水通道蛋白在细胞运动中的功能研究
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摘要
水通道蛋白(aquaporin,AQP)是一类存在于细胞膜上的水通透性蛋白,在哺乳动物各种组织细胞中广泛分布,自从九十年代红细胞膜上的水通道蛋白(AQP1)被发现以来,目前在哺乳类已发现至少有13个成员(AQP0~12),大量研究表明,AQP在多种器官的生理和病理中发挥重要作用。近期研究发现的水通道蛋白在细胞迁移和血管新生中的重要作用,为细胞迁移的分子机制增加了新的内容,也为水通道基因功能研究开启了一个新的领域。
肿瘤细胞的迁移是肿瘤浸润和转移的关键步骤。目前已知水通道蛋白在多种类型的肿瘤细胞中表达,水通道蛋白在肿瘤细胞迁移中的作用目前国内外均未见报道,我们推测水通道蛋白可能在肿瘤细胞迁移活动中发挥重要作用。本研究发现水通道蛋白介导的细胞膜高水通透性促进肿瘤细胞迁移。对高转移性SMMC-7221人肝癌细胞系进行系统的RT-PCR、免疫荧光和免疫印迹分析,发现水通道蛋白AQP1表达。进一步分析发现SMMC-7221细胞系含细胞膜具有高水通透性(SMMC-7221hPf)和低水通透性(SMMC-7221lPf)的两个亚群,分别与细胞膜AQP1表达量相一致。SMMC-7221hPf细胞的穿孔迁移速率和平面迁移率均显著高于SMMC-7221lPf,而细胞的贴附和增殖能力没有显著差别。AQP1腺病毒感染SMMC-7221lPf细胞提高了细胞膜AQP1表达、细胞膜水通透性和细胞迁移速率。上述结果显示,水通道蛋白AQP1介导的细胞膜高水通透性促进SMMC-7221人肝癌细胞细胞的迁移并且可能参与肿瘤的浸润和转移过程。
为了进一步研究水通道蛋白在细胞迁移活动中的作用,我们利用基因打靶技术制作了对氯离子高度敏感的EYFP-V163S绿色荧光蛋白转基因小鼠。通过对EYFP-V163S转基因小鼠各组织器官体内原位灌注并监测其荧光的动态变化,我们可以直接测定各个组织细胞膜的水通透性;同时我们可以体外培养表达EYFP-V163S的各组织细胞,研究水通道蛋白在这些不同类型细胞迁移活动中的表现特征;另外,我们还可以在小鼠活体动物模型中研究水通道蛋白在白细胞参与抗肿瘤、抗感染过程中的作用及水通道蛋白在胚胎发育、组织损伤修复等诸多与细胞迁移相关的重要生理病理活动中的作用。
Aquaporins (AQPs) are membrane water channels that play pivotal roles in physiological and pathophysiological processes in diverse mammalian organs. Thirteen mammalian AQP have been molecularly identified since AQP1 was first cloned from the membrane of erythrocyte in 1990. Recent studies uncovered an important role of aquaporins in cell migration, and migration-associated cell function such as angiogenesis, wound healing, and neutrophil motility, provided a new molecular mechanism of cell migration and opend a new field of aquaporin gene function .
Migration of tumor cells is a crucial step in tumor invasion and metastasis. Previous studies demonstrated the expression of AQPs in many types of tumor cells. The role of aquaporins in tumor cell migration has not been reported. We hypothesize that aquaporins also play a critical role in tumor cell migration. Here we provide evidence that aquaporin expression is involved in tumor cell migration. RT-PCR, Immunofluorescence and Western blot analysis demonstrated AQP1 protein expression on the plasma membrane of SMMC-7221 human hepatoma cells. SMMC-7221 cell clones with high (SMMC-7221hPf) and low (SMMC-7221lPf) water permeability were identified by functional assays with corresponding high and low AQP1 expression. Cell migration rate was remarkably higher in SMMC-7221hPf cells as compared to SMMC-7221lPf cells, assessed by Boyden chamber and wound healing assays, whereas cell growth and adhesion were not different. Adenovirus-mediated AQP1 expression in SMMC-7221lPf cells increased their water permeability and migration rate. These results provide the first evidence that aquaporin-mediated membrane water permeability enhances tumor cell migration and may be associated with tumor invasion and metastasis.
To further investigate the functions of aquaporin water channels in cell migration, we established the transgenic mouse model expressing the fluorescent protein EYFP-V163S sensitive to Cl-. The establishment of EYFP-V163S transgenic mouse model will bring it into realization that measure directly water and Cl- channel function in different tissues by perfusing in vivo tissues with halides and detecting dynamically the change of fluorescent. At the same time, cells from tissues of EYFP-V163S transgenic mouse could be cultured as cell models for studing the roles of aquaporin water channels in cell migration.
肿瘤细胞的迁移是肿瘤浸润和转移的关键步骤。目前已知水通道蛋白在多种类型的肿瘤细胞中表达,水通道蛋白在肿瘤细胞迁移中的作用目前国内外均未见报道,我们推测水通道蛋白可能在肿瘤细胞迁移活动中发挥重要作用。本研究发现水通道蛋白介导的细胞膜高水通透性促进肿瘤细胞迁移。对高转移性SMMC-7221人肝癌细胞系进行系统的RT-PCR、免疫荧光和免疫印迹分析,发现水通道蛋白AQP1表达。进一步分析发现SMMC-7221细胞系含细胞膜具有高水通透性(SMMC-7221hPf)和低水通透性(SMMC-7221lPf)的两个亚群,分别与细胞膜AQP1表达量相一致。SMMC-7221hPf细胞的穿孔迁移速率和平面迁移率均显著高于SMMC-7221lPf,而细胞的贴附和增殖能力没有显著差别。AQP1腺病毒感染SMMC-7221lPf细胞提高了细胞膜AQP1表达、细胞膜水通透性和细胞迁移速率。上述结果显示,水通道蛋白AQP1介导的细胞膜高水通透性促进SMMC-7221人肝癌细胞细胞的迁移并且可能参与肿瘤的浸润和转移过程。
为了进一步研究水通道蛋白在细胞迁移活动中的作用,我们利用基因打靶技术制作了对氯离子高度敏感的EYFP-V163S绿色荧光蛋白转基因小鼠。通过对EYFP-V163S转基因小鼠各组织器官体内原位灌注并监测其荧光的动态变化,我们可以直接测定各个组织细胞膜的水通透性;同时我们可以体外培养表达EYFP-V163S的各组织细胞,研究水通道蛋白在这些不同类型细胞迁移活动中的表现特征;另外,我们还可以在小鼠活体动物模型中研究水通道蛋白在白细胞参与抗肿瘤、抗感染过程中的作用及水通道蛋白在胚胎发育、组织损伤修复等诸多与细胞迁移相关的重要生理病理活动中的作用。
Aquaporins (AQPs) are membrane water channels that play pivotal roles in physiological and pathophysiological processes in diverse mammalian organs. Thirteen mammalian AQP have been molecularly identified since AQP1 was first cloned from the membrane of erythrocyte in 1990. Recent studies uncovered an important role of aquaporins in cell migration, and migration-associated cell function such as angiogenesis, wound healing, and neutrophil motility, provided a new molecular mechanism of cell migration and opend a new field of aquaporin gene function .
