大鼠脑缺血再灌注和丁苯酞干预后海马组织中Smad4的表达变化及Smad4在高尔基体定位的研究
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摘要
目的：观察大鼠脑缺血再灌注损伤以及丁苯酞干预后Smad4的表达变化,以及Smad4亚细胞定位,探讨丁苯酞的神经保护机制。
方法：(1)分组：健康SD大鼠50只,随机分为正常对照组、假手术组、缺血再灌注组(I／R)、丁苯酞干预组(NI/R)；观察在脑缺血再灌注后6h、1d、3d、7d的各相应时间点Smad4的表达：(2)模型制作：缺血再灌注组大鼠予以夹闭双侧颈总动脉15min以及硝普钠控制低血压后再灌注；假手术组大鼠仅分离双侧颈总动脉不予以夹闭;丁苯酞干预组在实验前两天开始丁苯酞灌胃(80mg/kg,BID)直到处死,余步骤同缺血再灌注组；(3)HE染色观察病理变化；(4)免疫组织化学染色观察Smad4表达变化。(5)采用免疫荧光共聚焦的方法观察Smad4在额叶皮质细胞高尔基体的定位情况。
全部数据采用SPSS13.0进行统计分析。
结果：
(1)HE染色：1.大鼠海马CA1区神经元细胞减少,神经元变性、坏死,这种改变在缺血再灌注后3天及7天最为明显。丁苯酞干预后,干预组中存活的海马CA1区神经细胞较非干预组明显增加。
(2)免疫组化：Smad4在神经细胞胞核及胞质中均有阳性表达。正常对照组与假手术组大鼠海马CA3区神经元中Smad4阳性细胞表达较少,Smad4在缺血再灌注损伤后在各时间点表达显著上调,1d时明显升高,在3d和7d时达到高峰,与对照组比较,有显著性差异(P<0.05)。丁苯酞干预组Smad4表达在各相应时间点较对照组表达上调,趋势与缺血再灌注组一致,阳性率明显低于缺血再灌注组(P<0.05)。
(3)高尔基体特异性标志物TGN46的免疫荧光和Smad4的免疫荧光在大鼠皮质细胞内明显发生重叠。
结论：
1. Smad4在缺血再灌注的脑组织中表达升高并可能发挥神经保护作用。
2.丁苯酞可能通过与Smad4的协同作用来减轻脑组织损伤程度,发挥神经保护作用。
3.在大鼠皮质细胞内,Smad4存在于高尔基体,表明Smad4的分泌依赖高尔基体,同时Smad4可能对高尔基体具有保护作用。
Objective:To investigate the protective mechanisms of NBP after transient brain ischemia, and further study of expression changes and subcellular localization of smad4 in rats
Methods:(1) Animal Groups:Fifty healthy male SD rats, devided into four groups:Normal Group (n=5); Sham Operation Group (n=5); Ischemia Reperfusion Group (I/R) (n=20); NBP Intervention Group (NI/R) (n=20); I/R Group and NI/R Group are devided into four subgroups (each group n=5):6 hours,1 day,3 days,7 days after I/R ingury; (2) Models:15 minutes'common carotid artery occlusion(CAO) of both sides and reperfusion for 6 hours,1 day,3 days,7 days,Sodium Nitroprusside (SNP)control low blood pressure in Rats; The Sham Operation Group only give segregation but no occlusion; gavage of NBP(80mg/kg,BID) until death,;(3)HE Staining; (4)Immunohistochemistry.(5) Confocal Immuno-fluorographs of Smad4 and TGN46 were taken in rats models postocclusion
Results:There were significant histological changes and elevated expression of Smad4 protein in I/R group compared with sham operation group in the hippocampus of the Rats,6h expression increased, 1d moderately increased,3d and 7d highest.P<0.05compared with the sham operation group; The histological changes in hippocampus of CA1 were significantly increased in NBP group compared with I/R group(P<0.05). Smad4 was colocalized with TGN46,a marker molecule for the Golgi apparatus.
Conclusions:
1. Expressions of Smad4 in hippocampus of CA3 of rats were significantly increased following cerebral ischemia-reperfusion, this suggested that the increased expressions of Smad4 could have protected the brain tissue from damage.
2. NBP can relieve the brain damage induced by focal I/R in rats, which may be correlated with the inhibition of expression of Smad4.
3. Smad4 was presented in the Golgi apparatus, suggesting that both continuous protein synthesis and transportation via the Golgi complex were required for Smad4 secretion and Smad4 may be essential for physiological functions involving GA
方法：(1)分组：健康SD大鼠50只,随机分为正常对照组、假手术组、缺血再灌注组(I／R)、丁苯酞干预组(NI/R)；观察在脑缺血再灌注后6h、1d、3d、7d的各相应时间点Smad4的表达：(2)模型制作：缺血再灌注组大鼠予以夹闭双侧颈总动脉15min以及硝普钠控制低血压后再灌注；假手术组大鼠仅分离双侧颈总动脉不予以夹闭;丁苯酞干预组在实验前两天开始丁苯酞灌胃(80mg/kg,BID)直到处死,余步骤同缺血再灌注组；(3)HE染色观察病理变化；(4)免疫组织化学染色观察Smad4表达变化。(5)采用免疫荧光共聚焦的方法观察Smad4在额叶皮质细胞高尔基体的定位情况。
全部数据采用SPSS13.0进行统计分析。
结果：
(1)HE染色：1.大鼠海马CA1区神经元细胞减少,神经元变性、坏死,这种改变在缺血再灌注后3天及7天最为明显。丁苯酞干预后,干预组中存活的海马CA1区神经细胞较非干预组明显增加。
(2)免疫组化：Smad4在神经细胞胞核及胞质中均有阳性表达。正常对照组与假手术组大鼠海马CA3区神经元中Smad4阳性细胞表达较少,Smad4在缺血再灌注损伤后在各时间点表达显著上调,1d时明显升高,在3d和7d时达到高峰,与对照组比较,有显著性差异(P<0.05)。丁苯酞干预组Smad4表达在各相应时间点较对照组表达上调,趋势与缺血再灌注组一致,阳性率明显低于缺血再灌注组(P<0.05)。
(3)高尔基体特异性标志物TGN46的免疫荧光和Smad4的免疫荧光在大鼠皮质细胞内明显发生重叠。
结论：
1. Smad4在缺血再灌注的脑组织中表达升高并可能发挥神经保护作用。
2.丁苯酞可能通过与Smad4的协同作用来减轻脑组织损伤程度,发挥神经保护作用。
3.在大鼠皮质细胞内,Smad4存在于高尔基体,表明Smad4的分泌依赖高尔基体,同时Smad4可能对高尔基体具有保护作用。
Objective:To investigate the protective mechanisms of NBP after transient brain ischemia, and further study of expression changes and subcellular localization of smad4 in rats
Methods:(1) Animal Groups:Fifty healthy male SD rats, devided into four groups:Normal Group (n=5); Sham Operation Group (n=5); Ischemia Reperfusion Group (I/R) (n=20); NBP Intervention Group (NI/R) (n=20); I/R Group and NI/R Group are devided into four subgroups (each group n=5):6 hours,1 day,3 days,7 days after I/R ingury; (2) Models:15 minutes'common carotid artery occlusion(CAO) of both sides and reperfusion for 6 hours,1 day,3 days,7 days,Sodium Nitroprusside (SNP)control low blood pressure in Rats; The Sham Operation Group only give segregation but no occlusion; gavage of NBP(80mg/kg,BID) until death,;(3)HE Staining; (4)Immunohistochemistry.(5) Confocal Immuno-fluorographs of Smad4 and TGN46 were taken in rats models postocclusion
Results:There were significant histological changes and elevated expression of Smad4 protein in I/R group compared with sham operation group in the hippocampus of the Rats,6h expression increased, 1d moderately increased,3d and 7d highest.P<0.05compared with the sham operation group; The histological changes in hippocampus of CA1 were significantly increased in NBP group compared with I/R group(P<0.05). Smad4 was colocalized with TGN46,a marker molecule for the Golgi apparatus.
