [J]. J Biol Chem, 2000, 275: 34399-34406.
[42] Rubinfeld B, Robbins P, El-Gamil M, et al. Stabilization of beta-catenin by genetic defects in melanoma cell lines [J]. Science, 1997, 275: 1790-1792.
[43] Kawahara K, Morishita T, Nakamura T, et al. Down-regulation of beta-catenin by the colorectal tumor suppressor APC requires association with Axin and beta-catenin [J]. J Biol Chem, 2000, 275: 8369-8374.
[44] Nakamura T, Hamada F, Ishidate T, et al. Axin, an inhibitor of the Wnt signaling pathway, interacts with β-catenin, GSK-3β and APC and reduces the β-catenin leve [J]l. Genes Cells, 1998, 3: 395-403.
[45] Itoh K, Antipova A, Ratcliffe M J, et al. Interaction of dishevelled and xenopus axin2 related protein is required for wnt signal transduction [J]. Mol Cell Biol, 2000, 20: 2228-2238.
[46] Ding Y, Dale T: Wnt signal transduction: Kinase cogs in a nano-machine [J]? Trends Biochem Sci, 2002, 27: 327-329.
[47] Gumbiner B M, McCrea P D. Catenins as mediators of the cytoplasmic functions of cadherins [J]. J Cell Sci Suppl, 1993, 7:155-158.
[48] Schneider S, Herrenknecht K, Butz S, et al. Catenins in Xenopus embryogenesis and their relation to the cadherin-mediated cell-cell adhesion system [J]. Development, .1993, 118:629-640.
[49] Peifer M, Orsulic S, Pai L M, et al. A model system for cell adhesion and signal transduction in Drosophila [J]. Dev Suppl, 1993, 163-176.
[50] Papkoff J, Rubinfeld B, Schryver B, et al. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes [J]. Mol Cell Biol, 1996, 16:2128-2134.
[51] Peifer M, Sweeton D, Casey M, et al.Wingless signal and Zeste-white 3 kinase trigger opposing changes in the intracellular distribution of Armadillo [J]. Development, 1994, 120:369-380.
[52] Liu C, Li Y, Semenov M, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism [J]. Cell, 2002, 108: 837-847.
[53] Aberle H A, Bauer A, Stappert J, et al. β-Catenin is a target for the ubiquitin-proteasome pathway [J]. EMBO J, 1997, 16:3797-3804.
[54] Liu J, Stevens J, Rote CA, et al. Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein [J]. Mol Cell, 2001, 7: 927-936.
[55] Matsuzawa S I, Reed J C. Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses [J]. Mol Cell, 2001, 7: 915-926.
[56] Levina E, Oren M, Ben-Ze'ev A. Downregulation of beta-catenin by p53 involves changes in the rate of beta-catenin phosphorylation and Axin dynamics [J]. Oncogene, 2004, 23: 4444-4453.
[57] Plyte S E, Hughes K, Nikolakaki E, et al. Glycogen synthase kinase-3β functions in oncogenesis and development [J]. Biochim Biophys Acta, 1992, 1114: 147-162.
[58] Mandelkow E M, Drewes G, Biernat J, et al. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau [J]. FEBS Lett, 1992, 314: 315-321.
[59] Dajani R, Fraser E, Roe S M, et al. Structural basis for recruitment of glycogen synthase kinase 3β to the axin-APC scaffold complex [J]. EMBO J, 2003, 22: 494-501.
[60] Fujimuro M, Wu F Y, ApRhys C, et al. Anovel viral mechanism for dysregulation of β-catenin in Kaposi's sarcoma- associated herpesvirus latency. Nat Med, 2003, 9: 300-J306.
[61] Yamamoto K, Ichijo H, Korsmeyer S J. BCL-2 is phosphorylated and inactivated by an ASKl/Jun N-terminal protein kinase pathway normally activated at G(2)/M [J]. Mol Cell Biol, 1999, 19: 8469-8478.
[62] Janssens V, Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signaling. Biochem J, 2001, 353: 417-439.
[63] Seeling J M, Miller J R, Gil R, et al. Regulation of β-catenin signaling by the B56 subunit of protein phosphatase 2 A. Science, 1999, 283: 2089-2091.
[64] Hsu W, Zeng L, Costantini F. Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a selfbinding domain [J]. J Biol Chem, 1999, 274: 3439-3445.
[65] Ikeda S, Kishida M, Matsuura Y, et al. GSK-3β-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by beta-catenin and protein phosphatase 2A complexed with axin [J]. Oncogene, 2000,19: 537-45.
[66] Ratcliffe M J, Itoh K, Sokol S Y. A positive role for the PP2A catalytic subunit in Wnt signal transduction [J]. J Biol Chem, 2000, 275: 35680-35683.
[67] Rubinfeld B, Souza B, Albert I, et al. Association of the APC gene product with beta-catenin [J]. Science, 1993,262:1731-1734.
[68] Burnett G, Kennedy E P. The enzymatic phosphorylation of proteins [J]. J Biol Chem, 1954, 211:969-980.
[69] Pinna L A, Clani G, Moret V. Isolation and enzymatic phosphorylation of rat liver cytosol phosphoproteins [J]. FEBS Lett, 1969, 5: 77-80.
[70] Gorss S D, Anderson R A. Casein kinase Ⅰ: spatial organization and positioning of a multifunctional protein kinase family [J]. Cell Signal, 1998, 10: 699-711.
[71] Tuazon P T, Traugh J A. Casein kinase Ⅰ and Ⅱ-multipotential serine protein kinase: structure, function, and regulation [J]. Adv Second Messenger phosphoprotein Res, 1991, 23: 123-164.
[72] Graves P R, Roach P J. Role of COOH-terminal phosphorylation in the regulation of casein kinase Iδ [J]. J Biol Chem, 1995, 270: 21689-21692.
[73] Knippschild U, Gocht A, Wolff S, et al. The casein kinase I family: Participation in multiple cellular processes in eukaryotes [J]. Cell Signal, 2005, 17: 675-689.
[74] McKay R M, Peters J M, Graf J M. The casein kinase Ⅰ# family in Wnt signaling [J]. Dev Biol, 2001,235:388-96.
[75] Hino S, Michiue T, Asashima M, et al. Casein kinase I epsilon enhances the binding of Dvl-1 to Frat-1 and is essential for Wnt-3a-induced accumulation of p-catenin [J]. J Biol Chem, 2003,278:14066-14073.
[76] Rubinfeld B, Tice DA, Polakis P. Axin-dependent phosphorylation of the adenomatous polyposis coli protein mediated by casein kinase Iε [J]. J Biol Chem, 2001, 276: 39037-39045.
[77] Lee E, Salic A, Kirschner M W. Physiological regulation of β-catenin stability by Tcf3 and CKI [J]. J Cell Biol, 2001, 154: 983-993.
[78] Amit S, Hatzubai A, Birman Y et al. Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a molecular switch for the Wnt pathway [J]. Genes Dev, 2002, 16:1066-1076.
[79] Wodarz A, Nusse R. Mechanisms of wnt signaling in development [J]. Ann Rev Cell Dev Biol, 1998, 14: 59-88.
[80] Semenov M V, Snyder M. Human dishevelled genes constitute a DHR2 containing multigene family [J]. Genomics, 1997,42: 302-310.
[81] Peters J M, McKay R M, McKay J P, et al. Casein kinase I transduces Wnt signals [J]. Nature, 1999, 40: 345-350.
[82] Willert K, Brink M, Wodarz A, et al. Casein kinase 2 associates with and phosphorylates dishevelled [J]. EMBO J, 1997, 16: 3089-3096.
[83] Li L, Yuan H, Weaver C D, et al. Axin and Fratl interact with Dvl and GSK, bridging Dvl to GSK in Wnt- mediated regulation of LEF-1 [J]. EMBO J, 1999, 18:4233-4240.
[84] Jonkers J, Korswagen H C, Acton D, et al. Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas [J]. EMBO J, 1997, 16:441-450.
[85] Johnson G L, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 p rotein kinases [J]. Science, 2002, 298: 1911-1912.
[86] Bogoyevitch M A, Court N W. Counting on mitogen activated protein kinases-ERKs 3, 4, 5, 6, 7 and 8 [J]. Cell S ignal, 2004, 16: 1345-1354.
[87] Dent P, Yacoub A, Fisher, P B, et al. MAPK pathways in radiation responses [J]. Oncogene, 2003,22:5885-5896.
[88] Engelberg D. Stress-activated protein kinases-tumor suppressors or tumor initiators [J]? Sem in Cancer Biol, 2004, 14: 271-282.
[89] Hagemann C, Blank J L. The ups and downs of MEK kinase interactions. Cell Signal, 2001 13:863-875.
[90] Zhang Y, Neo S Y, Wang X, et al. Axin forms a complex with MEKK1 and activates c-Jun NH (2)-terminal kinase/stress-activated protein kinase through domains distinct from Wnt signaling [J]. J Biol Chem, 1999, 274: 35247-3554.
[91] Luo W, Ng W W, Jin LH, et al. Axin utilizes distinct regions for competitive MEKK1 and MEKK4 binding and JNK activation [J]. J Biol Chem, 2003, 278: 37451-37458.
[92] Moriguchi T, Kawachi K, Kamakura S, et al. Distinct domains of mouse dishevelled are responsible for the c-Jun N-terminal kinase/stress-activated protein kinase activation and the axis formation in vertebrates [J]. J Biol Chem, 1999,274: 30957-30962.