Migration of tumor cells is a crucial step in tumor invasion and metastasis. Previous studies demonstrated the expression of AQPs in many types of tumor cells. The role of aquaporins in tumor cell migration has not been reported. We hypothesize that aquaporins also play a critical role in tumor cell migration. Here we provide evidence that aquaporin expression is involved in tumor cell migration. RT-PCR, Immunofluorescence and Western blot analysis demonstrated AQP1 protein expression on the plasma membrane of SMMC-7221 human hepatoma cells. SMMC-7221 cell clones with high (SMMC-7221hPf) and low (SMMC-7221lPf) water permeability were identified by functional assays with corresponding high and low AQP1 expression. Cell migration rate was remarkably higher in SMMC-7221hPf cells as compared to SMMC-7221lPf cells, assessed by Boyden chamber and wound healing assays, whereas cell growth and adhesion were not different. Adenovirus-mediated AQP1 expression in SMMC-7221lPf cells increased their water permeability and migration rate. These results provide the first evidence that aquaporin-mediated membrane water permeability enhances tumor cell migration and may be associated with tumor invasion and metastasis.
To further investigate the functions of aquaporin water channels in cell migration, we established the transgenic mouse model expressing the fluorescent protein EYFP-V163S sensitive to Cl-. The establishment of EYFP-V163S transgenic mouse model will bring it into realization that measure directly water and Cl- channel function in different tissues by perfusing in vivo tissues with halides and detecting dynamically the change of fluorescent. At the same time, cells from tissues of EYFP-V163S transgenic mouse could be cultured as cell models for studing the roles of aquaporin water channels in cell migration.
引文
[1] 麻彤辉,杨红。膜通道研究再获诺贝尔奖[J].特邀评论。生物物理学报,2003,19(4):343-346.
[2] Agre, P., King, L. S., Yasui, M., et al. 2002. Aquaporin water channels—from atomic structure to clinical medicine[J]. J Physiol., 542: 3-16
[3] 冯学超,麻彤辉.水通道蛋白的生理功能[J].生物化学与生物物理进展,2005,21(4):291-297.
[4] A.S.Verkman.Physiological importance of aquaporin water channels[J]. Ann Med.2002,34 (3): 192-200.
[5] A.S.Verkman. More than just water channels: unexpected cellular roles of aquaporins[J]. J.Cell Sci. 2005,118:3225-3232.
[6] S.Saadoun, M.C. Papadopoulos, M. Hara-Chikuma, et al. Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption[J]. Nature. 2005,434 :786-792.
[7] Denker, B. M., Smith, B. L., Kuhajda, F. P., et al. Identification, purification, and partial characterization of a novel Mr 28,000 integral membrane protein from erythrocytes and renal tubules[J]. J Biol Chem. 1988, 263:15634-15642.
[8] Preston, G. M., Carroll, T. P., Guggino, W. B., et al. Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein[J]. Science.1992,256: 385-87.
[9] Agre P, Kozono D. Aquaporin water channels: molecular mechanisms for human diseases[J]. FEBS Lett. 2003,1: 72-78.
[10] Fujiyoshi Y, Mitsuoka K, de Groot B. L., et al. Structure and function of water channels[J].Curr Opin Struct Biol. 2002, 4:509-515.
[11] King LS, Kozono D, Agre P. From structure to disease: the evolving tale of aquaporin biology [J]. Nat Rev Mol Cell Biol 2004,5:687-698.
[12] Morishita Y, Matsuzaki T, Hara-chikuma M, et al. Disruption of aquaporin-11 produces polycystic kidneys following vacuolization of the proximal tubule[J]. Mol Cell Biol. 2005,25:7770-7779.
[13] Itoh T, Rai T, Kuwahara M, et al. Identification of a novel aquaporin, AQP12, expressed in pancreatic acinar cells[J]. Biochem Biophys Res Commun 2005,330:832-838.
[14] King LS, Yasui M. Aquaporins and disease: lessons from mice to humans[J]. Trends Endocrinol Metab.2002,8:355-360.
[15]A.S.Verkman, Yang BX, Song YL, et al. Role of water channels in fluid transport studied by phenotype analysis of aquaporin knockout mice[J]. EXP PHYSIOL 2000,85: 233-241.
[16]M.C. Papadopoulos, S.Krishna, A.S.Verkman. Aquaporin water channels and brain edema[J]. Mt Sinai J Med. 2002,4:242-248.
[17] Hasegawa H., Ma T, Skach W, et al. Molecular-cloning of a mercurial-insensitive water channel expressed in selected water-transporting tissues[J]. J Biol Chem. 1994,269(8):5497-5500.
[18] A.S.Verkman, Alok K. Structure and function of aquaporin water channel[J]. Am.J.Physiol.Renal Physiol. 2000,278:F13-28.
[19] Ren G, Cheng A , Melnyk P , et al. Polymorphism in the packing of aquaporin-1 tetramers in 2-D crystals[J]. J Struct Biol. 2000,130(1):45-53.
[20] Sui H X, Han B G, Lee J K,et al. Structural basis of water-specific transport through the AQP1 water channel[J]. Nature , 2001 , 414 : 872-878.
[21] 隋海心, 任罡等. 水分子通道蛋白的结构与功能[J]. 化学进展,2004 16(2):145-152.
[22] Burghardt B, Elkaer ML, Kwon TH, et al. Distribution of aquaporin water channels AQP1 and AQP5 in the ductal system of the human pancreas[J]. Gut.2003,52(7): 1008-1016.
[23] Gresz V, Kwon TH, Hurley PT, et al. Identification and localization of aquaporin water channels in human salivary glands[J]. Am J Physiol Gastrointest Liver Physiol. 2001,281(1):G247-254.
[24] Elkjaer ML, Nejsum LN, Gresz V, et al. Immunolocalization of aquaporin-8 in rat kidney, gastrointestinal tract, testis, and airways[J]. Am J Physiol Renal Physiol. 2001, 281(6):F1047-1057.
[25] Nejsum LN, Elkjaer M, Hager H, et al. Localization of aquaporin-7 in rat and mouse kidney using RT-PCR, immunoblotting, and immunocytochemistry[J]. Biochem Biophys Res Commun. 2000 ,277(1):164-170.
[26] Li J, Kuang K, Nielsen S, et al. Molecular identification and immunolocalization of the water channel protein aquaporin 1 in CBCECs[J]. Invest Ophthalmol Vis Sci. 1999, 40(6):1288-1292.
[27] Kim IB, Oh SJ, Nielsen S, et al. Immunocytochemical localization of aquaporin 1 in he rat retina[J]. Neurosci Lett. 1998,244(1):52-54.
[28] Zhong SX, Liu ZH. Expression of aquaporins in the cochlea and endolymphatic sac of guinea pig[J]. ORL J Otorhinolaryngol Relat Spec. 2003 ,65(5):284-289.
[29] J. Terris, C. A. Ecelbarger, D. Marples, et al. Distribution of aquaporin-4 water channel expression within rat kidney[J]. Am J Physiol Renal Physiol.1995,269: 775 – 785.