Conclusions:
1. Expressions of Smad4 in hippocampus of CA3 of rats were significantly increased following cerebral ischemia-reperfusion, this suggested that the increased expressions of Smad4 could have protected the brain tissue from damage.
2. NBP can relieve the brain damage induced by focal I/R in rats, which may be correlated with the inhibition of expression of Smad4.
3. Smad4 was presented in the Golgi apparatus, suggesting that both continuous protein synthesis and transportation via the Golgi complex were required for Smad4 secretion and Smad4 may be essential for physiological functions involving GA
引文
[1]杨期东.神经病学.北京：人民卫生出版社,2001,118-152.
[2]冯亦璞,胡盾。张丽英。丁基苯酞对小鼠全脑缺血的保护作用[J]. 药学学报,1995,30(10)：741—744
[3]熊杰,冯亦璞.丁基苯酞对局灶性脑缺血过程中线粒体损伤的保护作用[J].药学学报,2000,35(6)：408—412
[4]种兆忠,冯亦璞.丁基苯酞对蛛网膜下腔出血后脑血流的改善及血脑屏障的保护作用[J].药学学报,1998,33(4)：245—249.
[5]Chang Zhao. Zhong, Feng Yi-Pu. D1·3·u·hutylphthalide attenuates repeffusion·induced blood-brain barrier after focal cerebral ischemia in rats[J]. Acta Phamacal Sin,1999,20(8):696—700.
[6]徐皓亮.丁摹苯酞对局灶性脑缺血大鼠软脑膜微循环障碍的影响[J].药学学报,1999,34(3)：172—175
[7]种兆忠,冯亦璞.丁基苯酞对缺血组织中及低糖低氧刺激后培养的神经细胞中胆碱乙酰化酶的影响[J].中国药学杂志,1999,34(8)： 519—522
[8]GraffenriedCL, BertozziCR. The roles of enzyme localisation and complex formation in glycan assembly within the Golgi complex. Curr Opin [J]Cell Biol 2004;16:356-363.
[9]WuCC, MacCossMJ, Mardones G, FinniganC, MogelsvangS, YatesJR3rd, HowellKE. Organellar proteomics reveals Golgi arginine dimethylation. Mol Biol Cell [J]2004; 15:2907-2919.
[10]HabuchiH, HabuchiO, KimataK. Sulfation pattern in glycosaminoglycan:does it have a code? Glycoconj J[J] 2004;21:47-52.
[11]PreisingerC, BarrFA. Kinases regulating Golgi complex structure and function. [J]Biochem Soc Symp 2005;72:15-30.
[12]HolthuisJC, PomorskiT, RaggersRJ, SprongH, Van MeerG. The organizing potential of sphingolipids in intracellular membrane transport. [J]Physiol Rev 2001;81:1689-1723.
[13]N.K. Gonatas. The Golgi apparatus in disease. In:E.G Berger and J. Roth, Editors, The Golgi apparatus, Birkhauser [J]Verlag, Basel,1997;pp 247-273.
[14]Hu Z,Fan J,Zeng L,Lu W,Tang X,Zhang J Transient cerebral ischemia lead to TGF-beta2 expression in Golgi apparatus organelles [J]Curr Neurovasc Res 2008 Aug;5(3):178-84
[15]Hu Z, Zeng L,Xie L,Lu W, Zhang J,Li T. Morphological alteration of Golgi apparatus and subcellular compartmentalization of TGF-betal in Golgi apparatus in gerbils following transient forebrain ischemia.[J]Neurochem Rem 2007 Nov;32(11):1927-31
[16]Bottner M, Krieglstein K, Unsicker K:The transforming growth factor-[beta]s:structure, signaling, and roles in nervous system. J Neuro-chem 2000,75:2227-2240
[17]Ruocco A.Nicole O,Docagne Fecal. Increased expression of TGF in brain tissue after ischemic strock in humans Stroke,2000,27(5):852-857
[18]Prehn JH, Miller R J. Opposite effects of TGF on rapidly and slowly triggered excitotoxic injury Neuropharmacology,2002,34(3)249-256
[19]Ueberham u,Ueberham E Gruschka H et Altered subcellular location of phosphorylated Smads in Alzheimer's disease. [J]Eur Neurosci 2006 Oct;24(8):2327-34
[20]Baiq S, Van Helmond Z, Love S el,al. Tau hyperphosphorylation affects Smad 2/3 translocation.[J] Epub 2009 Jun 23;163(2):561-70
[21]SHAO Bu-yun, CHEN Qian-xue,LIU Gang,et,al. Expression and Effect of Smad4 and Smad7 in Human Glioma [J]Tumor of R 2009 Feb;32(3)132-134
[22]SANCH EZ2EL SNER T, BOTELL A L M, VEL AS-COB,et al. Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways [J].J Biol Chem, 2005,277:43799-43808.
[23]ART HU RH M,URE J,SMIT HAJ, et al. Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development [J]. Dev Biol,2008,217:42-53.
[24]CHIPUKJ E, BHAT M, HSINGA Y,et al. Bel-xl blocks transforming growth-beta 1-induced apoptosis by inhibiting cytochrome release and not by directly antagonizing Apaf-1-dependent caspase activation in prostate epithelial cells[J]. J Biol chem,2008,276:26614-26621
[25]Yamasaki Y, Itoyama Y, Kogure K.2001. Involvement of cytokine production in pathogenesis of transient cerebral ischemic damage. Keio J Med. 45(3),225-9.
[26]ZHOU Wei-Jun, HU Zhi-Ping. Expression of Smad2 and Smad4 protein in brain tissue following cerebral ischemia/reperfusion in gerbils.[J]International Neurology and Neurosurgery 2008,35(2)
[27]JIAO Dong-Liang, NI Xiu-Shi, GAO Yan,et. Effect of dl-3n-butylphthalide on the Expression of caspase-3 in the Rat Model of Focal Cerebral Ischemia-reperfusion.[J]Chin J Clin Neurosci 2007,15(1),19-23
[28]Bottner M, Krieglstein K, Unsicker K:The transforming growth factor-[beta]s:structure, signaling, and roles in nervous system. J Neuro-chem 2000,75:2227-2240
[29]Prehn JH, Miller R J. Opposite effects of TGF on rapidly and slowly triggered excitotoxic injury Neuropharmacology,2002,34(3)249-256
[30]Chalmers KA, Love S. Phosphorylated Smad2/3 colocalizes with phospho-tau inclusions in Pick disease,progressive supranuclear palsy, and corticobasal degeneration but not with alpha-synuclein inclusions in multiple system atrophy or dementia with Lewy bodies.2007 Nov;66(11):1019-26
[31]Burton T,Liang B,Dibrob A.Transforming growth factor-beta-induced transcription of the Alzheimer beta-amyloid precursor protein gene involvs interaction between the CTCF-complex and Smads.2002 Jul 19;295(3)713-23
[32]Chalmers KA,Love S. Neurofibrillary tangles may interfere with Smad2/3 signaling in neurons 2007 Feb;66(2)158-67
[33]Mirshafiey A, Mohsenzadegan M.TGF-beta an a promising option in the treatment of multiple sclerosis [J]Neuropharmacology.2009 May Jun;56(6-7) 929-36
[34]PONCELET A C, SCHNAPER H W. Spl and Smad proteins cooperate to mediate transforming growth factor-beta 1-induced alpha2(J) collagen expression in human glomerular mesangial cells [J]. J Biol Chem,2006, 276:6983-6992.