[93] Zhang Y, Neo S Y, Han J, et al. Dimerization choices control the ability of axin and dishevelled to activate c-Jun NH2-terminal kinase/stress-activated protein kinase [J]. J Biol Chem, 2000 275: 25008-25014.
[94] Shiomi K, Uchida H, Keino-Masu K, et al. Ccdl a novel protein with a DIX domain is a positive regulator in the Wnt signaling during Zebrafish neural patterning [J]. Curr Biol, 2003, 13:73-77.
[95] Wong C K, Luo W, Deng Y, et al. The DIX Domain Protein Coiled-coil-DIX1 Inhibits c-Jun N-terminal Kinase Activation by Axin and Dishevelled through Distinct Mechanisms [J]. J Biol Chem, 2004, 279: 39366-39373.
[96] Rui Y, Xu Z, Xiong B, et al. A P-catenin-independent dorsalization pathway activated by Axin/JNK signaling and antagonized by Aida [J]. Dev Cell, 2007, 13:268-282.
[97] Chung C D, Liao J, Liu B, et al. Specific inhibition of Stat3 signal transduction by PIAS3 [J]. Science, 1997,278: 1803-1805.
[98] Kotajan N, Karvonen U, Janne OA, et al. PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases [J]. Mol Cell Biol, 2002, 22: 5222-5234.
[99] Rui H L, Fan E, Zhou H M, et al. SUMO-1 modification of the C-terminal KVEKVD of Axin is required for JNK activation but has no effect on Wnt signaling [J]. J Biol Chem, 2002, 277: 42981-42986.
[100] Zhang Y, Qiu W J, Liu DX, et al. Differential molecular assemblies underlie the dual function of Axin in modulating the Wnt and JNK pathways [J]. J Biol Chem, 2001, 276: 32152-32159.
[101] Hochstrasser M. SP-RING for SUMO: new functions bloom for a ubiquitin-like protein [J]. Cell, 2001, 107:5-8.
[102] Schmidt D, M(?)ller S. Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity [J]. Proc Natl Acad Sci USA, 2002, 99: 2872-2877.
[103] Muller S, Hoege C, Pyrowolakis G, et al. SUMO, ubiquitin's mysterious cousin [J]. Nat Rev Mol Cell Biol, 2001,2: 202-210.
[104] Kwek S S, Derry J, Tyner A L, et al. Functional analysis and intracellular localization of p53 modified by SUMO-1 [J]. Oncogene, 2001, 20: 2587-2599.
[105] Melchior F, Hengst L. SUMO-1 and p53 [J]. Cell Cycle, 2002, 1: 245-249.
[106] Verger A, Perdomo J, Crossley M. Modification with SUMO: A role in transcriptional regulation [J]. EMBO Rep, 2003, 4: 137-142.
[107] Cowan C A, Henkemeyer M. The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals [J]. Nature, 2001,413: 174-179.
[108] Gottlieb T M, Oren M. p53 in growth control and neoplasia [J]. Biochim Biophys Acta, 1996,1287:77-102.
[109] Ko L J, Prives C. p53: puzzle and paradigm [J]. Genes Dev, 1996, 10: 1054-1072.
[110] Levine A J. p53, the cellular gatekeeper for growth and division [J]. Cell, 1997, 88: 323-331.
[111] Sharpless N E, DePinho R A. p53: good cop/bad cop [J]. Cell, 2002, 110: 9-12.
[112] Attardi L D, DePinho R A. Conquering the complexity of p53 [J]. Nat Genet, 2004, 36: 7-8.
[113] Chehab N H, Malikzay A, Stavridi ES, et al. Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage [J]. Proc Natl Acad Sci USA, 1999, 96: 13777-13782.
[114] Dumaz N, Meek D W. Serinel5 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2 [J]. EMBO J, 1999 18: 7002-7010.
[115] D'Orazi G, Cecchinelli B, Bruno T, et al. Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis [J]. Nat Cell Biol, 2002,4: 11-19.
[116] Hofmann T G, Moller A, Sirma H, et al. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2 [J]. Nat Cell Biol, 2002, 4:1-10.
[117] Zhang Q, Yoshimatsu Y, Hildebrand J, et al. Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP [J]. Cell, 2003, 115:177-186.
[118] Rui Y, Xu Z, Lin S, et al. Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation [J]. EMBO J, 2004, 23: 4583-4594.
[119] Yang X, Khosravi-Far R, Chang H Y, et al. Daxx, a novel Fas-binding protein that activates INK and apoptosis [J]. Cell, 1997, 89:1067-1076.
[120] Li Q, Wang X, Wu X, et al. Daxx cooperates with the Axin/HIPK2/p53 complex to induce cell death [J]. Cancer Res, 2007, 67: 66-74.
[121] Massague J. How cells read TGF-βeta signals [J]. Nat Rev Mol Cell Biol, 2000, 1: 169-178.
[122] Hata A, Lagna G, Massague J, et al. Smad6 inhibits BMP/Smadl signaling by specifically competing with the Smad4 tumor suppressor [J]. Genes Dev, 1998,12: 186-197.
[123] Massague J, Chen Y G. Controlling TGF-β signaling [J]. Genes Dev, 2000, 14: 627-644.
[124] Massague J, Wotton D. Transcriptional control by the TGFbeta/Smad signaling system [J]. EMBO J, 2000, 19: 1745-1754.
[125] Hayashi H, Abdollah S, Qiu Y, et al. The MAD-related protein Smad7 associates with the TGF-beta receptor and functions as an antagonist of TGF-beta signaling [J]. Cell, 1997, 89: 1165-1173.
[126] Imamura T, Takase M, Nishihara A, et al. Smad6 inhibits signalling by the TGF-β superfamily [J]. Nature, 1997, 389: 622-626.
[127] Episkopou V, Arkell R, Timmons P M, et al. Induction of the mammalian node requires Arkadia function in the extraembryonic lineages [J]. Nature, 2001,410: 825-830.
[128] Niederlander C, Walsh J J, Episkopou V, et al. Arkadia enhances nodal-related signalling to induce mesendoderm [J]. Nature, 2001,410: 830-834.
[129] Koinuma D, Shinozaki M, Komuro A, et al. Arkadia amplifies TGF-β superfamily signalling through degradation of Smad7 [J]. EMBO J, 2003, 22: 6458-6470.
[130] Liu W, Rui H, Wang J, et al. Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia [J]. EMBO J. 2006, 25:1646-1658.
[131] Furuhashi M, Yagi K, Yamamoto H, et al. Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway [J]. Mol Cell Biol, 2001, 21: 5132-5141.
[132] Hermans, E. Biochemical and pharmacological control of the multiplicity of coupling at G-protein-coupled receptors [J]. Pharmacol Ther, 2003, 99: 25-44.
[133] Castellone M D, Teramoto H, Williams B O, et al. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-β-catenin signaling axis [J]. Science, 2005, 310: 1504-1510.
[134] Inoki K, Ouyang H, Zhu T, et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth [J]. Cell, 2006, 12: 955-968.
[135] Sharma R P, Chopra V L. Effect of the Wingless (wgl) mutation on wing and haltere development in Drosophila melanogaster [J]. Dev Biol, 1976,48: 461-465.
[136] Nusse R, Varmus H E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome [J]. Cell, 1982, 31: 99-109.
[137] Nusse R, Brown A, Papkoff J, et al. A new nomenclature for intl and related genes: the wnt gene family [J]. Cell, 1991, 64: 231-232.
[138] http: PPwww. Stanford. eduP - rnussePwntwindow[Z]. Html [139] Cadigan KM, Nusse R. Wnt signaling: a commom theme in animal development [J]. Gene Dev, 1997,11:3286-3305.
[140] Miller JR. The Wnts [J]. Genome Biol, 2001 3: reviews 3001. 1-3001.15.
[141] Pereira L, Yi F, MerrillBJ, et al. Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal [J]. Mol Cell Biol, 2006, 26: 7479-7491.
[142] Medina A, Reintsch W, Steinbeisser H. Xenopus frizzled 7 can act in canonical and noncanonical Wnt signaling pathways :implications on early patterning and morphogenesis [J]. Mech Dev, 2000, 92: 227-237.
[143] Huelsken J, Behrens J. The Wnt signaling pathway [J]. Cell Sci, 2002, 115: 3977-3978.
[144] Reya T, Clevers H. Wnt signalling in stem cells and cancer [J]. Nature, 2005, 434: 843-850.
[145] Logan C Y, Nusse R. The Wnt signaling pathway in development and-disease [J]. Annu Rev Cell Dev Biol, 2004,20: 781-810.
[146] Johnson M L, Rajamannan N. Diseases of Wnt signaling [J]. Rev Endocr Metab Disord, 2006,7:41-49.
[147] Joyner A L. Engrailed, Wnt and Pax genes regulate midbrain2hindbrain development. Trends Genetics, 1996, 12: 15-20.
[148] Parr B A, Shea M J, Vassileva G, et al. Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds [J]. Development, 1993, 119: 247-261.
[149] McMahon A P, Joyner A L, Bradley A, et al. The midbrain-hindbrain phenotype of Wnt-1-/Wnt-1-mice resultsfrom stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum [J]. Cell, 1992, 69: 581-595.
[150] Heasman J. Maternal determinants of embryonic cell fate [J]. Semi CellDev Biol, 2006, 17: 93-98.
[151] Yamaguchi T. Heads or tails: Wnts and anterior-posteri- or patterning [J]. Curr Biol, 2001, 11:713-724.
[152] Leptin M. Gastrulation movements: the logic and the nuts and bolts [J]. Dev Cell, 2005, 8: 305-320.