[30] Pedro Gallardo, Nancy Olea, Francisco V. Sepúlveda.Distribution of aquaporins in the colon of Octodon degus, a South American desert rodent[J]. Am J Physiol Regulatory Integrative Comp Physiol. 2002,283: 779 – 788.
[31] Grazia P. Nicchia, Antonio Frigeri, Beatrice Nico, et al. Tissue Distribution and Membrane Localization of Aquaporin-9 Water Channel: Evidence for Sex-linked Differences in Live[J]. J. Histochem. Cytochem.2001,49: 1547 – 1556.
[32] R. M. Effros, C. Darin, E. R. Jacobs, et al. Water transport and the distribution of aquaporin-1 in pulmonary air spaces[J]. J Appl Physiol.1997,83:1002–1016.
[33] K.L. Schey, L.E. Ball, R.K. Crouch,et al. The Distribution of Phosphorylated and Posttranslationally Modified Aquaporin 0 Within the Normal Human Lens[J]. Invest. Ophthalmol. Vis. Sci. 2003, 44: 4483.
[34] S?ren Nielsen, Landon S. King, Birgitte M?nster Christensen, et al. Aquaporins in complex tissues. II. Subcellular distribution in respiratory and glandular tissues of rat[J].Am J Physiol Cell Physiol. 1997, 273: 1549 – 1561.
[35] Steffen Hamann, Thomas Zeuthen, Morten La Cour, et al. Aquaporins in complex tissues: distribution of aquaporins 1-5 in human and rat eye[J]. Am J Physiol Cell Physiol. 1998, 274: 1332 – 1345.
[36] B. K. Kishore, J. M. Terris, M. A. Knepper. Quantitation of aquaporin-2 abundance in microdissected collecting ducts: axial distribution and control by AVP[J]. Am J Physiol Renal Physiol. 1996,271: 62 – 70.
[37] S Nielsen, BL Smith, EI Christensen, et al. Distribution of the Aquaporin CHIP in Secretory and Resorptive Epithelia and Capillary Endothelia[J]. PNAS. 1993, 90: 7275– 7279.
[38] Johannes Loffing, Dominique Loffing-Cueni, Andreas Macher, et al. Localization of epithelial sodium channel and aquaporin-2 in rabbit kidney cortex[J]. Am J Physiol Renal Physiol. 2000,278: 530 – 539.
[39] Mandon B, Nielsen S, Kishore BK, et al. Expression of syntaxins in rat kidney[J]. Am J Physiol. 1997,273(5 Pt 2):F718-730.
[40] Marie-Louise Elkj?r, Lene N. Nejsum, Veronika Gresz,et al. Immunolocalization of aquaporin-8 in rat kidney, gastrointestinal tract, testis, and airways[J]. Am J Physiol Renal Physiol.2001, 281: 1047 – 1057.
[41] Giuseppe Calamita, Amelia Mazzone, Yoon S. Cho,et al. Expression and Localization of the Aquaporin-8 Water Channel in Rat Testis[J]. Biol Reprod.2001, 64: 1660 – 1666.
[42] Nuria Pastor-Soler, Corinne Bagnis, Ivan Sabolic,et al. Aquaporin 9 Expression along the Male Reproductive[J] Tract.Biol Reprod. 2001, 65: 384-393.
[43] Haruko Funaki, Tadashi Yamamoto, Yu Koyama,et al. Localization and expression of AQP5 in cornea, serous salivary glands, and pulmonary epithelial cells[J]. Am J Physiol Cell Physiol.1998, 275: 1151 – 1157.
[44] Morishita Y, Sakube Y, Sasaki S, et al. Molecular mechanisms and drug development in aquaporin water channel diseases: aquaporin superfamily (superaquaporins): expansion of aquaporins restricted to multicellular organisms[J]. J Pharmacol Sci. 2004,96(3):276-279.
[45]Verbalis JG, Murase T, Ecelbarger CA, et al. Studies of renal aquaporin-2 expression during renal escape from vasopressin-induced antidiuresis[J]. Adv Exp Med Biol. 1998, 449:395-406.
[46] Christensen BM, Zelenina M, Aperia A, et al. Localization and regulation of PKA-phosphorylated AQP2 in response to V(2)-receptor agonist/antagonist treatment[J]. Am J Physiol Renal Physiol. 2000 Jan,278(1):F29-42.
[47]Katsura T, Verbavatz Jm, Farinas J, et al. Constitutive And Regulated Membrane Expression of aquaporin-1 and aquaporin-2 water channels in stably transfected Llc-pk1 epithelial-cells[J]. Proc. Natl. Acad. Sci. U.S.A. 1995,92 (16): 7212-7216.
[48] Hayashi, M, Sasaki S, Tsuganezawa H, et al. Expression and distribution of aquaporin of collecting duct are regulated by vasopressin V2 receptor in rat kidney[J]. J Clin Invest. 1994,94:1778-1783.
[49] Matsumura, Y, Uchida S, Rai T, et al. Transcriptional regulation of aquaporin-2 waterchannel gene by cAMP[J]. J Am Soc Nephrol. 1997,8: 861-867.
[50]King, LS, Nielsen, S, and Agre,P. Aquaporin-1 water channel protein in lung: ontogeny, steroid-induced expression, and distribution in rat[J]. J Clin Invest. 1996, 97, 2183-2191.
[51]Marinelli, RA, Tietz PS, Pham LD, et al. Secretin induces the apical insertion of aquaporin-1 water channels in rat cholangiocytes[J]. Am J Physiol Gastrointest Liver Physiol. 1999,276: G280-G286.
[52]Carreras FI, Gradilone SA, Mazzone A, et al. Rat hepatocyte aquaporin-8 water channels are down-regulated in extrahepatic cholestasis[J]. Hepatology. 2003, 37(5):1026-33.
[53]Pastor-Soler N, Isnard-Bagnis C, Herak-Kramberger C, et al. Expression of aquaporin 9 in the adult rat epididymal epithelium is modulated by androgens[J]. Biol Reprod. 2002 Jun,66(6):1716-22.
[54]Smith JK, Siddiqui AA, Modica LA, et al.Interferon-alpha upregulates gene expression of aquaporin-5 in human parotid glands[J]. J Interferon Cytokine Res. 1999 Aug,19(8):929- -935.
[55]Borok Z, Li X, Fernandes VF, et al. Differential regulation of rat aquaporin-5 promoter/enhancer activities in lung and salivary epithelial cells[J]. J Biol Chem. 2000 Aug 25,275(34):26507-26514.
[56] Bai C, Fukuda N, Song Y, et al. Lung fluid transport in aquaporin-1 and aquaporin-4 knockout mice[J]. J Clin Invest.1999,103(4): 555-561.
[57] Ma T, Fukuda N, Song Y, et al. Lung fluid transport in aquaporin-5 knockout mice [J]. J Clin Invest.2000,105(1): 93-100.
[58] Song Y,Ma T. Matthay MA, et al. Role ofAQP4 in airspace-to-capillary water permeability inintact mouse lung measured by a novel gravimetric method [J]. J.Gen.Physiol. 2000,1 (15):17-27.