[35]周俊,陆国平,戚文航,等. 核转录因子N F-2κB对血管损伤和新生内膜形成的影响[J]. 临床心血管病杂志,2007,23(12)：927-931.
[36]HAO J, JU H, ZHAO S, et al. Elevation of expression of Smads 2,3, and 4, decorin and TGF-beta in the chronic phase of myocardial infarct scar healing[J]. J Mol Cell Cardiol,2007,31:667-678.
[37]ARTHU R HM,URE J,SMITHA J,et al.Endoglin,an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development [J].Dev Biol,2000,217:42-53.
[38]BANN ISTER A J,KOU ZARID ES T.The CBP coactivator is a histone acetyltransferase [J]. Nature,1996,384:641-643.
[39]SANCH EZ-EL SN ER T, BOTELL A L M, VELASCO B, et al. Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways[J]. J Biol Chem, 2002,277:43799-43808.
[40]Yamasaki Y, Itoyama Y, Kogure K.2001. Involvement of cytokine production in pathogenesis of transient cerebral ischemic damage. Keio J Med. 45(3),225-9.
[41]Li J,Qu Y,Li X, Li D,Zhao F,et,al. The role of integrin alpha(v)beta(8) in neonatal hypoxic-ischemic brain injury.[J] Neurotox Res.2010 May; 17(4): 406-17
[42]Buisson A,Lesne S,Docagne F..Transforming growth factor beta andischemic brain injury. [J]Cell MolNeurobiol,2003.23,539-550
[43]Yin J, Sakamoto K,Zhang H,Ito Z et,al. Transforming growth factor-betal upregulates keratan sulfate and chondroitin sulfate biosynthesis in microglias after brain injury.[J] Brain Res 2009 Mar 31;1263:10-12
[44]Wang Y,Moges H,Bharucha Y, Symes A. Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex.[J] Exp Neurol 2007 Jan;203(1):168-84
[45]Komuta Y,Teng X,Yanagisawa H, Sango K,et,al Expression of transforming growth factor-beta receptors in meninge fibroblasts of the injured mouse brain.[L] Cell Mol Neurobiol 2010 Jan;30(1):101-11
[46]Grammas P, Ovase R. Cerebrovascular transforming growth factor-beta contributes to inflammation in the Alzhemer's disease brain.[J] Am J Pathol. 2002 May;160(5)1583-7
[47]Pang L, YeW, Che XM, et al. Reduction of inflammatory response in the mouse brain with adenoviral mediated transforming growth factor-ssl expression. [J]Stroke,2001,32:544-552.
[48]Chun L, Song L, Jin Z,et,al.dl-3n-butylphthalide prevents stroke via impro vement of cerebral microvessels in RHRSP.[J] Neurological Sciences 260 (2007)106-113
[49]Feng YP,Hu D,Zhang L Y.Effect of DL-butylphthalide(NBP) on mouse brain energy metablizm in complete brain ischemia induced by decapitation [J].Acta Pharm Sin,1995,30:741.
[50]Liu XG,Feng YP. Protective effect of DL-3-butylphthalide on ischemic neurological damage and abnormal behavior in rats subjected to focal ischemia[J].Acta Pharm Sin,1995,30:896.
[51]Deng WB,Feng YP.Effect of dl-3-n2butylphthalide on brain edema in rats subjected to focal cerebral ischemia.[J].Chin Med Sci J,1997,12:102.
[52]Xiong J, Feng YP. Effect of butylphthalide on the activities of complexes of the mitochondrial respiratory chain[J].Acta Pharm Sin,1999,34:241
[53]Xu Hao-Liang.Feng Yi Pu. Inhibitory effects of ehiral 3-n-bu-tylphthalide on inflammation following focal ischemic brain injury in rata [J].Acts Pharma Sin,2000,21(5):433-438.
[54]Chang Zhao-Zhong, Feng Yi Pu. Effect of 3-n butylphthalide on reperfusion induced lipid peroxidation following cerebral ischemia in and superoxide radical formation in vitro[J]. Journal of Chinese Pharmaceu-tical Sciences, 1999.8(2):95-99.
[55]Jiao D L,NI Xiu S,Gao Y,Zhao Y,et,al. Effect of dl-3n-butylphthalide on the Expression of caspase-3 in the Rat Model of Focal Cerebral Ischemia-reperfuson [J]Chin J Clin Neurosci 2007,15(1)19-23
[56]Chang Zhao.Zhong,Feng Yi-Pu.D1-3-u-hutylphthalide attenuates repeffusion induced blood brain barrier after focal cerebral ischemia in rats[J]. Acta Phamacal Sin,2004,20(8):696-700.
[57]Williams AO, Knapton AD, Geiser A et al The liver in transforming growth factor-Beta-1 (TGF-beta 1) null mutant mice. Ultrastruct Pathol 1996 Sep-Oct;20(5):477-90
[1]Pelton RW,Saxena B Jones M,et al. Immunohistochemical localization of TGF-β1,TGF-β2,and TGF-β3 in the mouse embryo:expression patterns suggest multiple roles during embryonic development [J] Cell Biol,1991,115: 1091-1105
[2]Yamamoto T, Noble NA, Cohen AH,et al. Transforming growth factor-β isoforms in human glomerular diseases [J] Kidney Int,1996,49:461
[3]Luukko K,Ylikorkala A,Mkel TP.Developmentally regulated expression of Smad3, Smad4, Smad6, and Smad7 involved in TGF-β signaling [J]. MechDev,2001, 101 (1-2):209-212
[4]SAVAGE C, DAS P, LIFA, et all Caenorhabditis elegans genes Smad2, smad3, and sma4 define a conserved family of transforming growth factor β pathway components[J]. Proc Natl Acad Sci USA,2003,93 (2):79027941
[5]Kretzschmar M,Massague J. SMADs mediators and regulator of TGF-beta signaling [J]. Curr Opin Genet Dev,1998,8 (1):103-111
[6]WU G, CHEN Y G, OZDAMAR B, et al. Structural basis of Smad2 recognition by the Smad anchor for recep tor activation [J].Science,2000,287 (5450) 922971
[7]Massague J,Blain SW, Lo RS. TGF-β Signaling in Growth Conlrol,Cancer and Heritable Disorders [J]. Cell,2000,103(2):295-309.