[153] Winklbauer R, Medina A, Swain R K, et al. Frizzled-7 signalling controls tissue separation during Xenopus gastrulation [J]. Nature, 2001,413: 856-860.
[154] Barembaum M, Bronner-Fraser M. Early step s in neural crest specification [J]. Semi Cell Dev Biol, 2005, 1:642-646.
[155] Kiecker C, Niehrs C. A morphogen gradient of Wnt/β-catenin signaling regulates anteroposterior neural patterning in Xenopus [J]. Development, 2001, 128:4189-4200.
[156] Usha V, Herbert M, et al. PITX2, β-catenin and LEF-1 interact to synergistically regulate the LEF-1 promoter [J]. Cell Science, 2005, 118: 1129-1137.
[157] Katanaev V L, Ponzielli R, Semeriva M, et al. Trimeric G protein-dependent frizzled signaling in Drosophila [J]. Cell, 2005, 120: 111-122.
[158] Vainio S, Heikkila M, KispertA, et al. Female development in mammals is regulated by Wnt-4 signalling [J]. Nature, 1999, 397: 405-409.
[159] Jordan B K, Mohammed M, Ching S T, et al. Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans [J]. Am J Hum Genet, 2001, 68: 1102-1109.
[160] Burden S J. Wnts as retrograde signals for Axon and growth cone differentiation [J]. Cell, 2000, 100: 495-497.
[161] Korinek V, Barker N, Moerer P, et al. Depletion of epithelia stem-cell compartments in the small intestine of mice lacking Tcf-4 [J]. Nat Genet, 1998, 19: 1-5.
[162] Kim K A, Kakitani M, Zhao J, et al. Mitogenic influence of human R-spondin1 on the intestinal epithelium [J]. Science, 2005, 309:1256-1259.
[163] van Genderen C, Okamura R M, Farinas I, et al. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice [J]. Genes Dev, 1994, 8: 2691-2703.
[164] Reya T, Duncan A W, Allies L, et al. A role for Wnt signaling in self-renewal of haematopoietic stem cells. Nature, 2003, 423: 409-414.
[165] Hartmann C. A Wnt canon orchestrating osteoblastogenesis [J].Trends Cell Biol, 2006, 16: 151-158.
[166] Cheng L, Lai M D. Aberrant cryp t foci as microscopic precursors of colorectal cancer [J]. World J Gastroenterol, 2003, 9: 2642-2649.
[167] Kinzler K W, Vogelstein B. Lessons from hereditary colorectal cancer [J]. Cell, 1996, 87: 159-170.
[168] Gat U, Dasgupta R, Degenstein L, et al. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell, 1998, 95: 605-614.
[169] Lo Celso C, Prowse D M, Watt F M. Transient activation of beta-catenin signaling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours [J]. Development, 2004, 131: 1787-1799.
[170] Chan E F, Gat U, McNiff J M, et al. A common human skin tumour is caused by activating mutations in beta-catenin [J]. Nat Genet, 1999, 21: 410-413.
[171] Jamieson C H, Allies L E, Dylla S J, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML [J]. N Engl J Med, 2004, 351: 657-667.
[172] Hibi M, Lin A, Smeal T, et al. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain [J]. Genes Dev, 1993, 7: 2135-48.
[173] Davis R J. Signal transduction by the JNK group of MAP kinases [J]. Cell, 2000, 103: 239-52.
[174] Chang L, Karin M. Mammalian MAP kinase signalling cascades [J]. Nature, 2001, 410: 37-40.
[175] Shaulian E, Karin M. AP-1 as a regulator of cell life and death [J]. Nat Cell Bio, 2002, 4: E131-136.
[176] Lin A. Activation of the JNK signaling pathway: breaking the break on apoptosis [J]. Bioessays, 2003, 25:1-8.
[177] Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem, 1995,270:16483-16486.
[178] Maundrell K, Antonsson B, Magnenat E, et al. Bcl-2 undergoes phosphorylation by c-Jun N-terminal kinase/stress- activated protein kinases in the presence of the constitutively active GTP binding protein Racl [J]. J Biol Chem, 1997, 272: 25238-25242.
[179] Yu C, Minemoto Y, Zhang J, et al. JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD [J]. Molecular Cell, 2004, 13: 329-340.
[180] Jiang Y, Li Z, Schwarz E M, et al. Structure-function studies of p38 mitogen-activated protein kinase: Loop 12 influences substrate specificity and autophosphorylation, but not upstream kinase selection [J]. J Biol Chem, 1997, 17: 11096-11102.
[181] Widmarm C, Gibson S, Jarpe M B, et al. Mitogen-activated protein kinase conservation of a three-kinase module from yeast to human [J]. Physiol Rev, 1999, 79: 143-180.
[182] Lin A, Minden A, Martinetto H, et al. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2 [J]. Science, 1995, 268:286-290.
[183] Fleming Y, Armstrong CG, Morrice N, et al. Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7 [J]. Biochem J, 2000,352 Pt 1:145-154.
[184] Tournier C, Dong C, Turner T K, et al. MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines [J]. Genes Dev, 2001, 15: 1419-1426.
[185] Xia Y, Makris C, Su B, et al. MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration [J]. Proc Natl Acad Sci USA, 2000, 97: 5243-5248.
[186] Yujiri T, Sather S, Fanger G R, et al. Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption [J]. Science, 1998,282: 1911-1914.
[187] Xia Z, DickensM, Raingeaud J, et al. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis [J]. Science, 1995, 270: 1326-1331.
[188] Yang D D, Kuan C Y, Whitmarsh A J, et al. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene [J]. Nature, 1997, 389: 865-870.
[189] Behrens A, Sibilia M, Wagner E F. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation [J]. Nat Genet, 1999, 21: 326-329.
[190] Milne D M, Campbell L E, Campbell D G, et al. p53 is phosphorylated in vitro and in vivo by an ultraviolet radiation-induced protein kinase characteristic of the c-Jun kinase, JNK1 [J]. J Biol Chem, 1995,270:5511-5518.
[191] Fuchs S Y, Adler V, Pincus M R, et al. MEKK1/JNK signaling stabilizes and activates p53 [J]. Proc Natl Acad Sci USA, 1998, 95: 10541-10546.
[192] Fuchs S Y, Adler V, Buschmann T, et al. JNK targets p53 ubiquitination and degradation in nonstressed cells [J]. Genes Dev, 1998, 12: 2658-2663.
[193] Tournier C, Hess P, Yang D D, et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway [J]. Science, 2000, 288: 870-874.
[194] Noguchi K, Kitanaka C, Yamana H, et al. Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase [J]. J Biol Chem, 1999: 274: 32580-32587.
[195] Kuan C Y, Yang D D, Samanta Roy D R, et al. The Jnkl and Jnk2 protein kinases are required for regional specific apoptosis during early brain development [J]. Neuron, 1999, 22: 667-676.
[196] Sabapathy K, Hu Y, Kallunki T, et al. JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development [J]. Curr Biol, 1999, 9: 116-125.
[197] Adachi-Yamada T, Fujimura-Kamada K, Nishida Y, et al. Distortion of proximodistal information causes JNK-dependent apoptosis in Drosophila wing. Nature, 1999, 400: 166-169.
[198] Rincon M, Whitmarsh A, Yang D D, et al. The JNK pathway regulates the in vivo deletion of immature CD4 (1) CD8 (1) thymocytes [J]. J Exp Med, 1998,188: 1817-1830.
[199] Sabapathy K, Jochum W, Hochedlinger K, et al. Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2 [J]. Mech Dev, 1999, 89: 115-124.
[200] Nishina H, Fischer K D, Radvanyi L, et al. Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3 [J]. Nature, 1997, 385: 350-353.
[201] Bost F, McKay R, Bost M, et al. The Jun kinase 2 isoform is preferentially required for epidermal growth factor-induced transformation of human A549 lung carcinoma cells [J]. Mol Cell Biol, 1999, 19: 1938-1949.
[202] Potapova O, Anisimov S V, Gorospe M, et al. Targets of c-Jun NH(2)-terminal kinase 2-mediated tumor growth regulation revealed by serial analysis of gene expression [J]. Cancer Res, 2002, 62: 3257-3263.
[203] Potapova O, Gorospe M, Dougherty R H, et al. Inhibition of c-Jun N-terminal kinase 2 expression suppresses growth and induces apoptosis of human tumor cells in a p53-dependent manner [J]. Mol Cell Biol, 2000, 20: 1713-1722.
[204] Chen N, Nomura M, She QB, et al. Suppression of skin tumorigenesis in c-Jun NH(2)-terminal kinase-2- deficient mice [J]. Cancer Res, 2001, 61: 3908-3912.
[205] She Q B, Chen N, Bode A M, et al. Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate [J]. Cancer Res, 2002, 62:1343-1348.
[206] Liu J, Minemoto Y, Lin A. c-Jun N-terminal protein kinase 1 (JNK1), but not JNK2, is essential for tumor necrosis factor alpha-induced c-Jun kinase activation and apoptosis [J]. Mol Cell Biol, 2004, 24: 10844-10856.
[207] Johnson R, Spiegelman B, Hanahan D, et al. Cellular transformation and malignancy induced by ras require c-jun [J]. Mol Cell Biol, 1996, 16: 4504-4511.
[208] Pulverer B J, Kyriakis J M, Avruch J, et al. Phosphorylation of c-jun mediated by MAP kinases [J]. Nature, 1991, 353: 670-674.
[209] Smeal T, Binetruy B, Mercola D A, et al. Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73 [J]. Nature, 1991, 354: 494-496.