[59] Song Y, Verkman A S. Aquaporin-5 dependent fluid secretion in airway submucosal glands [J]. J Biol Chem.2001,276(44): 41288-41292.
[60] Krane C M, Fortner C N, Hand A R, et al. Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation[J]. Proc Natl Acad Sci U S A. 2001,98(24): 14114-14119.
[61] Ma T, Verkman A S. Aquaporin water channels in gastrointestinal physiology[J]. J Physiol-London.1999,517 (2): 317-326.
[62] Ma T, Song Y, Gillespie A, et al. Defective secretion of saliva in transgenic mice lacking aquaporin-5 water channels[J]. J Biol Chem.1999,274(29): 20071-20074.
[63] Yang B, Song Y, Zhao D,et al. Phenotype Analysis of Aquaporin-8 Null Mice [J]. Am J Physiol Cell Physiol.2005,288(5):C1161-1170.
[64] Ma T, Jayaraman S, Wang K S, et al. Defective dietary fat processing in transgenic mice lacking aquaporin-1 water channels[J]. Am J Physiol Cell Physiol. 2001,280(1): C126-134.
[65] Wang K S, Komar A R, Ma T, et al. Gastric acid secretion in aquaporin-4 knockout mice[J]. Am J Physiol Gastrointest Liver Physiol.2000,279(2): G448-453.
[66] Wang K S, Ma T, Filiz F, et al. Colon water transport in transgenic mice lacking aquaporin-4 water channels[J]. Am J Physiol Gastrointest Liver Physiol. 2000,279(2):G463-470.
[67] Verkman A S. Renal concentrating and diluting function in deficiency of specific aquaporin genes [J]. Exp Nephrol.2002,10(4): 235-240.
[68] Ma T, Yang B, Gillespie A, et al. Severely impaired urinary concentrating ability in transgenic mice lacking aquaporin-1 water channels[J]. J Biol Chem. 1998,273(8): 4296-4299.
[69] Schnermann J, Chou C L, Ma T, et al. Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice[J]. Proc Natl Acad Sci U S A. 1998,95(16): 9660-9664.
[70] Chou CL , Knepper MA , Van Hoek AN , et al. Reduced water permeability and altered ultrastructure in thin descending limb of Henle in aquaprin1 null mice [J ] . J Clin Invest , 1999 ,103 : 491- 496.
[71] Ma T, Song Y, Yang B, et al. Nephrogenic diabetes insipidus in mice lacking aquaporin-3 water channels[J]. Proc Natl Acad Sci U S A.2000,97(8): 4386-4391.
[72] Yang B, Ma T, Verkman A S. Erythrocyte water permeability and renal function in double knockout mice lacking aquaporin-1 and aquaporin-3[J]. J Biol Chem. 2001,276(1): 624-628.
[73] Ma T, Yang B, Gillespie A, et al. Generation and phenotype of a transgenic knockout mouse lacking the mercurial-insensitive water channel aquaporin-4[J]. J Clin Invest.1997,100(5): 957-962.
[74] Chou C L, Ma T, Yang B, et al. Fourfold reduction of water permeability in inner medullary collecting duct of aquaporin-4 knockout mice[J]. Am J Physiol.1998,274(2 Pt1):C549-554.
[75] Van Os C H, Deen P M. Aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus[J]. Proc Assoc Am Physicians. 1998,110(5):395-400.
[76] Tamarappoo B K, Verkman A S. Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones[J]. J Clin Invest. 1998, 101(10): 2257-2267.
[77] Knoers N V, Deen P M. Molecular and cellular defects in nephrogenic diabetes insipidus[J]. Pediatr Nephrol.2001,16(12): 1146-1152.
[78] Oshio K, Watanabe H, Song Y, et al. Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1[J]. FASEB J.2005,19(1): 76-78.
[79] Oshio K, Song Y, Verkman A S,ET AL. Aquaporin-1 deletion reduces osmotic water permeability and cerebrospinal fluid production[J]. Acta Neurochir Suppl. 2003,86: 525-528.
[80] Manley GT, Fujimura M, Ma T, et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke [J]. Nat Med.2000,6(2): 159-163.
[81] Papadopoulos MC, Manley GT, Krishna S, et al. Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema[J]. FASEB J.2004,18(11):1291-1293.
[82] Da T, Verkman A S. Aquaporin-4 gene disruption in mice protects against impaired retinal function and cell death after ischemia[J]. Invest Ophthalmol Vis Sci.2004, 45(12): 4477-4483.
[83] Thiagarajah J R, Verkman A S. Aquaporin deletion in mice reduces corneal water permeability and delays restoration of transparency after swelling[J]. J Biol Chem. 2002,277(21): 19139-19144.
[84] Zhang D, Vetrivel L, Verkman A S. Aquaporin deletion in mice reduces intraocular pressure and aqueous fluid production[J]. J Gen Physiol.2002,119(6): 561-569.
[85] Ma T, Hara M, Sougrat R, et al. Impaired stratum corneum hydration in mice lacking epidermal water channel aquaporin-3[J]. J Biol Chem.2002,277(19): 17147-17153.
[86] Hara M, Ma T, Verkman A S. Selectively reduced glycerol in skin of aquaporin-3-deficient mice may account for impaired skin hydration, elasticity, and barrier recovery[J]. J Biol Chem.2002,277(48): 46616-46621.
[87] Hara M, Verkman A S. Glycerol replacement corrects defective skin hydration, elasticity, and barrier function in aquaporin-3-deficient mice[J]. Proc Natl Acad Sci U S A.2003,100(12): 7360-7365.
[88] Yang B, Verbavatz J M, Song Y, et al. Skeletal muscle function and water permeaility in aquaporin-4 deficient mice[J]. Am J Physiol Cell Physiol.2000,278(6): 1108-1115
[89] S. Saadoun, M.C. Papadopoulos, M. Hara-Chikuma, et al. Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption[J]. Nature. 2005,434: 786-92.
[90] S. Saadoun, M.C. Papadopoulos, H. Watanabe, D. et al. Involvement of aquaporin-4 in astroglial cell migration and glial scar formation[J]. J. Cell Sci. 2005,118: 5691-8.
[91] M. Hara-Chikuma, A.S. Verkman. Aquaporin-1 facilitates epithelial cell migration in kidney proximal tubule[J]. J. Am. Soc. Nephrol. 2006,17 :39-45.
[92] V.M. Loitto, T. Forslund, T. Sundqvist, et al. Neutrophil leukocyte motility requires directed water influx[J]. J. Leukoc. Biol. 2002,71 :212-222.
[93] V.M. Loitto, K.E. Magnusson. Hg2+ and small-sized polyethylene glycols have inverse effects on membrane permeability, while both impair neutrophil cell motility[J]. Biochem. Biophys. Res. Commun. 2004,316: 370-378.
[94] A. Harlozinska. Progress in molecular mechanisms of tumor metastasis and angiogenesis[J]. Anticancer Res. 2005,25: 3327-33.
[95] T. Bogenrieder, M. Herlyn. Axis of evil: molecular mechanisms of cancer metastasis[J]. Oncogene. 2003,22:6524-36.