[8]Ueberham u,Ueberham E Gruschka H et Altered subcellular location of phosphorylated Smads in Alzheimer's disease.[J]Eur Neurosci 2006 Oct;24(8): 2327-34
[9]WU G, CHEN YG, OZDAMAR B,et all. Structural basis of Smad2 recognition by the Smad anchor for recep tor activation [J] Science,2000,287 (5450):92-97
[10]N ISH MOTO S, NISHIDA E1 MAPK signalling:ERK5 versus ERK1/2 [J] EMBO reports,2006,7(8):782-786
[11]NAKAMURA K，JOHNSON G L. Noncanonical Function of ME-KK2 and MEK5 PB1 domains for coordinated extracellular signal-regulated kinase 5 and c-Jun N-term inal kinase signaling[J]. Mol Cell Biol,2007,27 (12):4566-4577
[12]NAKAMURA K, JOHNSON G L.PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway [J]. J Biol Chem,2003,278 (39):36989-369921
[13]ZHAO B M,HOFFMANN FM. Inhibition of transforming growthFactor-β1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide ap tamer Trx-SARA [J].Mol Biol Cell,2006s 17 (9): 3819-38311
[14]SUN Y,DING L, ZHANG H, et all Potentiation of Smad-media-ted transcrip-tional activation by the RNA-binding protein RBPMS[J]. Nucleic Acids Res, 2006,34 (21):6314-6326
[15]KRETZSCHMAR M, DOODY J, MASSAGUE J. Opposing BMP and EGF signaling pathways converge on the TGF-β family mediator Smadl [J].Nature, 1997,389 (6651):618-622
[16]DERYNCK R, ZHANG Y E. Smad-dependent and Smad independent pathways in TGF-p family signaling[J]. Nature,2003,425(6958):577-5841
[17]MASSAGUE J. Integration of Smad and MAPK pathways:a link and a linker revisited[J].Genes Dev,2003,17 (24):2993-2997
[18]BROWN J D, DICH IARA M R, ANDERSON K R, et al. MEKK-1, acomponent of the stress (stress-activated p rotein kinase/c-Jun N-terminal kinase)pathway, can selectively activate Smad2-medi-ated transcriptional activation in endothelial cells [J].J Biol Chem,1999,274 (13):8797-8805
[19]LIANG M,LIANG Y Y, WRIGHTON K, et al. Ubiquitination and proteolysis of cancer-derived Smad4 mutants by SCFSkp2 [J].Mol Cell Biol,2004,24 (17): 7524-7537
[20]DZIEMBOW SKA M, DANILKIEW ICZ M, W ESOLOW SKAA,et al. Cross-talk between Smad and p38 MAPK signaling in transforming growth factor beta signal transduction in human glioblastoma cells[J]. Biochem Biophys Res Commun,2007,354 (4):1101-1106.
[21]MATSUURA I, DENISSOVAN G, WANG G, et al. Cyclin-de-pendent kinases regulate the antip roliferative function of Smads [J]. Nature,2004,430(6996): 226-231
[22]CONERY A R, CAO Y,THOMPSON E A,et all Akt interacts directly with Smad3 to regulate the sensitivity to TGF-P induced apoptosis[J]. Nat Cell Biol, 2004,6(4):366-372
[23]ROBERTS A B,RUSSO A, FELICIA, et al.Smad 3:akey player in pathogenetic mechanisms dependenton TGF-β[J].Ann N Y Acad Sci,2003,1995:1-10
[24]SHI Y, WANG Y F，JAYARAMAN L,et al.Crystal structure of a Smad MH1 domain bound to DNA:insights on DNA binding in TGF-β signaling [J]. Cell, 1998,94(5):585-594
[25]FREDER ICK J P, LIBERATIN T, WADDELLD S, et al. Transforming growth factorβ-mediated transcrip tionalrep ression of c-mycis dependention direct binding of Smad 3 to a novel rep ressive Smad binding element[J].Mol Cell Biol, 2004,24(6):2546-2559
[26]RANDALLR A, HOW ELL M, PAGE C S,et al. Recognition of Phosp-horylated Smad 2 containing comp lexes by a novel Smad interaction motif[J]. Mol Cell Biol,2004,24 (3):1106-1121
[27]BLOKZIJL A, TEND IJKE P, IBANEZC F1 Physical and functional interaction between GATA-3 and Smad 3 allows TGF-β regulation of GAT A target genes[J]. Curr Biol,2002,12(1):35-45
[28]KURISAKI K, KUR ISAKI A, VALCOURT U, et al. Nuclear factor YY1 inhibits transform ing growth factor-β and bone morphogenetic protein-induced cell differentiation[J]. Mol Cell Biol,2003,23(13):4494-4510.
[29]HIRATOCH IM, NAGASE H, KURAMOCH I Y, et alThe Delta intracellular domain mediates TGF-β/Activin signaling through binding to Smads and has an important bi-directional function in the Notch-Delta signaling pathway[J]. Nucleic Acids Res,2007,35(3):912-922
[30]CORDENONSI M, MONTAGNER M, ADORNO M, et al. Integration of TGF-β and Ras/MAPK signaling through p53 phosphorylation[J].Science,2007, 315 (5813):840-843
[31]XIAO Z, LIU X, HENISY I,et al.A distinct nuclear localization signal in the Nterminus of Smad 3 determ ines its ligand-induce nuclear translocation[J]. Proc Natl Acad Sci USA,2000,97(14):7853-7858
[32]. Chao CC, Hu S, Frey WH, II, AlaTA，Tourtellotte WW, Peterson PK: Transforming growth factor beta in Alzheimer's disease. Clin Diag Lab Immunol 1994,1:109-110
[33]Flanders KC, Lippa CF, Smith TW， Pollen DA, Sporn MB:Altered expression of transforming growth factor-beta in Alzheimer's disease. Neurology 2003, 45:1561-1569 [PubMed]
[34]Vander Wal EA, Gomez-Pinilla F, Cotman CW:Transforming growth factor-beta 1 is in plaques in Alzheimer and Down pathologies. Neuroreport 2004,4:69-72 [PubMed]
[35]Ueberham u,Ueberham E Gruschka H et Altered subcellular location of phosphorylated Smads in Alzheimer's disease.[J]Eur Neurosci 2006 Oct;24(8): 2327-34
[36]LEE HG,Ueda M, Zhu X,Perry G,Smith MA:Ectopic expression of phospho-Smad2 in Alzheimer's disease:uncoupling of the transforming growth factor-beta pathway. J Neurosci Res 2006 Dec;84(8)1856-61
[37]Baig S,Van Helmond Z,Love S Tau hyperphosphorylation affect Smad2/3 translocation.(2009)Oct6;561-70.Epub 2009 Jun 23
[38]Selkoe, D.J,Schenk, D.Alzheimer's disease:Molecular understanding predicts amyloid-based therapeutics (2003) Annu. Rev. Pharmacol. Toxicol.43,545-584
[39]Grammas,P,and Ovase,R Cerebrovascular Transforming Growth Factor-β Contributes to Inflammation in the Alzheimer's Disease Brain (2002)Am, J, Pathol,160.1583-1587
[40]Lesne,S.,Docagne,F.,Gabriel,C.,Liot,G.,Lahiri,D.K.,Buee,L.,Plawinski,L.,Delaco urte,A.,Mackenzie,E.T.,Buisson,A.,and Vivien,D Transforming Growth Factor-β1 Potentiates Amyloid-β Generation in Astrocytes and in Transgenic Mice (2003)J, Biol Chem,278,18408-18418.