[210] Behrens A, Jochum W, Sibilia M, et al. Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation [J]. Oncogene, 2000, 19: 2657-2663.
[211] Ip Y T, Davis R J. Signal transduction by the c-Jun N-terminal kinase (JNK)-from inflammation to development [J]. Curr Opin Cell Biol, 1998, 10: 205-219.
[212] Adler V, Yin Z, Fuchs S Y, et al. Regulation of JNK signaling by GSTp [J]. EMBO J, 1999, 18:1321-1334.
[213] Kurokawa M, Mitani K, Yamagata T, et al. The Evi-1 oncoprotein inhibits c-Jun N-terminal kinase and prevents stress-induced cell death [J]. EMBO J, 2000, 19: 2958-2968.
[214] Teng D H, Perry W L 3rd, Hogan J K, et al. Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor [J]. Cancer Res, 1997, 57: 4177-4182.
[215] Su G H, Hilgers W, Shekher M C, et al. Alterations in pancreatic, biliary and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene [J]. Cancer Res, 1998,58:2339-2342.
[216] Yoshida B A, Dubauskas Z, Chekmareva M A, et al. Mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17 [J]. Cancer Res, 1999, 59: 5483-5487.
[217] Garay M, Gaarde W, Monia B P, et al. Inhibition of hypoxia/reoxygenation-induced apoptosis by an antisense oligonucleotide targeted to JNK1 in human kidney cells [J]. Biochem Pharmacol, 2000, 59: 1033-1043.
[218] Ho F M, Liu S H, Liau C S, et al. High glucose-induced apoptosis in human endothelial cells is mediated by sequential activations of c-Jun NH2-terminal kinase and caspase-3 [J]. Circulation, 2000, 101: 2618-2624.
[219] Kawasaki M, Hisamoto N, lino Y, et al. A Caenorhabditis elegans JNK signal transduction pathway regulates coordinated movement via type-DGABAergic motor neurons [J]. EMBO J, 1999,18:3604-3615.
[220] Riesgo-Escovar J R, Jenni M, Fritz A, et al. The Drosophila Jun-N-terminal kinase is required for cell morphogenesis but not for DJun-dependent cell fate specification in the eye [J]. Genes Dev, 1996, 10: 2759-2768.
[221] Sluss H K, Han Z, Barrett T, Davis R J, Ip Y T. A JNK signal transduction pathway that mediates morphogenesis and an immune response in Drosophila [J]. Genes Dev, 1996, 10: 2745-2758.
[222] Leppa S, and Bohmann D. Diverse functions of JNK signaling and c-Jun in stress response and apoptosis [J]. Oncogene, 1999,18: 6158-6162.
[223] Mlodzik, M. Planar, polarity in the Drosophila eye: a multifaceted view of signaling specificity and cross-talk [J]. EMBO J, 1999, 18,6873-6879.
[224] Boutros M, Paricio N, Strutt D I, et al. Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling [J], Cell, 1998, 94: 109-118.
[225] Marzars G R, Jeanteur P, Lynch H T, et al. Nucleotide sequence polymorphism in a hot spot mutation region of the p53 gene [J]. Oncogene, 1992, 7: 781-782.
[226] Soussi T C, de Fromental C, May P. Structural aspects of the p53 protein in relation to gene evlution [J]. Oncogene, 1990, 5: 945-952.
[227] Candau R, Scolnick D M, Darpino P, et al. Two tandem and independent sub-activation domains in the amino terminus of p53 require the adaptor complex for activity [J]. Oncogene, 1997, 15: 807-816.
[228] Venot C, Maratrat M, Sierra V, et al. Definition of a p53 transactivation function-deficient mutant and characterization of two independent p53 transactivation subdomains [J]. Oncogene, 1999, 18:2405-2410.
[229] Momand J, Wu H H, Dasgupta G. MDM2-master regulator of the p53 tumor suppressor protein [J] .Gene, 2000,242: 15-29.
[230] Venot C, Maratrat M, Dureuil C, et al. The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression [J]. EMBO J, 1998, 17: 4668-4679.
[231] Wolkowicz R, Rotter V. The DNA binding regulatory domain of p53: see the C [J]. Pathol Biol (Paris), 1997,45: 785-796.
[232] Kaghad M, Bonnet H, Yang A, et al. Monoallelically expressed gene related to p53 at Ip36, a region frequently deleted in neuroblastoma and other human cancers [J]. Cell, 1997, 90: 809-819.
[233] Yang A, Kaghad M, Wang Y, et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities [J]. Mol Cell, 1998,2:305-316.
[234] Wolf D, Harris N, Goldfinger N, et al. Isolation of a full-length mouse cDNA clone coding for an immunologically distinct p53 molecule [J]. Mol Cell Biol, 1985, 5: 127-132.
[235] Ikeguchi M, Makino M, Kaibara N. Telomerase activity and p53 genemutation in familial polyposis coli [J]. Anticancer Res, 2000, 20: 3833-3837.
[236] Porter PL, Gown A M, Kramp S G, et al. Wids pread p53 over expression in human malignant tumor [J]. Am J Pathol, 1992, 140: 145-153.
[237] Caelles C, Helmberg A, Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes [J]. Nature, 1994, 37: 220-223.
[238] Chipuk JE, Maurer U, Green DR, et al. Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription [J]. Cancer Cell, 2003, 4: 371-381.
[239] Zhao Y F, Chaiswing L, Velez J M, et al. p53 translocation tomitochondriaprecedes its nuclear translocation and target mitochondria oxidative defense protein manganese superoxide dismutase [J]. Cancer Res, 2005, 65: 3745-3750.
[240] Talos F, Petenko O, Mena P, et al. Mitochondrially targeted p53 has tumor suppressor activities in vivo [J]. Cancer Res, 2005, 65: 9971-9981.
[241] Leng R P, Lin Y P, Ma W L, et al. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation [J]. Cell, 2003,112: 779-791.
[242] Dornan D, Wertz I, Shimizu H, et al. The ubiquitin ligase COP1 is a critical negative regulator of p53 [J]. Nature, 2004, 429: 86-92.
[243] Chipuk JE, Bouchier-Hayes L, Kuwana T, et al. PUMA couples the nuclear and cytoplasmic proapoptotic function of p53 [J]. Science, 2005, 309: 1732-1735.
[244] Wu WS, Heinrichs S, Xu D, et al. Slug antagonizes p53-madiated apoptosis of hematopoietic progenitors by repressing puma [J]. Cell, 2005, 123: 641-653.
[245] Sayan B S, Sayan A E, Kinight R A, et al. p53 is cleaved by caspases generating fragments localizing to mitochondria [J]. J Biol Chem, 2006, 281: 13566-13573.
[246] Yamaguchi A, Kurosaka Y, Fushida S, et al. Expression of p53 protein in colorectal cancer and its relationship to short term prognosis [J]. Cancers, 1992, 70: 2778-2784.
[247] Wu X, Zhao H, Amosc I, et al. p53 Genotypes and haplotypes associated with lung cancer susceptibility and ethnicity [J]. J Natl Cancer Inst, 2002,94:681-690.
[248] Puisieux A, Lim S, Groopman J, et al. Selective targeting of p53 genemutational hotspots in human cancers by etiologically defined carcinogens [J]. Cancer Res, 1991, 51: 6185-6189.
[249] Fagotto F, Jho E, Zeng L, et al. Domains of axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization [J]. J Cell Biol, 1999, 145: 741-56.
[250] Kishida S, Yamamoto H, Hino S, et al. DIX domains of Dvl and Axin are necessary for protein interactions and their ability to regulate β-catenin stability [J]. Mol Cell Biol, 1999, 19: 4414-4422.
[251] Liao G, Tao Q, Kofron M, et al. Jun NH2-terminal kinase (JNK) prevents nuclear beta-catenin accumulation and regulates axis formation in Xenopus embryos [J]. Proc Nat Acad Sci USA, 2006 103:16313-16318.
[28] Gumbiner B M: Signal transduction of betacatenin [J]. Curr Opin Cell Biol, 1995, 7: 634-640.
[29] Willert K, Shibamoto S, Nusse R. Wnt-induced dephosphorylation of axin releases beta-catenin from the axin complex [J]. Genes Dev, 1999, 13: 1768-1773.
[30] Cong F, Varmus H. Nuclear-cytoplasmic shuttling of Axin regulates subcellular localization of beta-catenin [J]. Proc Natl Acad Sci USA, 2004, 101: 2882-2887.
[31] Wiechens N, Heinle K, Englmeier L, et al. Nucleo-cytoplasmic shuttling of Axin, a negative regulator of the Wnt-beta-catenin pathway [J]. J Biol Chem, 2004, 279: 5263-5267.
[32] Yamamoto H, Kishida S, Kishida M, et al. Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3β regulates its stability [J]. J Biol Chem, 1999, 274: 10681-10684.
[33] Cliffe A, Hamada F, Bienz M. A role of Dishevelled in relocating Axin to the plasma membrane during wingless signaling [J]. Curr Biol, 2003, 13: 960-966.
[34] Choi J, Park S Y, Costantini F, et al. Adenomatous polyposis coliis down-ergulated by the ubiquitin-proteasome pathway in a process facilitated by Axin [J]. J Biol Chem, 2004, 279: 49188-49198.
[35] Behrens J, Jerchow B A, Wurtele M, et al. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta [J]. Science, 1998, 280: 596-599.