[96] A. Mobasheri, R. Airley, S.M. Hewitt, et al. Heterogeneous expression of the aquaporin 1 water channel in tumors of the prostate, breast, ovary, colon and lung: a study using high density multiple human tumor tissue microarrays[J]. Int J Oncol. 2005 ,26 :1149-58.
[97] Ransom, C.B. O’Neal, J.T. Sontheimer, H. Volume-activated chloride currents contribute to the resting conductance and invasive migration of human glioma cells[J]. J. Neurosci. 2001, 21: 7674-83.
[98] Mao J W, Wang L W, Sun X R, et al. Volume-activated Cl- current in migrated nasopharyngeal carcinoma cells[J]. Acta Physiologica Sinica. 2004, 56: 525-530
[99] Soroceanu, L. Manning Jr., TJ. Sontheimer, H. Modulation of glioma cell migration and invasion using Cl(-) and K(+) ion channel blockers[J]. J.Neurosci. 1999,19: 5942-54.
[100]Schwab,A. Ion channels and transporters on the move[J]. News. Physiol. Sci. 2001, 16: 29-33.
[101]Endo M., Jain, R.K. Witwer, B. et al. Water channel (aquaporin 1) expression and distribution in mammary carcinomas and glioblastomas[J]. Microvasc Res. 1999, 58: 89-98.
[102]Yang, J.H. Shi, Y.F. Cheng, et al. Expression and localization of aquaporin-5 in the epithelial ovarian tumors [J]. Gynecol Oncol. 2006,100:294-99.
[103]Moon, C. Soria, J.C. Jang, et al. Involvement of aquaporins in colorectal carcinogenesis[J]. Oncogene. 2003,22:6699-703.
[104]Mazal, P.R. Susani, M. Wrba, et al. Diagnostic significance of aquaporin-1 in liver tumors[J]. Hum. Pathol. 2005, 36: 1226-31.
[105]Warth A, Mittelbronn M, Wolburg H. Redistribution of the water channel protein aquaporin-4 and the K+ channel protein Kir4.1 differs in low- and high-grade human brain tumors[J]. Acta Neuropathol (Berl). 2005,109: 418-26.
[106]Schw ab A. Function and spatial distribution of ion channels and transporters in cell m igration[J].Am J Physiol Renal Physiol. 2001,280: F739- F747.
[107]Shimomura O. Structure of the chromophore of Aequorea green fluorescent protein[J]. FEBS Letters.1979,104 :220 – 222.
[108]Prasher D ,Echenrode V ,Wand W, et al. Primary structure of the Aequores victoria green fluorescent protein[J]. Gene.1992 ,111:229–233.
[109]Chalfie M,Ta Y,Euskirchen G, et al. Green fluorescent protein as a marker for gene expression[J]. Science.1994,263 :802–805.
[110] Wei, Hu; Chi-Lien, Cheng. Expression of Aequorea green fluorescent protein in plant cells[J]. FEBS Letters.1995,369( 2-3): 331-334.
[111] Reil?nder, Helmut; Haase, Winfried; Maul, Gabi. Functional Expression of the Aequorea Victoria Green Fluorescent Protein in Insect Cells Using the Baculovirus Expression System[J]. Biochemical and Biophysical Research Communications. 1996,219(1):14-20.
[112] Ward WW, Bokman SH. Reversible denaturation of Aequore a green-fluorescent protein:physical separation and characterization of the renatured protein[J]. Biochemistry.1982,21(19):4535-4540.
[113] YANG F, Moss LG, Phillips GN , et al. The Molecular Structure of Green Fluorescent Protein[J]. Nat Biotechnol. 1996,14 (10) : 1246-1251.
[114]Ormo M , Cubitt A B, Kallio K, et a l. Crystal Structure of the A equorea V ictoria Green Fluorescent Protein[J]. Science.1996, 273 (5280): 1392-1395.
[115]Youvan D C, M ichel-Beyerle M E. Structure and Fluorescence Mechanism of GFP[J]. Nat Biotechnol. 1996,14 (10): 1219-1220.
[116]Chalfie M , Kain S. Green fluorescent protein: properties,applications, and protocols [M ]. N ew York: W iley L iss,1998. 83.
[117]Cubitt AB, Heim R, Adams SR, et al. Understanding, improving and using green fluorescent proteins[J]. Trends Biochem Sci. 1995,20:448-455.
[118]黄国存,朱生伟,董越梅,等. 绿色荧光蛋白及其在植物研究中的应用[J]. 植物学通报.1998 ,15(5) :24 - 30.
[119]Zolotukhin S ,Potter M,Hauswirth W W, et al . A“Humanized”green fluorescent protein cDNA adapted for high-level expression in mammalian cells[J]. Journal of Virology , 1996 ,70(7) :4646 - 4654.
[120]Heim R ,Cubitt A B ,Tsien R Y. Improved green fluorescence [J]. Nature. 1995 ,373 : 663 – 664.
[121]Heim R , Tsien RY. Engineering green fluorescent protein for improved brightness, longer wavelengths and fluorescece resonance energy transfer[J]. Curr Biol.1996 ,6:178- 182.
[122]Juan Llopis, J. Michael Mccaffey, Atsushi Miyawaki,et al. Surement of cytosolic, mitochondrial, and Golgi pH in single iving cells with green fluorescent proteins [J]. Proc. Natl. Acad. Sci. USA .1998,95: 6803–6808.
[123]Elsliger MA, Wachter RM, Hanson GT,et al. Structural and spectral response of green fluorescent protein variants to changes in pH [J]. Biochemistry 1999,38(17): 5296-5301.
[124]Wachter RM, Elsliger MA, Kallio K,et al. Structural basis of spectral shifts in the yellow-emission variants of green fluorescent protein [J]. Structure.1998,6(10): 1267-1277.
[125]Rebekka M, Wachter , S.James Remington. Sensitivity of the yellow variant of green fluorescent protein to halides and nitrate [J]. Curr.Biol.1999,9:R268-269.
[126]Luis J.V.,Galietta,Peter M.Haggie,et al. Green fluorescent protein-based halide indicators with improved chloride and iodide affinityies [J]. FEBS Letters.2001, 499:220-224.
[127]Radder H. Exploiting abstract possibilities: a critique of the concept and practice of productpatenting [J]. J Agric Environ Ethics. 2004, 17 (3) :275-291.
[128]Gordon K, Lee E, Vital J, et al. Genetic transformation of mouse milk [J]. Bio- technology .1980 ,5:1183-1187.
[129] Palmiter,R.D. et al. Dramatic growth of mice that develop from eggs microinjected with metalothionein growth hormone fusion gene[J]. Nature.1982,300: 611-615.
[130]Nagueh SF ,Chen S ,Patel R , et al. Evolution of expression of cardiac phenotypes over a 42-year period in the beta-myosin heavy chain transgenic rabbit model of human hypertrophic cardiomyopathy [J]. J Mol Cell Cardiol ,2004 ,36 (5) :663-673.