[41]Wyss-Coray, T., Masliah, E., Mallory, M., McConlogue, L., Johnson-Wood, K., Lin, C, and Mucke, L. Amyloidogenic role of cytokine TGF-betal in transgenic mice and in Alzheimer's disease (1997) Nature 389,603-606
[42]Cordoliani-Mackowiak, M. A., Henon, H., Pruvo, J. P., Pasquier, F., and Leys, D. Influence of Hippocampal Atrphy(2003) Arch. Neurol.60,585-590
[43]Luedecking, E. K., DeKosky, S. T., Mehdi, H., Ganguli, M., and Kamboh, M. I. Analysis of genetic polymorphisms in the transforming growth factor-betal gene and the risk of Alzheimer's disease (2000) Hum. Genet.106,565-569
[44]Wyss-Coray, T., Lin, C., Yan, F.,Yu, G. Q., Rohde, M., McConlogue, L., Masliah, E., and Mucke, L. TGF-betal promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice (2001) Nat. Med.7, 612-61
[45]Ren, R. F., Hawver, D. B., Kim, R. S., and Flanders, K. C. Transforming growth factor-beta protects human hNT cells from degeneration induced by beta-amyloid peptide:involvement of the TGF-beta type Ⅱ receptor (1997) Mol. Brain Res.48,315-322
[46]Flanders, K. C., Ren, R. F., and Lippa, C. F. Transforming growth factor-betas in neurodegenerative disease (1998) Prog. Neurobiol.54,71-85
[47]Wyss-Coray, T., Masliah, E., Mallory, M., McConlogue, L., Johnson-Wood, K., Lin, C., and Mucke, L. Amyloidogenic role of cytokine TGF-betal in transgenic mice and in Alzheimer's disease (1997) Nature 389,603-606
[48]Harris-White, M. E., Chu, T., Balverde, Z., Sigel, J. J., Flanders, K. C., and Frautschy, S. A. The Amyloid-P Peptide Suppresses Transforming Growth Factor-β1-induced Matrix Metalloproteinase-2 Production via Smad7 Expression in Human Monocytic THP-1 Cells (1998) J. Neurosci.18,10366-10374
[49]Fabian DOCAGNE, Cecilia GABRIEL, Nathalie LEBEURRIER,etc. Sp1 and Smad transcription factors co-operate to mediate TGF-β-dependent activation of amyloid-β precursor protein gene transcription Biochem. J. (2004) 383, 393-399
[50]Thiery JP:Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer 2:442-454,2002
[51]Wick W,Grimmel C, Wild-Bode C, Platten M, Arpin M and Weller M:Ezrin-dependent promotion of glioma cell clonogenicity, motility, and invasion mediated by bcl-2 and Trans-forming Growth Factor-β2. J Neurosci 21:3360-3368,2001
[52]Platten M, Wick W and Weller M:Malignant glioma biology:role for TGF-β in growth, motility, angiogenesis and immune escape. Microsc Res Tech 52: 401-410,2001
[53]TNICKL-JOCKSCHAT, F ARSLAN, U BOGDAHN et,al. An imbalance between Smad and MAPK pathway is responsible for TGF-β tumor promoting effects in high-grade gliomas [J] International journal of oncology 30: 499-507,2007.
[54]Penuelas S, Anido J, Prieto-Sanchez RM, Folch G, Barba I, Cuartas I,et,al. TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma.[J]Cancer cell.2009 Apr 7; 15(4)315-27
[55]ARTHU R H M,URE J, SMITHA J,et al. Endoglin, an ancillary TGF-beta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development [J]. Dev Biol,2000,217:42-53
[56]BANN ISTER A J,KOU ZARID ES. The CBP coactivator is a histone acetyltransferase [J]. Nature,1996,384:641-643
[57]Isselbacher EM. Thoracic and abdominal aortic aneurysms. Circulation 2005;111:816-828. [PubMed:15710776]
[58].Thompson RW. Reflections on the pathogenesis of abdominal aortic aneurysms. Cardiovasc Surg 2002;10:389-394. [PubMed:12359414]
[59]Bobik A. Transforming growth factor-betas and vascular disorders. Arterioscler Thromb Vasc Biol 2006;26:1712-1720. [PubMed:16675726]
[60]Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA,Falanga V, Kehrl JH, et al. Transforming growth factor type beta:rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A 1986;83:4167-4171. [PubMed:2424019]
[61]Kim ES, Kim MS, Moon A. TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 2004;25:1375-1382. [PubMed:15492828]
[62]Laiho M, Saksela O, Keski-Oja J. Transforming growth factor beta alters plasminogen activator activity in human skin fibroblasts. Exp Cell Res 1986; 164:399-407. [PubMed:3519251]
[63]Safina A, Vandette E, Bakin AV. ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. Oncogene 2007; 26: 2407-2422. [PubMed:17072348]
[64]Selvamurugan N, Kwok S, Alliston T, Reiss M, Partridge NC. Transforming growth factor-beta 1 regulation of collagenase-3 expression in osteoblastic cells by cross-talk between the Smad and MAPK signaling pathways and their components, Smad2 and Runx2. J Biol Chem 2004;279:19327-19334. [PubMed: 14982932]
[2]冯亦璞,胡盾。张丽英。丁基苯酞对小鼠全脑缺血的保护作用[J]. 药学学报,1995,30(10)：741—744
[3]熊杰,冯亦璞.丁基苯酞对局灶性脑缺血过程中线粒体损伤的保护作用[J].药学学报,2000,35(6)：408—412
[4]种兆忠,冯亦璞.丁基苯酞对蛛网膜下腔出血后脑血流的改善及血脑屏障的保护作用[J].药学学报,1998,33(4)：245—249.
[5]Chang Zhao. Zhong, Feng Yi-Pu. D1·3·u·hutylphthalide attenuates repeffusion·induced blood-brain barrier after focal cerebral ischemia in rats[J]. Acta Phamacal Sin,1999,20(8):696—700.
[6]徐皓亮.丁摹苯酞对局灶性脑缺血大鼠软脑膜微循环障碍的影响[J].药学学报,1999,34(3)：172—175
[7]种兆忠,冯亦璞.丁基苯酞对缺血组织中及低糖低氧刺激后培养的神经细胞中胆碱乙酰化酶的影响[J].中国药学杂志,1999,34(8)： 519—522
[8]GraffenriedCL, BertozziCR. The roles of enzyme localisation and complex formation in glycan assembly within the Golgi complex. Curr Opin [J]Cell Biol 2004;16:356-363.
[9]WuCC, MacCossMJ, Mardones G, FinniganC, MogelsvangS, YatesJR3rd, HowellKE. Organellar proteomics reveals Golgi arginine dimethylation. Mol Biol Cell [J]2004; 15:2907-2919.
[10]HabuchiH, HabuchiO, KimataK. Sulfation pattern in glycosaminoglycan:does it have a code? Glycoconj J[J] 2004;21:47-52.
[11]PreisingerC, BarrFA. Kinases regulating Golgi complex structure and function. [J]Biochem Soc Symp 2005;72:15-30.
[12]HolthuisJC, PomorskiT, RaggersRJ, SprongH, Van MeerG. The organizing potential of sphingolipids in intracellular membrane transport. [J]Physiol Rev 2001;81:1689-1723.
[13]N.K. Gonatas. The Golgi apparatus in disease. In:E.G Berger and J. Roth, Editors, The Golgi apparatus, Birkhauser [J]Verlag, Basel,1997;pp 247-273.
[14]Hu Z,Fan J,Zeng L,Lu W,Tang X,Zhang J Transient cerebral ischemia lead to TGF-beta2 expression in Golgi apparatus organelles [J]Curr Neurovasc Res 2008 Aug;5(3):178-84
[15]Hu Z, Zeng L,Xie L,Lu W, Zhang J,Li T. Morphological alteration of Golgi apparatus and subcellular compartmentalization of TGF-betal in Golgi apparatus in gerbils following transient forebrain ischemia.[J]Neurochem Rem 2007 Nov;32(11):1927-31
[16]Bottner M, Krieglstein K, Unsicker K:The transforming growth factor-[beta]s:structure, signaling, and roles in nervous system. J Neuro-chem 2000,75:2227-2240
[17]Ruocco A.Nicole O,Docagne Fecal. Increased expression of TGF in brain tissue after ischemic strock in humans Stroke,2000,27(5):852-857
[18]Prehn JH, Miller R J. Opposite effects of TGF on rapidly and slowly triggered excitotoxic injury Neuropharmacology,2002,34(3)249-256
[19]Ueberham u,Ueberham E Gruschka H et Altered subcellular location of phosphorylated Smads in Alzheimer's disease. [J]Eur Neurosci 2006 Oct;24(8):2327-34
[20]Baiq S, Van Helmond Z, Love S el,al. Tau hyperphosphorylation affects Smad 2/3 translocation.[J] Epub 2009 Jun 23;163(2):561-70
[21]SHAO Bu-yun, CHEN Qian-xue,LIU Gang,et,al. Expression and Effect of Smad4 and Smad7 in Human Glioma [J]Tumor of R 2009 Feb;32(3)132-134
[22]SANCH EZ2EL SNER T, BOTELL A L M, VEL AS-COB,et al. Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways [J].J Biol Chem, 2005,277:43799-43808.