[36] Nakamura Y, Nishisho I, Kinzler K W, et al. Mutations of the APC (adenomatous polyposis coli) gene in FAP (familial polyposis coli) patients and in sporadic colorectal tumors [J]. Tohoku J Exp Med, 1992, 168: 141-147.
[37] Rubinfeld B, Albert I, Porfiri E, et al. Loss of beta-catenin regulation by the APC tumor suppressor protein correlates with loss of structure due to common somatic mutations of the gene [J]. Cancer Res, 1997, 57: 4624-4630.
[38] Rosin-Arbesfeld R, Cliffe A, Brabletz T, et al. Nuclear export of the APC tumor suppressor controls beta-catenin function in transcription [J]. EMBO J, 2003, 22: 1101-1113.
[39] Henderson B R, Fagotto F: The ins and outs of APC and beta-catenin nuclear transport [J]. EMBO Rep, 2002, 3: 834-839.
[40] Ahmed Y, Hayashi S, Levine A, Wieschaus E: Regulation of armadillo by a Drosophila APC inhibits neuronal apoptosis during retinal development [J]. Cell, 1998, 93:1171-1182.
[41] Hinoi T, Yamamoto H, Kishida M, et al. Complex formation of adenomatous polyposis coli gene product and axin facilitates glycogen synthase kinase-3beta dependent phosphorylation of beta-catenin and down-regulates beta-catenin [J]. J Biol Chem, 2000, 275: 34399-34406.
[42] Rubinfeld B, Robbins P, El-Gamil M, et al. Stabilization of beta-catenin by genetic defects in melanoma cell lines [J]. Science, 1997, 275: 1790-1792.
[43] Kawahara K, Morishita T, Nakamura T, et al. Down-regulation of beta-catenin by the colorectal tumor suppressor APC requires association with Axin and beta-catenin [J]. J Biol Chem, 2000, 275: 8369-8374.
[44] Nakamura T, Hamada F, Ishidate T, et al. Axin, an inhibitor of the Wnt signaling pathway, interacts with β-catenin, GSK-3β and APC and reduces the β-catenin leve [J]l. Genes Cells, 1998, 3: 395-403.
[45] Itoh K, Antipova A, Ratcliffe M J, et al. Interaction of dishevelled and xenopus axin2 related protein is required for wnt signal transduction [J]. Mol Cell Biol, 2000, 20: 2228-2238.
[46] Ding Y, Dale T: Wnt signal transduction: Kinase cogs in a nano-machine [J]? Trends Biochem Sci, 2002, 27: 327-329.
[47] Gumbiner B M, McCrea P D. Catenins as mediators of the cytoplasmic functions of cadherins [J]. J Cell Sci Suppl, 1993, 7:155-158.
[48] Schneider S, Herrenknecht K, Butz S, et al. Catenins in Xenopus embryogenesis and their relation to the cadherin-mediated cell-cell adhesion system [J]. Development, .1993, 118:629-640.
[49] Peifer M, Orsulic S, Pai L M, et al. A model system for cell adhesion and signal transduction in Drosophila [J]. Dev Suppl, 1993, 163-176.
[50] Papkoff J, Rubinfeld B, Schryver B, et al. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes [J]. Mol Cell Biol, 1996, 16:2128-2134.
[51] Peifer M, Sweeton D, Casey M, et al.Wingless signal and Zeste-white 3 kinase trigger opposing changes in the intracellular distribution of Armadillo [J]. Development, 1994, 120:369-380.
[52] Liu C, Li Y, Semenov M, et al. Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism [J]. Cell, 2002, 108: 837-847.
[53] Aberle H A, Bauer A, Stappert J, et al. β-Catenin is a target for the ubiquitin-proteasome pathway [J]. EMBO J, 1997, 16:3797-3804.
[54] Liu J, Stevens J, Rote CA, et al. Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein [J]. Mol Cell, 2001, 7: 927-936.
[55] Matsuzawa S I, Reed J C. Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses [J]. Mol Cell, 2001, 7: 915-926.
[56] Levina E, Oren M, Ben-Ze'ev A. Downregulation of beta-catenin by p53 involves changes in the rate of beta-catenin phosphorylation and Axin dynamics [J]. Oncogene, 2004, 23: 4444-4453.
[57] Plyte S E, Hughes K, Nikolakaki E, et al. Glycogen synthase kinase-3β functions in oncogenesis and development [J]. Biochim Biophys Acta, 1992, 1114: 147-162.
[58] Mandelkow E M, Drewes G, Biernat J, et al. Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau [J]. FEBS Lett, 1992, 314: 315-321.
[59] Dajani R, Fraser E, Roe S M, et al. Structural basis for recruitment of glycogen synthase kinase 3β to the axin-APC scaffold complex [J]. EMBO J, 2003, 22: 494-501.
[60] Fujimuro M, Wu F Y, ApRhys C, et al. Anovel viral mechanism for dysregulation of β-catenin in Kaposi's sarcoma- associated herpesvirus latency. Nat Med, 2003, 9: 300-J306.
[61] Yamamoto K, Ichijo H, Korsmeyer S J. BCL-2 is phosphorylated and inactivated by an ASKl/Jun N-terminal protein kinase pathway normally activated at G(2)/M [J]. Mol Cell Biol, 1999, 19: 8469-8478.
[62] Janssens V, Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signaling. Biochem J, 2001, 353: 417-439.
[63] Seeling J M, Miller J R, Gil R, et al. Regulation of β-catenin signaling by the B56 subunit of protein phosphatase 2 A. Science, 1999, 283: 2089-2091.
[64] Hsu W, Zeng L, Costantini F. Identification of a domain of Axin that binds to the serine/threonine protein phosphatase 2A and a selfbinding domain [J]. J Biol Chem, 1999, 274: 3439-3445.
[65] Ikeda S, Kishida M, Matsuura Y, et al. GSK-3β-dependent phosphorylation of adenomatous polyposis coli gene product can be modulated by beta-catenin and protein phosphatase 2A complexed with axin [J]. Oncogene, 2000,19: 537-45.
[66] Ratcliffe M J, Itoh K, Sokol S Y. A positive role for the PP2A catalytic subunit in Wnt signal transduction [J]. J Biol Chem, 2000, 275: 35680-35683.
[67] Rubinfeld B, Souza B, Albert I, et al. Association of the APC gene product with beta-catenin [J]. Science, 1993,262:1731-1734.
[68] Burnett G, Kennedy E P. The enzymatic phosphorylation of proteins [J]. J Biol Chem, 1954, 211:969-980.
[69] Pinna L A, Clani G, Moret V. Isolation and enzymatic phosphorylation of rat liver cytosol phosphoproteins [J]. FEBS Lett, 1969, 5: 77-80.
[70] Gorss S D, Anderson R A. Casein kinase Ⅰ: spatial organization and positioning of a multifunctional protein kinase family [J]. Cell Signal, 1998, 10: 699-711.
[71] Tuazon P T, Traugh J A. Casein kinase Ⅰ and Ⅱ-multipotential serine protein kinase: structure, function, and regulation [J]. Adv Second Messenger phosphoprotein Res, 1991, 23: 123-164.
[72] Graves P R, Roach P J. Role of COOH-terminal phosphorylation in the regulation of casein kinase Iδ [J]. J Biol Chem, 1995, 270: 21689-21692.
[73] Knippschild U, Gocht A, Wolff S, et al. The casein kinase I family: Participation in multiple cellular processes in eukaryotes [J]. Cell Signal, 2005, 17: 675-689.
[74] McKay R M, Peters J M, Graf J M. The casein kinase Ⅰ# family in Wnt signaling [J]. Dev Biol, 2001,235:388-96.
[75] Hino S, Michiue T, Asashima M, et al. Casein kinase I epsilon enhances the binding of Dvl-1 to Frat-1 and is essential for Wnt-3a-induced accumulation of p-catenin [J]. J Biol Chem, 2003,278:14066-14073.
[76] Rubinfeld B, Tice DA, Polakis P. Axin-dependent phosphorylation of the adenomatous polyposis coli protein mediated by casein kinase Iε [J]. J Biol Chem, 2001, 276: 39037-39045.
[77] Lee E, Salic A, Kirschner M W. Physiological regulation of β-catenin stability by Tcf3 and CKI [J]. J Cell Biol, 2001, 154: 983-993.
[78] Amit S, Hatzubai A, Birman Y et al. Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a molecular switch for the Wnt pathway [J]. Genes Dev, 2002, 16:1066-1076.
[79] Wodarz A, Nusse R. Mechanisms of wnt signaling in development [J]. Ann Rev Cell Dev Biol, 1998, 14: 59-88.
[80] Semenov M V, Snyder M. Human dishevelled genes constitute a DHR2 containing multigene family [J]. Genomics, 1997,42: 302-310.
[81] Peters J M, McKay R M, McKay J P, et al. Casein kinase I transduces Wnt signals [J]. Nature, 1999, 40: 345-350.
[82] Willert K, Brink M, Wodarz A, et al. Casein kinase 2 associates with and phosphorylates dishevelled [J]. EMBO J, 1997, 16: 3089-3096.
[83] Li L, Yuan H, Weaver C D, et al. Axin and Fratl interact with Dvl and GSK, bridging Dvl to GSK in Wnt- mediated regulation of LEF-1 [J]. EMBO J, 1999, 18:4233-4240.
[84] Jonkers J, Korswagen H C, Acton D, et al. Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas [J]. EMBO J, 1997, 16:441-450.
[85] Johnson G L, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 p rotein kinases [J]. Science, 2002, 298: 1911-1912.
[86] Bogoyevitch M A, Court N W. Counting on mitogen activated protein kinases-ERKs 3, 4, 5, 6, 7 and 8 [J]. Cell S ignal, 2004, 16: 1345-1354.