[131]Chang P ,Torres J ,Lewis RA , et al . Localization of RNAs to the Mitochondrial Cloud in Xenopus Oocytes through Entrapment and Association with Endoplasmic Reticulum[J]. Mol Biol Cell ,2004 ,15 (10): 4669-4681.
[132] Hammer, R.E., Pursel, V.G., Rexroad, C.E. Jr., et al. Production of transgenic rabbits, sheep and pigs by microinjection[J]. Nature. 1985,;315: 680–683.
[133]Koo BC ,Kwon MS ,Choi BR , et al. Retrovirus-mediated gene transfer and expression of EGFP in chicken[J] .Mol Reprod Dev ,2004 ,68 (4) :429-434
[134]Zhao J ,Liu B ,Ren WZ , et al. Production of transgenic mice by in vivo sperm atogonia-mediated gene transfer[J]. Shi Yan Sheng Wu Xue Bao. 2003 ,36(3):197-201.
[135]Lavitrano M,Camaioni A ,Fazio VM, et al . Sperm cells as vectors for introducing foreign DNA into eggs :genetic transformation of mice [J] . Cell. 1989 ,59(2) :239-241.
[136] Shiels PG, Jardine AG. Dolly, no longer the exception: telomeres and implications for transplantation[J]. Cloning Stem Cells. 2003,5(2):157-160.
[137] Kuehn BM.Goodbye. Dolly; first cloned sheep dies at six years old[J]. J Am Vet Med Assoc. 2003,222(8):1060-1061, 1065.
[138] Williams N. Death of Dolly marks cloning milestone[J]. Curr Biol. 2003;13(6):R209- -210
[139]Gerald D ,Fischbach and Ruth L , et al . Stem cells: science ,policy ,and ethics[J]. J Clin Invest ,2004 ,114(10) :1364-1370.
[140]Thomas KR , Capecchi MR. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells[J]. Cell. 1987 ,51 :503-512.
[141]Doetschman T , Gregg RG, Maeda N , et al. Targeted correction of a mutant HPRT gene in mouse embryonic stem cells[J]. Nature. 1987,330:576-578.
[142]Koller BH , Smithies O. Inactivating the beta microglobin locus in mouse embryonic stem cells by homologous recombination[J]. Proc Natl Acad Sci USA .1989,86:8932- -8935.
[143]Mansour SL , Thomas KR , Deng C , et al. Introduction of a lacZ reporter gene into the mouse intlocus by homologous recombination[J]. Proc Natl Acad Sci USA. 1990,87:7688-7692.
[144]Capecchi MR. Targeted gene replacement[J]. Scientific American .1994, 270(3):52-59.
[145]Orban PC , Chui D , Marth JD. Tissue and site-specific DNA recombine-tion in transgenic mice[J]. Proc Natl Acad Sci USA.1992,89 :6861-6865.
[146]Lakso M,Pichel JG, Gorman JR , et al. Efficient in vivo manipulation of mouse enomic sequences at the zygote stage [J]. Proc Natl Acad Sci USA. 1996,93:5860-5865.
[147]Thomson AJ , Mcwhir J. Biomedical and agricultural applications of animal transgenesis[J]. Mol Biotechnol. 2004 ,27 (3):231-244.
[148]Soudais C , Bielinska M, Heikinheimo M, et al. Targeted mutagenesis of the transcription factor GATA24 gene in mouse embryonic stem cells dis-rupts visceral endoderm differentiation in vitro[J]. Development.1995,121:3877-3888.
[149]Smih F , Rouet P , Romanienko PJ , et al. Double-strand breaks at the target locus stimulate gene targeting in embryonic stem cells[J]. Nucleic Ac-ids Res, 1995,23 :5012-5019.
[150]Piedrahita JA. Gene targeting in domestic species: a new beginning[J]. Transgenic Res. 2000,9(425):261-262.
[151]Friedrich G, Soriano P. Promoter traps in embryonic stem cells: a genetic screen to identify and mutate developmental genes in mice [J]. Genes Dev. 1991,5(9): 1513-1523.
[152]Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain[J]. Nat Genet.1999,21(1):70-71.
[153]Brain P. Zambrowicz, Akira Imamoto, Steve Fiering,et al. Disruption of overlapping transcripts in the ROSA bgeo 26 gene trap strain leads to widespread expression of b-galactosidase inmouse embryos and hematopoietic cells[J]. Proc. Natl. Acad. Sci. USA. 1997,94:3789–3794.
[154] Lai KM, Gonzalez M;,Poueymirou WT,et al. Conditional activation of akt in adult skeletal muscle induces rapid hypertrophy[J]. Mol Cell Biol. 2004,24(21):9295-9304
[155]Vooijs M, Jonkers J, Berns A. A highly efficient ligand-regulated Cre recombinase mouse line shows that LoxP recombination is position dependent[J]. EMBO Rep. 2001 ,2(4):292-297.
[156]Bex A, Vooijs M, Horenblas S,et al. Controlling gene expression in the urothelium using transgenic mice with inducible bladder specific Cre-lox recombination[J].J Urol .2002 ,168(6):2641-2644.
[157]Srinivas S, Watanabe T, Lin CS,et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus[J].BMC Dev Biol.2001,1(1):4
[158]Mouse Genome Informatics (MGI), Information obtained from the NIH Mouse Knockout Inventory, 2004.
[159]Mao X, Fujiwara Y, Chapdelaine A,et al. Activation of EGFP expression by cre-mediated excision in a new ROSA26 reporter mouse strain[J].Blood. 2001,97(1):324-326.
[160]Kisseberth WC, Brettingen NT, Lohse JK,et al. Ubiquitous expression of marker transgenes in mice and rats[J]. Dev Biol. 1999,214(1):128-138.
[2] Agre, P., King, L. S., Yasui, M., et al. 2002. Aquaporin water channels—from atomic structure to clinical medicine[J]. J Physiol., 542: 3-16
[3] 冯学超,麻彤辉.水通道蛋白的生理功能[J].生物化学与生物物理进展,2005,21(4):291-297.
[4] A.S.Verkman.Physiological importance of aquaporin water channels[J]. Ann Med.2002,34 (3): 192-200.
[5] A.S.Verkman. More than just water channels: unexpected cellular roles of aquaporins[J]. J.Cell Sci. 2005,118:3225-3232.
[6] S.Saadoun, M.C. Papadopoulos, M. Hara-Chikuma, et al. Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption[J]. Nature. 2005,434 :786-792.
[7] Denker, B. M., Smith, B. L., Kuhajda, F. P., et al. Identification, purification, and partial characterization of a novel Mr 28,000 integral membrane protein from erythrocytes and renal tubules[J]. J Biol Chem. 1988, 263:15634-15642.
[8] Preston, G. M., Carroll, T. P., Guggino, W. B., et al. Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein[J]. Science.1992,256: 385-87.
[9] Agre P, Kozono D. Aquaporin water channels: molecular mechanisms for human diseases[J]. FEBS Lett. 2003,1: 72-78.
[10] Fujiyoshi Y, Mitsuoka K, de Groot B. L., et al. Structure and function of water channels[J].Curr Opin Struct Biol. 2002, 4:509-515.