[23]ART HU RH M,URE J,SMIT HAJ, et al. Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development [J]. Dev Biol,2008,217:42-53.
[24]CHIPUKJ E, BHAT M, HSINGA Y,et al. Bel-xl blocks transforming growth-beta 1-induced apoptosis by inhibiting cytochrome release and not by directly antagonizing Apaf-1-dependent caspase activation in prostate epithelial cells[J]. J Biol chem,2008,276:26614-26621
[25]Yamasaki Y, Itoyama Y, Kogure K.2001. Involvement of cytokine production in pathogenesis of transient cerebral ischemic damage. Keio J Med. 45(3),225-9.
[26]ZHOU Wei-Jun, HU Zhi-Ping. Expression of Smad2 and Smad4 protein in brain tissue following cerebral ischemia/reperfusion in gerbils.[J]International Neurology and Neurosurgery 2008,35(2)
[27]JIAO Dong-Liang, NI Xiu-Shi, GAO Yan,et. Effect of dl-3n-butylphthalide on the Expression of caspase-3 in the Rat Model of Focal Cerebral Ischemia-reperfusion.[J]Chin J Clin Neurosci 2007,15(1),19-23
[28]Bottner M, Krieglstein K, Unsicker K:The transforming growth factor-[beta]s:structure, signaling, and roles in nervous system. J Neuro-chem 2000,75:2227-2240
[29]Prehn JH, Miller R J. Opposite effects of TGF on rapidly and slowly triggered excitotoxic injury Neuropharmacology,2002,34(3)249-256
[30]Chalmers KA, Love S. Phosphorylated Smad2/3 colocalizes with phospho-tau inclusions in Pick disease,progressive supranuclear palsy, and corticobasal degeneration but not with alpha-synuclein inclusions in multiple system atrophy or dementia with Lewy bodies.2007 Nov;66(11):1019-26
[31]Burton T,Liang B,Dibrob A.Transforming growth factor-beta-induced transcription of the Alzheimer beta-amyloid precursor protein gene involvs interaction between the CTCF-complex and Smads.2002 Jul 19;295(3)713-23
[32]Chalmers KA,Love S. Neurofibrillary tangles may interfere with Smad2/3 signaling in neurons 2007 Feb;66(2)158-67
[33]Mirshafiey A, Mohsenzadegan M.TGF-beta an a promising option in the treatment of multiple sclerosis [J]Neuropharmacology.2009 May Jun;56(6-7) 929-36
[34]PONCELET A C, SCHNAPER H W. Spl and Smad proteins cooperate to mediate transforming growth factor-beta 1-induced alpha2(J) collagen expression in human glomerular mesangial cells [J]. J Biol Chem,2006, 276:6983-6992.
[35]周俊,陆国平,戚文航,等. 核转录因子N F-2κB对血管损伤和新生内膜形成的影响[J]. 临床心血管病杂志,2007,23(12)：927-931.
[36]HAO J, JU H, ZHAO S, et al. Elevation of expression of Smads 2,3, and 4, decorin and TGF-beta in the chronic phase of myocardial infarct scar healing[J]. J Mol Cell Cardiol,2007,31:667-678.
[37]ARTHU R HM,URE J,SMITHA J,et al.Endoglin,an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development [J].Dev Biol,2000,217:42-53.
[38]BANN ISTER A J,KOU ZARID ES T.The CBP coactivator is a histone acetyltransferase [J]. Nature,1996,384:641-643.
[39]SANCH EZ-EL SN ER T, BOTELL A L M, VELASCO B, et al. Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways[J]. J Biol Chem, 2002,277:43799-43808.
[40]Yamasaki Y, Itoyama Y, Kogure K.2001. Involvement of cytokine production in pathogenesis of transient cerebral ischemic damage. Keio J Med. 45(3),225-9.
[41]Li J,Qu Y,Li X, Li D,Zhao F,et,al. The role of integrin alpha(v)beta(8) in neonatal hypoxic-ischemic brain injury.[J] Neurotox Res.2010 May; 17(4): 406-17
[42]Buisson A,Lesne S,Docagne F..Transforming growth factor beta andischemic brain injury. [J]Cell MolNeurobiol,2003.23,539-550
[43]Yin J, Sakamoto K,Zhang H,Ito Z et,al. Transforming growth factor-betal upregulates keratan sulfate and chondroitin sulfate biosynthesis in microglias after brain injury.[J] Brain Res 2009 Mar 31;1263:10-12
[44]Wang Y,Moges H,Bharucha Y, Symes A. Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex.[J] Exp Neurol 2007 Jan;203(1):168-84
[45]Komuta Y,Teng X,Yanagisawa H, Sango K,et,al Expression of transforming growth factor-beta receptors in meninge fibroblasts of the injured mouse brain.[L] Cell Mol Neurobiol 2010 Jan;30(1):101-11
[46]Grammas P, Ovase R. Cerebrovascular transforming growth factor-beta contributes to inflammation in the Alzhemer's disease brain.[J] Am J Pathol. 2002 May;160(5)1583-7
[47]Pang L, YeW, Che XM, et al. Reduction of inflammatory response in the mouse brain with adenoviral mediated transforming growth factor-ssl expression. [J]Stroke,2001,32:544-552.
[48]Chun L, Song L, Jin Z,et,al.dl-3n-butylphthalide prevents stroke via impro vement of cerebral microvessels in RHRSP.[J] Neurological Sciences 260 (2007)106-113
[49]Feng YP,Hu D,Zhang L Y.Effect of DL-butylphthalide(NBP) on mouse brain energy metablizm in complete brain ischemia induced by decapitation [J].Acta Pharm Sin,1995,30:741.
[50]Liu XG,Feng YP. Protective effect of DL-3-butylphthalide on ischemic neurological damage and abnormal behavior in rats subjected to focal ischemia[J].Acta Pharm Sin,1995,30:896.
[51]Deng WB,Feng YP.Effect of dl-3-n2butylphthalide on brain edema in rats subjected to focal cerebral ischemia.[J].Chin Med Sci J,1997,12:102.
[52]Xiong J, Feng YP. Effect of butylphthalide on the activities of complexes of the mitochondrial respiratory chain[J].Acta Pharm Sin,1999,34:241
[53]Xu Hao-Liang.Feng Yi Pu. Inhibitory effects of ehiral 3-n-bu-tylphthalide on inflammation following focal ischemic brain injury in rata [J].Acts Pharma Sin,2000,21(5):433-438.
[54]Chang Zhao-Zhong, Feng Yi Pu. Effect of 3-n butylphthalide on reperfusion induced lipid peroxidation following cerebral ischemia in and superoxide radical formation in vitro[J]. Journal of Chinese Pharmaceu-tical Sciences, 1999.8(2):95-99.