[87] Dent P, Yacoub A, Fisher, P B, et al. MAPK pathways in radiation responses [J]. Oncogene, 2003,22:5885-5896.
[88] Engelberg D. Stress-activated protein kinases-tumor suppressors or tumor initiators [J]? Sem in Cancer Biol, 2004, 14: 271-282.
[89] Hagemann C, Blank J L. The ups and downs of MEK kinase interactions. Cell Signal, 2001 13:863-875.
[90] Zhang Y, Neo S Y, Wang X, et al. Axin forms a complex with MEKK1 and activates c-Jun NH (2)-terminal kinase/stress-activated protein kinase through domains distinct from Wnt signaling [J]. J Biol Chem, 1999, 274: 35247-3554.
[91] Luo W, Ng W W, Jin LH, et al. Axin utilizes distinct regions for competitive MEKK1 and MEKK4 binding and JNK activation [J]. J Biol Chem, 2003, 278: 37451-37458.
[92] Moriguchi T, Kawachi K, Kamakura S, et al. Distinct domains of mouse dishevelled are responsible for the c-Jun N-terminal kinase/stress-activated protein kinase activation and the axis formation in vertebrates [J]. J Biol Chem, 1999,274: 30957-30962.
[93] Zhang Y, Neo S Y, Han J, et al. Dimerization choices control the ability of axin and dishevelled to activate c-Jun NH2-terminal kinase/stress-activated protein kinase [J]. J Biol Chem, 2000 275: 25008-25014.
[94] Shiomi K, Uchida H, Keino-Masu K, et al. Ccdl a novel protein with a DIX domain is a positive regulator in the Wnt signaling during Zebrafish neural patterning [J]. Curr Biol, 2003, 13:73-77.
[95] Wong C K, Luo W, Deng Y, et al. The DIX Domain Protein Coiled-coil-DIX1 Inhibits c-Jun N-terminal Kinase Activation by Axin and Dishevelled through Distinct Mechanisms [J]. J Biol Chem, 2004, 279: 39366-39373.
[96] Rui Y, Xu Z, Xiong B, et al. A P-catenin-independent dorsalization pathway activated by Axin/JNK signaling and antagonized by Aida [J]. Dev Cell, 2007, 13:268-282.
[97] Chung C D, Liao J, Liu B, et al. Specific inhibition of Stat3 signal transduction by PIAS3 [J]. Science, 1997,278: 1803-1805.
[98] Kotajan N, Karvonen U, Janne OA, et al. PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases [J]. Mol Cell Biol, 2002, 22: 5222-5234.
[99] Rui H L, Fan E, Zhou H M, et al. SUMO-1 modification of the C-terminal KVEKVD of Axin is required for JNK activation but has no effect on Wnt signaling [J]. J Biol Chem, 2002, 277: 42981-42986.
[100] Zhang Y, Qiu W J, Liu DX, et al. Differential molecular assemblies underlie the dual function of Axin in modulating the Wnt and JNK pathways [J]. J Biol Chem, 2001, 276: 32152-32159.
[101] Hochstrasser M. SP-RING for SUMO: new functions bloom for a ubiquitin-like protein [J]. Cell, 2001, 107:5-8.
[102] Schmidt D, M(?)ller S. Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity [J]. Proc Natl Acad Sci USA, 2002, 99: 2872-2877.
[103] Muller S, Hoege C, Pyrowolakis G, et al. SUMO, ubiquitin's mysterious cousin [J]. Nat Rev Mol Cell Biol, 2001,2: 202-210.
[104] Kwek S S, Derry J, Tyner A L, et al. Functional analysis and intracellular localization of p53 modified by SUMO-1 [J]. Oncogene, 2001, 20: 2587-2599.
[105] Melchior F, Hengst L. SUMO-1 and p53 [J]. Cell Cycle, 2002, 1: 245-249.
[106] Verger A, Perdomo J, Crossley M. Modification with SUMO: A role in transcriptional regulation [J]. EMBO Rep, 2003, 4: 137-142.
[107] Cowan C A, Henkemeyer M. The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals [J]. Nature, 2001,413: 174-179.
[108] Gottlieb T M, Oren M. p53 in growth control and neoplasia [J]. Biochim Biophys Acta, 1996,1287:77-102.
[109] Ko L J, Prives C. p53: puzzle and paradigm [J]. Genes Dev, 1996, 10: 1054-1072.
[110] Levine A J. p53, the cellular gatekeeper for growth and division [J]. Cell, 1997, 88: 323-331.
[111] Sharpless N E, DePinho R A. p53: good cop/bad cop [J]. Cell, 2002, 110: 9-12.
[112] Attardi L D, DePinho R A. Conquering the complexity of p53 [J]. Nat Genet, 2004, 36: 7-8.
[113] Chehab N H, Malikzay A, Stavridi ES, et al. Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage [J]. Proc Natl Acad Sci USA, 1999, 96: 13777-13782.
[114] Dumaz N, Meek D W. Serinel5 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2 [J]. EMBO J, 1999 18: 7002-7010.
[115] D'Orazi G, Cecchinelli B, Bruno T, et al. Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis [J]. Nat Cell Biol, 2002,4: 11-19.
[116] Hofmann T G, Moller A, Sirma H, et al. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2 [J]. Nat Cell Biol, 2002, 4:1-10.
[117] Zhang Q, Yoshimatsu Y, Hildebrand J, et al. Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP [J]. Cell, 2003, 115:177-186.
[118] Rui Y, Xu Z, Lin S, et al. Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation [J]. EMBO J, 2004, 23: 4583-4594.
[119] Yang X, Khosravi-Far R, Chang H Y, et al. Daxx, a novel Fas-binding protein that activates INK and apoptosis [J]. Cell, 1997, 89:1067-1076.
[120] Li Q, Wang X, Wu X, et al. Daxx cooperates with the Axin/HIPK2/p53 complex to induce cell death [J]. Cancer Res, 2007, 67: 66-74.
[121] Massague J. How cells read TGF-βeta signals [J]. Nat Rev Mol Cell Biol, 2000, 1: 169-178.
[122] Hata A, Lagna G, Massague J, et al. Smad6 inhibits BMP/Smadl signaling by specifically competing with the Smad4 tumor suppressor [J]. Genes Dev, 1998,12: 186-197.
[123] Massague J, Chen Y G. Controlling TGF-β signaling [J]. Genes Dev, 2000, 14: 627-644.
[124] Massague J, Wotton D. Transcriptional control by the TGFbeta/Smad signaling system [J]. EMBO J, 2000, 19: 1745-1754.
[125] Hayashi H, Abdollah S, Qiu Y, et al. The MAD-related protein Smad7 associates with the TGF-beta receptor and functions as an antagonist of TGF-beta signaling [J]. Cell, 1997, 89: 1165-1173.
[126] Imamura T, Takase M, Nishihara A, et al. Smad6 inhibits signalling by the TGF-β superfamily [J]. Nature, 1997, 389: 622-626.
[127] Episkopou V, Arkell R, Timmons P M, et al. Induction of the mammalian node requires Arkadia function in the extraembryonic lineages [J]. Nature, 2001,410: 825-830.
[128] Niederlander C, Walsh J J, Episkopou V, et al. Arkadia enhances nodal-related signalling to induce mesendoderm [J]. Nature, 2001,410: 830-834.
[129] Koinuma D, Shinozaki M, Komuro A, et al. Arkadia amplifies TGF-β superfamily signalling through degradation of Smad7 [J]. EMBO J, 2003, 22: 6458-6470.
[130] Liu W, Rui H, Wang J, et al. Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia [J]. EMBO J. 2006, 25:1646-1658.
[131] Furuhashi M, Yagi K, Yamamoto H, et al. Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway [J]. Mol Cell Biol, 2001, 21: 5132-5141.
[132] Hermans, E. Biochemical and pharmacological control of the multiplicity of coupling at G-protein-coupled receptors [J]. Pharmacol Ther, 2003, 99: 25-44.
[133] Castellone M D, Teramoto H, Williams B O, et al. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-β-catenin signaling axis [J]. Science, 2005, 310: 1504-1510.
[134] Inoki K, Ouyang H, Zhu T, et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth [J]. Cell, 2006, 12: 955-968.
[135] Sharma R P, Chopra V L. Effect of the Wingless (wgl) mutation on wing and haltere development in Drosophila melanogaster [J]. Dev Biol, 1976,48: 461-465.
[136] Nusse R, Varmus H E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome [J]. Cell, 1982, 31: 99-109.
[137] Nusse R, Brown A, Papkoff J, et al. A new nomenclature for intl and related genes: the wnt gene family [J]. Cell, 1991, 64: 231-232.
[138] http: PPwww. Stanford. eduP - rnussePwntwindow[Z]. Html [139] Cadigan KM, Nusse R. Wnt signaling: a commom theme in animal development [J]. Gene Dev, 1997,11:3286-3305.
[140] Miller JR. The Wnts [J]. Genome Biol, 2001 3: reviews 3001. 1-3001.15.
[141] Pereira L, Yi F, MerrillBJ, et al. Repression of Nanog gene transcription by Tcf3 limits embryonic stem cell self-renewal [J]. Mol Cell Biol, 2006, 26: 7479-7491.
[142] Medina A, Reintsch W, Steinbeisser H. Xenopus frizzled 7 can act in canonical and noncanonical Wnt signaling pathways :implications on early patterning and morphogenesis [J]. Mech Dev, 2000, 92: 227-237.