[11] King LS, Kozono D, Agre P. From structure to disease: the evolving tale of aquaporin biology [J]. Nat Rev Mol Cell Biol 2004,5:687-698.
[12] Morishita Y, Matsuzaki T, Hara-chikuma M, et al. Disruption of aquaporin-11 produces polycystic kidneys following vacuolization of the proximal tubule[J]. Mol Cell Biol. 2005,25:7770-7779.
[13] Itoh T, Rai T, Kuwahara M, et al. Identification of a novel aquaporin, AQP12, expressed in pancreatic acinar cells[J]. Biochem Biophys Res Commun 2005,330:832-838.
[14] King LS, Yasui M. Aquaporins and disease: lessons from mice to humans[J]. Trends Endocrinol Metab.2002,8:355-360.
[15]A.S.Verkman, Yang BX, Song YL, et al. Role of water channels in fluid transport studied by phenotype analysis of aquaporin knockout mice[J]. EXP PHYSIOL 2000,85: 233-241.
[16]M.C. Papadopoulos, S.Krishna, A.S.Verkman. Aquaporin water channels and brain edema[J]. Mt Sinai J Med. 2002,4:242-248.
[17] Hasegawa H., Ma T, Skach W, et al. Molecular-cloning of a mercurial-insensitive water channel expressed in selected water-transporting tissues[J]. J Biol Chem. 1994,269(8):5497-5500.
[18] A.S.Verkman, Alok K. Structure and function of aquaporin water channel[J]. Am.J.Physiol.Renal Physiol. 2000,278:F13-28.
[19] Ren G, Cheng A , Melnyk P , et al. Polymorphism in the packing of aquaporin-1 tetramers in 2-D crystals[J]. J Struct Biol. 2000,130(1):45-53.
[20] Sui H X, Han B G, Lee J K,et al. Structural basis of water-specific transport through the AQP1 water channel[J]. Nature , 2001 , 414 : 872-878.
[21] 隋海心, 任罡等. 水分子通道蛋白的结构与功能[J]. 化学进展,2004 16(2):145-152.
[22] Burghardt B, Elkaer ML, Kwon TH, et al. Distribution of aquaporin water channels AQP1 and AQP5 in the ductal system of the human pancreas[J]. Gut.2003,52(7): 1008-1016.
[23] Gresz V, Kwon TH, Hurley PT, et al. Identification and localization of aquaporin water channels in human salivary glands[J]. Am J Physiol Gastrointest Liver Physiol. 2001,281(1):G247-254.
[24] Elkjaer ML, Nejsum LN, Gresz V, et al. Immunolocalization of aquaporin-8 in rat kidney, gastrointestinal tract, testis, and airways[J]. Am J Physiol Renal Physiol. 2001, 281(6):F1047-1057.
[25] Nejsum LN, Elkjaer M, Hager H, et al. Localization of aquaporin-7 in rat and mouse kidney using RT-PCR, immunoblotting, and immunocytochemistry[J]. Biochem Biophys Res Commun. 2000 ,277(1):164-170.
[26] Li J, Kuang K, Nielsen S, et al. Molecular identification and immunolocalization of the water channel protein aquaporin 1 in CBCECs[J]. Invest Ophthalmol Vis Sci. 1999, 40(6):1288-1292.
[27] Kim IB, Oh SJ, Nielsen S, et al. Immunocytochemical localization of aquaporin 1 in he rat retina[J]. Neurosci Lett. 1998,244(1):52-54.
[28] Zhong SX, Liu ZH. Expression of aquaporins in the cochlea and endolymphatic sac of guinea pig[J]. ORL J Otorhinolaryngol Relat Spec. 2003 ,65(5):284-289.
[29] J. Terris, C. A. Ecelbarger, D. Marples, et al. Distribution of aquaporin-4 water channel expression within rat kidney[J]. Am J Physiol Renal Physiol.1995,269: 775 – 785.
[30] Pedro Gallardo, Nancy Olea, Francisco V. Sepúlveda.Distribution of aquaporins in the colon of Octodon degus, a South American desert rodent[J]. Am J Physiol Regulatory Integrative Comp Physiol. 2002,283: 779 – 788.
[31] Grazia P. Nicchia, Antonio Frigeri, Beatrice Nico, et al. Tissue Distribution and Membrane Localization of Aquaporin-9 Water Channel: Evidence for Sex-linked Differences in Live[J]. J. Histochem. Cytochem.2001,49: 1547 – 1556.
[32] R. M. Effros, C. Darin, E. R. Jacobs, et al. Water transport and the distribution of aquaporin-1 in pulmonary air spaces[J]. J Appl Physiol.1997,83:1002–1016.
[33] K.L. Schey, L.E. Ball, R.K. Crouch,et al. The Distribution of Phosphorylated and Posttranslationally Modified Aquaporin 0 Within the Normal Human Lens[J]. Invest. Ophthalmol. Vis. Sci. 2003, 44: 4483.
[34] S?ren Nielsen, Landon S. King, Birgitte M?nster Christensen, et al. Aquaporins in complex tissues. II. Subcellular distribution in respiratory and glandular tissues of rat[J].Am J Physiol Cell Physiol. 1997, 273: 1549 – 1561.
[35] Steffen Hamann, Thomas Zeuthen, Morten La Cour, et al. Aquaporins in complex tissues: distribution of aquaporins 1-5 in human and rat eye[J]. Am J Physiol Cell Physiol. 1998, 274: 1332 – 1345.
[36] B. K. Kishore, J. M. Terris, M. A. Knepper. Quantitation of aquaporin-2 abundance in microdissected collecting ducts: axial distribution and control by AVP[J]. Am J Physiol Renal Physiol. 1996,271: 62 – 70.
[37] S Nielsen, BL Smith, EI Christensen, et al. Distribution of the Aquaporin CHIP in Secretory and Resorptive Epithelia and Capillary Endothelia[J]. PNAS. 1993, 90: 7275– 7279.
[38] Johannes Loffing, Dominique Loffing-Cueni, Andreas Macher, et al. Localization of epithelial sodium channel and aquaporin-2 in rabbit kidney cortex[J]. Am J Physiol Renal Physiol. 2000,278: 530 – 539.
[39] Mandon B, Nielsen S, Kishore BK, et al. Expression of syntaxins in rat kidney[J]. Am J Physiol. 1997,273(5 Pt 2):F718-730.
[40] Marie-Louise Elkj?r, Lene N. Nejsum, Veronika Gresz,et al. Immunolocalization of aquaporin-8 in rat kidney, gastrointestinal tract, testis, and airways[J]. Am J Physiol Renal Physiol.2001, 281: 1047 – 1057.
[41] Giuseppe Calamita, Amelia Mazzone, Yoon S. Cho,et al. Expression and Localization of the Aquaporin-8 Water Channel in Rat Testis[J]. Biol Reprod.2001, 64: 1660 – 1666.
[42] Nuria Pastor-Soler, Corinne Bagnis, Ivan Sabolic,et al. Aquaporin 9 Expression along the Male Reproductive[J] Tract.Biol Reprod. 2001, 65: 384-393.