[55]Jiao D L,NI Xiu S,Gao Y,Zhao Y,et,al. Effect of dl-3n-butylphthalide on the Expression of caspase-3 in the Rat Model of Focal Cerebral Ischemia-reperfuson [J]Chin J Clin Neurosci 2007,15(1)19-23
[56]Chang Zhao.Zhong,Feng Yi-Pu.D1-3-u-hutylphthalide attenuates repeffusion induced blood brain barrier after focal cerebral ischemia in rats[J]. Acta Phamacal Sin,2004,20(8):696-700.
[57]Williams AO, Knapton AD, Geiser A et al The liver in transforming growth factor-Beta-1 (TGF-beta 1) null mutant mice. Ultrastruct Pathol 1996 Sep-Oct;20(5):477-90
[1]Pelton RW,Saxena B Jones M,et al. Immunohistochemical localization of TGF-β1,TGF-β2,and TGF-β3 in the mouse embryo:expression patterns suggest multiple roles during embryonic development [J] Cell Biol,1991,115: 1091-1105
[2]Yamamoto T, Noble NA, Cohen AH,et al. Transforming growth factor-β isoforms in human glomerular diseases [J] Kidney Int,1996,49:461
[3]Luukko K,Ylikorkala A,Mkel TP.Developmentally regulated expression of Smad3, Smad4, Smad6, and Smad7 involved in TGF-β signaling [J]. MechDev,2001, 101 (1-2):209-212
[4]SAVAGE C, DAS P, LIFA, et all Caenorhabditis elegans genes Smad2, smad3, and sma4 define a conserved family of transforming growth factor β pathway components[J]. Proc Natl Acad Sci USA,2003,93 (2):79027941
[5]Kretzschmar M,Massague J. SMADs mediators and regulator of TGF-beta signaling [J]. Curr Opin Genet Dev,1998,8 (1):103-111
[6]WU G, CHEN Y G, OZDAMAR B, et al. Structural basis of Smad2 recognition by the Smad anchor for recep tor activation [J].Science,2000,287 (5450) 922971
[7]Massague J,Blain SW, Lo RS. TGF-β Signaling in Growth Conlrol,Cancer and Heritable Disorders [J]. Cell,2000,103(2):295-309.
[8]Ueberham u,Ueberham E Gruschka H et Altered subcellular location of phosphorylated Smads in Alzheimer's disease.[J]Eur Neurosci 2006 Oct;24(8): 2327-34
[9]WU G, CHEN YG, OZDAMAR B,et all. Structural basis of Smad2 recognition by the Smad anchor for recep tor activation [J] Science,2000,287 (5450):92-97
[10]N ISH MOTO S, NISHIDA E1 MAPK signalling:ERK5 versus ERK1/2 [J] EMBO reports,2006,7(8):782-786
[11]NAKAMURA K，JOHNSON G L. Noncanonical Function of ME-KK2 and MEK5 PB1 domains for coordinated extracellular signal-regulated kinase 5 and c-Jun N-term inal kinase signaling[J]. Mol Cell Biol,2007,27 (12):4566-4577
[12]NAKAMURA K, JOHNSON G L.PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway [J]. J Biol Chem,2003,278 (39):36989-369921
[13]ZHAO B M,HOFFMANN FM. Inhibition of transforming growthFactor-β1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide ap tamer Trx-SARA [J].Mol Biol Cell,2006s 17 (9): 3819-38311
[14]SUN Y,DING L, ZHANG H, et all Potentiation of Smad-media-ted transcrip-tional activation by the RNA-binding protein RBPMS[J]. Nucleic Acids Res, 2006,34 (21):6314-6326
[15]KRETZSCHMAR M, DOODY J, MASSAGUE J. Opposing BMP and EGF signaling pathways converge on the TGF-β family mediator Smadl [J].Nature, 1997,389 (6651):618-622
[16]DERYNCK R, ZHANG Y E. Smad-dependent and Smad independent pathways in TGF-p family signaling[J]. Nature,2003,425(6958):577-5841
[17]MASSAGUE J. Integration of Smad and MAPK pathways:a link and a linker revisited[J].Genes Dev,2003,17 (24):2993-2997
[18]BROWN J D, DICH IARA M R, ANDERSON K R, et al. MEKK-1, acomponent of the stress (stress-activated p rotein kinase/c-Jun N-terminal kinase)pathway, can selectively activate Smad2-medi-ated transcriptional activation in endothelial cells [J].J Biol Chem,1999,274 (13):8797-8805
[19]LIANG M,LIANG Y Y, WRIGHTON K, et al. Ubiquitination and proteolysis of cancer-derived Smad4 mutants by SCFSkp2 [J].Mol Cell Biol,2004,24 (17): 7524-7537
[20]DZIEMBOW SKA M, DANILKIEW ICZ M, W ESOLOW SKAA,et al. Cross-talk between Smad and p38 MAPK signaling in transforming growth factor beta signal transduction in human glioblastoma cells[J]. Biochem Biophys Res Commun,2007,354 (4):1101-1106.
[21]MATSUURA I, DENISSOVAN G, WANG G, et al. Cyclin-de-pendent kinases regulate the antip roliferative function of Smads [J]. Nature,2004,430(6996): 226-231
[22]CONERY A R, CAO Y,THOMPSON E A,et all Akt interacts directly with Smad3 to regulate the sensitivity to TGF-P induced apoptosis[J]. Nat Cell Biol, 2004,6(4):366-372
[23]ROBERTS A B,RUSSO A, FELICIA, et al.Smad 3:akey player in pathogenetic mechanisms dependenton TGF-β[J].Ann N Y Acad Sci,2003,1995:1-10
[24]SHI Y, WANG Y F，JAYARAMAN L,et al.Crystal structure of a Smad MH1 domain bound to DNA:insights on DNA binding in TGF-β signaling [J]. Cell, 1998,94(5):585-594
[25]FREDER ICK J P, LIBERATIN T, WADDELLD S, et al. Transforming growth factorβ-mediated transcrip tionalrep ression of c-mycis dependention direct binding of Smad 3 to a novel rep ressive Smad binding element[J].Mol Cell Biol, 2004,24(6):2546-2559
[26]RANDALLR A, HOW ELL M, PAGE C S,et al. Recognition of Phosp-horylated Smad 2 containing comp lexes by a novel Smad interaction motif[J]. Mol Cell Biol,2004,24 (3):1106-1121
[27]BLOKZIJL A, TEND IJKE P, IBANEZC F1 Physical and functional interaction between GATA-3 and Smad 3 allows TGF-β regulation of GAT A target genes[J]. Curr Biol,2002,12(1):35-45
[28]KURISAKI K, KUR ISAKI A, VALCOURT U, et al. Nuclear factor YY1 inhibits transform ing growth factor-β and bone morphogenetic protein-induced cell differentiation[J]. Mol Cell Biol,2003,23(13):4494-4510.