[143] Huelsken J, Behrens J. The Wnt signaling pathway [J]. Cell Sci, 2002, 115: 3977-3978.
[144] Reya T, Clevers H. Wnt signalling in stem cells and cancer [J]. Nature, 2005, 434: 843-850.
[145] Logan C Y, Nusse R. The Wnt signaling pathway in development and-disease [J]. Annu Rev Cell Dev Biol, 2004,20: 781-810.
[146] Johnson M L, Rajamannan N. Diseases of Wnt signaling [J]. Rev Endocr Metab Disord, 2006,7:41-49.
[147] Joyner A L. Engrailed, Wnt and Pax genes regulate midbrain2hindbrain development. Trends Genetics, 1996, 12: 15-20.
[148] Parr B A, Shea M J, Vassileva G, et al. Mouse Wnt genes exhibit discrete domains of expression in the early embryonic CNS and limb buds [J]. Development, 1993, 119: 247-261.
[149] McMahon A P, Joyner A L, Bradley A, et al. The midbrain-hindbrain phenotype of Wnt-1-/Wnt-1-mice resultsfrom stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum [J]. Cell, 1992, 69: 581-595.
[150] Heasman J. Maternal determinants of embryonic cell fate [J]. Semi CellDev Biol, 2006, 17: 93-98.
[151] Yamaguchi T. Heads or tails: Wnts and anterior-posteri- or patterning [J]. Curr Biol, 2001, 11:713-724.
[152] Leptin M. Gastrulation movements: the logic and the nuts and bolts [J]. Dev Cell, 2005, 8: 305-320.
[153] Winklbauer R, Medina A, Swain R K, et al. Frizzled-7 signalling controls tissue separation during Xenopus gastrulation [J]. Nature, 2001,413: 856-860.
[154] Barembaum M, Bronner-Fraser M. Early step s in neural crest specification [J]. Semi Cell Dev Biol, 2005, 1:642-646.
[155] Kiecker C, Niehrs C. A morphogen gradient of Wnt/β-catenin signaling regulates anteroposterior neural patterning in Xenopus [J]. Development, 2001, 128:4189-4200.
[156] Usha V, Herbert M, et al. PITX2, β-catenin and LEF-1 interact to synergistically regulate the LEF-1 promoter [J]. Cell Science, 2005, 118: 1129-1137.
[157] Katanaev V L, Ponzielli R, Semeriva M, et al. Trimeric G protein-dependent frizzled signaling in Drosophila [J]. Cell, 2005, 120: 111-122.
[158] Vainio S, Heikkila M, KispertA, et al. Female development in mammals is regulated by Wnt-4 signalling [J]. Nature, 1999, 397: 405-409.
[159] Jordan B K, Mohammed M, Ching S T, et al. Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans [J]. Am J Hum Genet, 2001, 68: 1102-1109.
[160] Burden S J. Wnts as retrograde signals for Axon and growth cone differentiation [J]. Cell, 2000, 100: 495-497.
[161] Korinek V, Barker N, Moerer P, et al. Depletion of epithelia stem-cell compartments in the small intestine of mice lacking Tcf-4 [J]. Nat Genet, 1998, 19: 1-5.
[162] Kim K A, Kakitani M, Zhao J, et al. Mitogenic influence of human R-spondin1 on the intestinal epithelium [J]. Science, 2005, 309:1256-1259.
[163] van Genderen C, Okamura R M, Farinas I, et al. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice [J]. Genes Dev, 1994, 8: 2691-2703.
[164] Reya T, Duncan A W, Allies L, et al. A role for Wnt signaling in self-renewal of haematopoietic stem cells. Nature, 2003, 423: 409-414.
[165] Hartmann C. A Wnt canon orchestrating osteoblastogenesis [J].Trends Cell Biol, 2006, 16: 151-158.
[166] Cheng L, Lai M D. Aberrant cryp t foci as microscopic precursors of colorectal cancer [J]. World J Gastroenterol, 2003, 9: 2642-2649.
[167] Kinzler K W, Vogelstein B. Lessons from hereditary colorectal cancer [J]. Cell, 1996, 87: 159-170.
[168] Gat U, Dasgupta R, Degenstein L, et al. De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell, 1998, 95: 605-614.
[169] Lo Celso C, Prowse D M, Watt F M. Transient activation of beta-catenin signaling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours [J]. Development, 2004, 131: 1787-1799.
[170] Chan E F, Gat U, McNiff J M, et al. A common human skin tumour is caused by activating mutations in beta-catenin [J]. Nat Genet, 1999, 21: 410-413.
[171] Jamieson C H, Allies L E, Dylla S J, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML [J]. N Engl J Med, 2004, 351: 657-667.
[172] Hibi M, Lin A, Smeal T, et al. Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain [J]. Genes Dev, 1993, 7: 2135-48.
[173] Davis R J. Signal transduction by the JNK group of MAP kinases [J]. Cell, 2000, 103: 239-52.
[174] Chang L, Karin M. Mammalian MAP kinase signalling cascades [J]. Nature, 2001, 410: 37-40.
[175] Shaulian E, Karin M. AP-1 as a regulator of cell life and death [J]. Nat Cell Bio, 2002, 4: E131-136.
[176] Lin A. Activation of the JNK signaling pathway: breaking the break on apoptosis [J]. Bioessays, 2003, 25:1-8.
[177] Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem, 1995,270:16483-16486.
[178] Maundrell K, Antonsson B, Magnenat E, et al. Bcl-2 undergoes phosphorylation by c-Jun N-terminal kinase/stress- activated protein kinases in the presence of the constitutively active GTP binding protein Racl [J]. J Biol Chem, 1997, 272: 25238-25242.
[179] Yu C, Minemoto Y, Zhang J, et al. JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD [J]. Molecular Cell, 2004, 13: 329-340.
[180] Jiang Y, Li Z, Schwarz E M, et al. Structure-function studies of p38 mitogen-activated protein kinase: Loop 12 influences substrate specificity and autophosphorylation, but not upstream kinase selection [J]. J Biol Chem, 1997, 17: 11096-11102.
[181] Widmarm C, Gibson S, Jarpe M B, et al. Mitogen-activated protein kinase conservation of a three-kinase module from yeast to human [J]. Physiol Rev, 1999, 79: 143-180.
[182] Lin A, Minden A, Martinetto H, et al. Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2 [J]. Science, 1995, 268:286-290.
[183] Fleming Y, Armstrong CG, Morrice N, et al. Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7 [J]. Biochem J, 2000,352 Pt 1:145-154.
[184] Tournier C, Dong C, Turner T K, et al. MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines [J]. Genes Dev, 2001, 15: 1419-1426.
[185] Xia Y, Makris C, Su B, et al. MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration [J]. Proc Natl Acad Sci USA, 2000, 97: 5243-5248.
[186] Yujiri T, Sather S, Fanger G R, et al. Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption [J]. Science, 1998,282: 1911-1914.
[187] Xia Z, DickensM, Raingeaud J, et al. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis [J]. Science, 1995, 270: 1326-1331.
[188] Yang D D, Kuan C Y, Whitmarsh A J, et al. Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene [J]. Nature, 1997, 389: 865-870.
[189] Behrens A, Sibilia M, Wagner E F. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation [J]. Nat Genet, 1999, 21: 326-329.
[190] Milne D M, Campbell L E, Campbell D G, et al. p53 is phosphorylated in vitro and in vivo by an ultraviolet radiation-induced protein kinase characteristic of the c-Jun kinase, JNK1 [J]. J Biol Chem, 1995,270:5511-5518.
[191] Fuchs S Y, Adler V, Pincus M R, et al. MEKK1/JNK signaling stabilizes and activates p53 [J]. Proc Natl Acad Sci USA, 1998, 95: 10541-10546.
[192] Fuchs S Y, Adler V, Buschmann T, et al. JNK targets p53 ubiquitination and degradation in nonstressed cells [J]. Genes Dev, 1998, 12: 2658-2663.
[193] Tournier C, Hess P, Yang D D, et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway [J]. Science, 2000, 288: 870-874.
[194] Noguchi K, Kitanaka C, Yamana H, et al. Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase [J]. J Biol Chem, 1999: 274: 32580-32587.
[195] Kuan C Y, Yang D D, Samanta Roy D R, et al. The Jnkl and Jnk2 protein kinases are required for regional specific apoptosis during early brain development [J]. Neuron, 1999, 22: 667-676.
[196] Sabapathy K, Hu Y, Kallunki T, et al. JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development [J]. Curr Biol, 1999, 9: 116-125.
[197] Adachi-Yamada T, Fujimura-Kamada K, Nishida Y, et al. Distortion of proximodistal information causes JNK-dependent apoptosis in Drosophila wing. Nature, 1999, 400: 166-169.
[198] Rincon M, Whitmarsh A, Yang D D, et al. The JNK pathway regulates the in vivo deletion of immature CD4 (1) CD8 (1) thymocytes [J]. J Exp Med, 1998,188: 1817-1830.
[199] Sabapathy K, Jochum W, Hochedlinger K, et al. Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2 [J]. Mech Dev, 1999, 89: 115-124.
[200] Nishina H, Fischer K D, Radvanyi L, et al. Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3 [J]. Nature, 1997, 385: 350-353.
[201] Bost F, McKay R, Bost M, et al. The Jun kinase 2 isoform is preferentially required for epidermal growth factor-induced transformation of human A549 lung carcinoma cells [J]. Mol Cell Biol, 1999, 19: 1938-1949.
[202] Potapova O, Anisimov S V, Gorospe M, et al. Targets of c-Jun NH(2)-terminal kinase 2-mediated tumor growth regulation revealed by serial analysis of gene expression [J]. Cancer Res, 2002, 62: 3257-3263.
[203] Potapova O, Gorospe M, Dougherty R H, et al. Inhibition of c-Jun N-terminal kinase 2 expression suppresses growth and induces apoptosis of human tumor cells in a p53-dependent manner [J]. Mol Cell Biol, 2000, 20: 1713-1722.
[204] Chen N, Nomura M, She QB, et al. Suppression of skin tumorigenesis in c-Jun NH(2)-terminal kinase-2- deficient mice [J]. Cancer Res, 2001, 61: 3908-3912.
[205] She Q B, Chen N, Bode A M, et al. Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate [J]. Cancer Res, 2002, 62:1343-1348.
[206] Liu J, Minemoto Y, Lin A. c-Jun N-terminal protein kinase 1 (JNK1), but not JNK2, is essential for tumor necrosis factor alpha-induced c-Jun kinase activation and apoptosis [J]. Mol Cell Biol, 2004, 24: 10844-10856.
[207] Johnson R, Spiegelman B, Hanahan D, et al. Cellular transformation and malignancy induced by ras require c-jun [J]. Mol Cell Biol, 1996, 16: 4504-4511.
[208] Pulverer B J, Kyriakis J M, Avruch J, et al. Phosphorylation of c-jun mediated by MAP kinases [J]. Nature, 1991, 353: 670-674.
[209] Smeal T, Binetruy B, Mercola D A, et al. Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73 [J]. Nature, 1991, 354: 494-496.
[210] Behrens A, Jochum W, Sibilia M, et al. Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation [J]. Oncogene, 2000, 19: 2657-2663.
[211] Ip Y T, Davis R J. Signal transduction by the c-Jun N-terminal kinase (JNK)-from inflammation to development [J]. Curr Opin Cell Biol, 1998, 10: 205-219.
[212] Adler V, Yin Z, Fuchs S Y, et al. Regulation of JNK signaling by GSTp [J]. EMBO J, 1999, 18:1321-1334.
[213] Kurokawa M, Mitani K, Yamagata T, et al. The Evi-1 oncoprotein inhibits c-Jun N-terminal kinase and prevents stress-induced cell death [J]. EMBO J, 2000, 19: 2958-2968.
[214] Teng D H, Perry W L 3rd, Hogan J K, et al. Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor [J]. Cancer Res, 1997, 57: 4177-4182.
[215] Su G H, Hilgers W, Shekher M C, et al. Alterations in pancreatic, biliary and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene [J]. Cancer Res, 1998,58:2339-2342.
[216] Yoshida B A, Dubauskas Z, Chekmareva M A, et al. Mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17 [J]. Cancer Res, 1999, 59: 5483-5487.
[217] Garay M, Gaarde W, Monia B P, et al. Inhibition of hypoxia/reoxygenation-induced apoptosis by an antisense oligonucleotide targeted to JNK1 in human kidney cells [J]. Biochem Pharmacol, 2000, 59: 1033-1043.
[218] Ho F M, Liu S H, Liau C S, et al. High glucose-induced apoptosis in human endothelial cells is mediated by sequential activations of c-Jun NH2-terminal kinase and caspase-3 [J]. Circulation, 2000, 101: 2618-2624.
[219] Kawasaki M, Hisamoto N, lino Y, et al. A Caenorhabditis elegans JNK signal transduction pathway regulates coordinated movement via type-DGABAergic motor neurons [J]. EMBO J, 1999,18:3604-3615.
[220] Riesgo-Escovar J R, Jenni M, Fritz A, et al. The Drosophila Jun-N-terminal kinase is required for cell morphogenesis but not for DJun-dependent cell fate specification in the eye [J]. Genes Dev, 1996, 10: 2759-2768.
[221] Sluss H K, Han Z, Barrett T, Davis R J, Ip Y T. A JNK signal transduction pathway that mediates morphogenesis and an immune response in Drosophila [J]. Genes Dev, 1996, 10: 2745-2758.
[222] Leppa S, and Bohmann D. Diverse functions of JNK signaling and c-Jun in stress response and apoptosis [J]. Oncogene, 1999,18: 6158-6162.
[223] Mlodzik, M. Planar, polarity in the Drosophila eye: a multifaceted view of signaling specificity and cross-talk [J]. EMBO J, 1999, 18,6873-6879.
[224] Boutros M, Paricio N, Strutt D I, et al. Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling [J], Cell, 1998, 94: 109-118.
[225] Marzars G R, Jeanteur P, Lynch H T, et al. Nucleotide sequence polymorphism in a hot spot mutation region of the p53 gene [J]. Oncogene, 1992, 7: 781-782.
[226] Soussi T C, de Fromental C, May P. Structural aspects of the p53 protein in relation to gene evlution [J]. Oncogene, 1990, 5: 945-952.
[227] Candau R, Scolnick D M, Darpino P, et al. Two tandem and independent sub-activation domains in the amino terminus of p53 require the adaptor complex for activity [J]. Oncogene, 1997, 15: 807-816.
[228] Venot C, Maratrat M, Sierra V, et al. Definition of a p53 transactivation function-deficient mutant and characterization of two independent p53 transactivation subdomains [J]. Oncogene, 1999, 18:2405-2410.
[229] Momand J, Wu H H, Dasgupta G. MDM2-master regulator of the p53 tumor suppressor protein [J] .Gene, 2000,242: 15-29.
[230] Venot C, Maratrat M, Dureuil C, et al. The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression [J]. EMBO J, 1998, 17: 4668-4679.
[231] Wolkowicz R, Rotter V. The DNA binding regulatory domain of p53: see the C [J]. Pathol Biol (Paris), 1997,45: 785-796.
[232] Kaghad M, Bonnet H, Yang A, et al. Monoallelically expressed gene related to p53 at Ip36, a region frequently deleted in neuroblastoma and other human cancers [J]. Cell, 1997, 90: 809-819.
[233] Yang A, Kaghad M, Wang Y, et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities [J]. Mol Cell, 1998,2:305-316.
[234] Wolf D, Harris N, Goldfinger N, et al. Isolation of a full-length mouse cDNA clone coding for an immunologically distinct p53 molecule [J]. Mol Cell Biol, 1985, 5: 127-132.
[235] Ikeguchi M, Makino M, Kaibara N. Telomerase activity and p53 genemutation in familial polyposis coli [J]. Anticancer Res, 2000, 20: 3833-3837.
[236] Porter PL, Gown A M, Kramp S G, et al. Wids pread p53 over expression in human malignant tumor [J]. Am J Pathol, 1992, 140: 145-153.
[237] Caelles C, Helmberg A, Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes [J]. Nature, 1994, 37: 220-223.
[238] Chipuk JE, Maurer U, Green DR, et al. Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription [J]. Cancer Cell, 2003, 4: 371-381.
[239] Zhao Y F, Chaiswing L, Velez J M, et al. p53 translocation tomitochondriaprecedes its nuclear translocation and target mitochondria oxidative defense protein manganese superoxide dismutase [J]. Cancer Res, 2005, 65: 3745-3750.
[240] Talos F, Petenko O, Mena P, et al. Mitochondrially targeted p53 has tumor suppressor activities in vivo [J]. Cancer Res, 2005, 65: 9971-9981.
[241] Leng R P, Lin Y P, Ma W L, et al. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation [J]. Cell, 2003,112: 779-791.
[242] Dornan D, Wertz I, Shimizu H, et al. The ubiquitin ligase COP1 is a critical negative regulator of p53 [J]. Nature, 2004, 429: 86-92.
[243] Chipuk JE, Bouchier-Hayes L, Kuwana T, et al. PUMA couples the nuclear and cytoplasmic proapoptotic function of p53 [J]. Science, 2005, 309: 1732-1735.
[244] Wu WS, Heinrichs S, Xu D, et al. Slug antagonizes p53-madiated apoptosis of hematopoietic progenitors by repressing puma [J]. Cell, 2005, 123: 641-653.
[245] Sayan B S, Sayan A E, Kinight R A, et al. p53 is cleaved by caspases generating fragments localizing to mitochondria [J]. J Biol Chem, 2006, 281: 13566-13573.
[246] Yamaguchi A, Kurosaka Y, Fushida S, et al. Expression of p53 protein in colorectal cancer and its relationship to short term prognosis [J]. Cancers, 1992, 70: 2778-2784.
[247] Wu X, Zhao H, Amosc I, et al. p53 Genotypes and haplotypes associated with lung cancer susceptibility and ethnicity [J]. J Natl Cancer Inst, 2002,94:681-690.
[248] Puisieux A, Lim S, Groopman J, et al. Selective targeting of p53 genemutational hotspots in human cancers by etiologically defined carcinogens [J]. Cancer Res, 1991, 51: 6185-6189.
[249] Fagotto F, Jho E, Zeng L, et al. Domains of axin involved in protein-protein interactions, Wnt pathway inhibition, and intracellular localization [J]. J Cell Biol, 1999, 145: 741-56.
[250] Kishida S, Yamamoto H, Hino S, et al. DIX domains of Dvl and Axin are necessary for protein interactions and their ability to regulate β-catenin stability [J]. Mol Cell Biol, 1999, 19: 4414-4422.
[251] Liao G, Tao Q, Kofron M, et al. Jun NH2-terminal kinase (JNK) prevents nuclear beta-catenin accumulation and regulates axis formation in Xenopus embryos [J]. Proc Nat Acad Sci USA, 2006 103:16313-16318.