[29]HIRATOCH IM, NAGASE H, KURAMOCH I Y, et alThe Delta intracellular domain mediates TGF-β/Activin signaling through binding to Smads and has an important bi-directional function in the Notch-Delta signaling pathway[J]. Nucleic Acids Res,2007,35(3):912-922
[30]CORDENONSI M, MONTAGNER M, ADORNO M, et al. Integration of TGF-β and Ras/MAPK signaling through p53 phosphorylation[J].Science,2007, 315 (5813):840-843
[31]XIAO Z, LIU X, HENISY I,et al.A distinct nuclear localization signal in the Nterminus of Smad 3 determ ines its ligand-induce nuclear translocation[J]. Proc Natl Acad Sci USA,2000,97(14):7853-7858
[32]. Chao CC, Hu S, Frey WH, II, AlaTA，Tourtellotte WW, Peterson PK: Transforming growth factor beta in Alzheimer's disease. Clin Diag Lab Immunol 1994,1:109-110
[33]Flanders KC, Lippa CF, Smith TW， Pollen DA, Sporn MB:Altered expression of transforming growth factor-beta in Alzheimer's disease. Neurology 2003, 45:1561-1569 [PubMed]
[34]Vander Wal EA, Gomez-Pinilla F, Cotman CW:Transforming growth factor-beta 1 is in plaques in Alzheimer and Down pathologies. Neuroreport 2004,4:69-72 [PubMed]
[35]Ueberham u,Ueberham E Gruschka H et Altered subcellular location of phosphorylated Smads in Alzheimer's disease.[J]Eur Neurosci 2006 Oct;24(8): 2327-34
[36]LEE HG,Ueda M, Zhu X,Perry G,Smith MA:Ectopic expression of phospho-Smad2 in Alzheimer's disease:uncoupling of the transforming growth factor-beta pathway. J Neurosci Res 2006 Dec;84(8)1856-61
[37]Baig S,Van Helmond Z,Love S Tau hyperphosphorylation affect Smad2/3 translocation.(2009)Oct6;561-70.Epub 2009 Jun 23
[38]Selkoe, D.J,Schenk, D.Alzheimer's disease:Molecular understanding predicts amyloid-based therapeutics (2003) Annu. Rev. Pharmacol. Toxicol.43,545-584
[39]Grammas,P,and Ovase,R Cerebrovascular Transforming Growth Factor-β Contributes to Inflammation in the Alzheimer's Disease Brain (2002)Am, J, Pathol,160.1583-1587
[40]Lesne,S.,Docagne,F.,Gabriel,C.,Liot,G.,Lahiri,D.K.,Buee,L.,Plawinski,L.,Delaco urte,A.,Mackenzie,E.T.,Buisson,A.,and Vivien,D Transforming Growth Factor-β1 Potentiates Amyloid-β Generation in Astrocytes and in Transgenic Mice (2003)J, Biol Chem,278,18408-18418.
[41]Wyss-Coray, T., Masliah, E., Mallory, M., McConlogue, L., Johnson-Wood, K., Lin, C, and Mucke, L. Amyloidogenic role of cytokine TGF-betal in transgenic mice and in Alzheimer's disease (1997) Nature 389,603-606
[42]Cordoliani-Mackowiak, M. A., Henon, H., Pruvo, J. P., Pasquier, F., and Leys, D. Influence of Hippocampal Atrphy(2003) Arch. Neurol.60,585-590
[43]Luedecking, E. K., DeKosky, S. T., Mehdi, H., Ganguli, M., and Kamboh, M. I. Analysis of genetic polymorphisms in the transforming growth factor-betal gene and the risk of Alzheimer's disease (2000) Hum. Genet.106,565-569
[44]Wyss-Coray, T., Lin, C., Yan, F.,Yu, G. Q., Rohde, M., McConlogue, L., Masliah, E., and Mucke, L. TGF-betal promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice (2001) Nat. Med.7, 612-61
[45]Ren, R. F., Hawver, D. B., Kim, R. S., and Flanders, K. C. Transforming growth factor-beta protects human hNT cells from degeneration induced by beta-amyloid peptide:involvement of the TGF-beta type Ⅱ receptor (1997) Mol. Brain Res.48,315-322
[46]Flanders, K. C., Ren, R. F., and Lippa, C. F. Transforming growth factor-betas in neurodegenerative disease (1998) Prog. Neurobiol.54,71-85
[47]Wyss-Coray, T., Masliah, E., Mallory, M., McConlogue, L., Johnson-Wood, K., Lin, C., and Mucke, L. Amyloidogenic role of cytokine TGF-betal in transgenic mice and in Alzheimer's disease (1997) Nature 389,603-606
[48]Harris-White, M. E., Chu, T., Balverde, Z., Sigel, J. J., Flanders, K. C., and Frautschy, S. A. The Amyloid-P Peptide Suppresses Transforming Growth Factor-β1-induced Matrix Metalloproteinase-2 Production via Smad7 Expression in Human Monocytic THP-1 Cells (1998) J. Neurosci.18,10366-10374
[49]Fabian DOCAGNE, Cecilia GABRIEL, Nathalie LEBEURRIER,etc. Sp1 and Smad transcription factors co-operate to mediate TGF-β-dependent activation of amyloid-β precursor protein gene transcription Biochem. J. (2004) 383, 393-399
[50]Thiery JP:Epithelial-mesenchymal transitions in tumor progression. Nat Rev Cancer 2:442-454,2002
[51]Wick W,Grimmel C, Wild-Bode C, Platten M, Arpin M and Weller M:Ezrin-dependent promotion of glioma cell clonogenicity, motility, and invasion mediated by bcl-2 and Trans-forming Growth Factor-β2. J Neurosci 21:3360-3368,2001
[52]Platten M, Wick W and Weller M:Malignant glioma biology:role for TGF-β in growth, motility, angiogenesis and immune escape. Microsc Res Tech 52: 401-410,2001
[53]TNICKL-JOCKSCHAT, F ARSLAN, U BOGDAHN et,al. An imbalance between Smad and MAPK pathway is responsible for TGF-β tumor promoting effects in high-grade gliomas [J] International journal of oncology 30: 499-507,2007.
[54]Penuelas S, Anido J, Prieto-Sanchez RM, Folch G, Barba I, Cuartas I,et,al. TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma.[J]Cancer cell.2009 Apr 7; 15(4)315-27
[55]ARTHU R H M,URE J, SMITHA J,et al. Endoglin, an ancillary TGF-beta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development [J]. Dev Biol,2000,217:42-53
[56]BANN ISTER A J,KOU ZARID ES. The CBP coactivator is a histone acetyltransferase [J]. Nature,1996,384:641-643
[57]Isselbacher EM. Thoracic and abdominal aortic aneurysms. Circulation 2005;111:816-828. [PubMed:15710776]
[58].Thompson RW. Reflections on the pathogenesis of abdominal aortic aneurysms. Cardiovasc Surg 2002;10:389-394. [PubMed:12359414]
[59]Bobik A. Transforming growth factor-betas and vascular disorders. Arterioscler Thromb Vasc Biol 2006;26:1712-1720. [PubMed:16675726]
[60]Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA,Falanga V, Kehrl JH, et al. Transforming growth factor type beta:rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A 1986;83:4167-4171. [PubMed:2424019]
[61]Kim ES, Kim MS, Moon A. TGF-beta-induced upregulation of MMP-2 and MMP-9 depends on p38MAPK, but not ERK signaling in MCF10A human breast epithelial cells. Int J Oncol 2004;25:1375-1382. [PubMed:15492828]
[62]Laiho M, Saksela O, Keski-Oja J. Transforming growth factor beta alters plasminogen activator activity in human skin fibroblasts. Exp Cell Res 1986; 164:399-407. [PubMed:3519251]
[63]Safina A, Vandette E, Bakin AV. ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells. Oncogene 2007; 26: 2407-2422. [PubMed:17072348]
[64]Selvamurugan N, Kwok S, Alliston T, Reiss M, Partridge NC. Transforming growth factor-beta 1 regulation of collagenase-3 expression in osteoblastic cells by cross-talk between the Smad and MAPK signaling pathways and their components, Smad2 and Runx2. J Biol Chem 2004;279:19327-19334. [PubMed: 14982932]