[43] Haruko Funaki, Tadashi Yamamoto, Yu Koyama,et al. Localization and expression of AQP5 in cornea, serous salivary glands, and pulmonary epithelial cells[J]. Am J Physiol Cell Physiol.1998, 275: 1151 – 1157.
[44] Morishita Y, Sakube Y, Sasaki S, et al. Molecular mechanisms and drug development in aquaporin water channel diseases: aquaporin superfamily (superaquaporins): expansion of aquaporins restricted to multicellular organisms[J]. J Pharmacol Sci. 2004,96(3):276-279.
[45]Verbalis JG, Murase T, Ecelbarger CA, et al. Studies of renal aquaporin-2 expression during renal escape from vasopressin-induced antidiuresis[J]. Adv Exp Med Biol. 1998, 449:395-406.
[46] Christensen BM, Zelenina M, Aperia A, et al. Localization and regulation of PKA-phosphorylated AQP2 in response to V(2)-receptor agonist/antagonist treatment[J]. Am J Physiol Renal Physiol. 2000 Jan,278(1):F29-42.
[47]Katsura T, Verbavatz Jm, Farinas J, et al. Constitutive And Regulated Membrane Expression of aquaporin-1 and aquaporin-2 water channels in stably transfected Llc-pk1 epithelial-cells[J]. Proc. Natl. Acad. Sci. U.S.A. 1995,92 (16): 7212-7216.
[48] Hayashi, M, Sasaki S, Tsuganezawa H, et al. Expression and distribution of aquaporin of collecting duct are regulated by vasopressin V2 receptor in rat kidney[J]. J Clin Invest. 1994,94:1778-1783.
[49] Matsumura, Y, Uchida S, Rai T, et al. Transcriptional regulation of aquaporin-2 waterchannel gene by cAMP[J]. J Am Soc Nephrol. 1997,8: 861-867.
[50]King, LS, Nielsen, S, and Agre,P. Aquaporin-1 water channel protein in lung: ontogeny, steroid-induced expression, and distribution in rat[J]. J Clin Invest. 1996, 97, 2183-2191.
[51]Marinelli, RA, Tietz PS, Pham LD, et al. Secretin induces the apical insertion of aquaporin-1 water channels in rat cholangiocytes[J]. Am J Physiol Gastrointest Liver Physiol. 1999,276: G280-G286.
[52]Carreras FI, Gradilone SA, Mazzone A, et al. Rat hepatocyte aquaporin-8 water channels are down-regulated in extrahepatic cholestasis[J]. Hepatology. 2003, 37(5):1026-33.
[53]Pastor-Soler N, Isnard-Bagnis C, Herak-Kramberger C, et al. Expression of aquaporin 9 in the adult rat epididymal epithelium is modulated by androgens[J]. Biol Reprod. 2002 Jun,66(6):1716-22.
[54]Smith JK, Siddiqui AA, Modica LA, et al.Interferon-alpha upregulates gene expression of aquaporin-5 in human parotid glands[J]. J Interferon Cytokine Res. 1999 Aug,19(8):929- -935.
[55]Borok Z, Li X, Fernandes VF, et al. Differential regulation of rat aquaporin-5 promoter/enhancer activities in lung and salivary epithelial cells[J]. J Biol Chem. 2000 Aug 25,275(34):26507-26514.
[56] Bai C, Fukuda N, Song Y, et al. Lung fluid transport in aquaporin-1 and aquaporin-4 knockout mice[J]. J Clin Invest.1999,103(4): 555-561.
[57] Ma T, Fukuda N, Song Y, et al. Lung fluid transport in aquaporin-5 knockout mice [J]. J Clin Invest.2000,105(1): 93-100.
[58] Song Y,Ma T. Matthay MA, et al. Role ofAQP4 in airspace-to-capillary water permeability inintact mouse lung measured by a novel gravimetric method [J]. J.Gen.Physiol. 2000,1 (15):17-27.
[59] Song Y, Verkman A S. Aquaporin-5 dependent fluid secretion in airway submucosal glands [J]. J Biol Chem.2001,276(44): 41288-41292.
[60] Krane C M, Fortner C N, Hand A R, et al. Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation[J]. Proc Natl Acad Sci U S A. 2001,98(24): 14114-14119.
[61] Ma T, Verkman A S. Aquaporin water channels in gastrointestinal physiology[J]. J Physiol-London.1999,517 (2): 317-326.
[62] Ma T, Song Y, Gillespie A, et al. Defective secretion of saliva in transgenic mice lacking aquaporin-5 water channels[J]. J Biol Chem.1999,274(29): 20071-20074.
[63] Yang B, Song Y, Zhao D,et al. Phenotype Analysis of Aquaporin-8 Null Mice [J]. Am J Physiol Cell Physiol.2005,288(5):C1161-1170.
[64] Ma T, Jayaraman S, Wang K S, et al. Defective dietary fat processing in transgenic mice lacking aquaporin-1 water channels[J]. Am J Physiol Cell Physiol. 2001,280(1): C126-134.
[65] Wang K S, Komar A R, Ma T, et al. Gastric acid secretion in aquaporin-4 knockout mice[J]. Am J Physiol Gastrointest Liver Physiol.2000,279(2): G448-453.
[66] Wang K S, Ma T, Filiz F, et al. Colon water transport in transgenic mice lacking aquaporin-4 water channels[J]. Am J Physiol Gastrointest Liver Physiol. 2000,279(2):G463-470.
[67] Verkman A S. Renal concentrating and diluting function in deficiency of specific aquaporin genes [J]. Exp Nephrol.2002,10(4): 235-240.
[68] Ma T, Yang B, Gillespie A, et al. Severely impaired urinary concentrating ability in transgenic mice lacking aquaporin-1 water channels[J]. J Biol Chem. 1998,273(8): 4296-4299.
[69] Schnermann J, Chou C L, Ma T, et al. Defective proximal tubular fluid reabsorption in transgenic aquaporin-1 null mice[J]. Proc Natl Acad Sci U S A. 1998,95(16): 9660-9664.
[70] Chou CL , Knepper MA , Van Hoek AN , et al. Reduced water permeability and altered ultrastructure in thin descending limb of Henle in aquaprin1 null mice [J ] . J Clin Invest , 1999 ,103 : 491- 496.
[71] Ma T, Song Y, Yang B, et al. Nephrogenic diabetes insipidus in mice lacking aquaporin-3 water channels[J]. Proc Natl Acad Sci U S A.2000,97(8): 4386-4391.
[72] Yang B, Ma T, Verkman A S. Erythrocyte water permeability and renal function in double knockout mice lacking aquaporin-1 and aquaporin-3[J]. J Biol Chem. 2001,276(1): 624-628.
[73] Ma T, Yang B, Gillespie A, et al. Generation and phenotype of a transgenic knockout mouse lacking the mercurial-insensitive water channel aquaporin-4[J]. J Clin Invest.1997,100(5): 957-962.
[74] Chou C L, Ma T, Yang B, et al. Fourfold reduction of water permeability in inner medullary collecting duct of aquaporin-4 knockout mice[J]. Am J Physiol.1998,274(2 Pt1):C549-554.
[75] Van Os C H, Deen P M. Aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus[J]. Proc Assoc Am Physicians. 1998,110(5):395-400.
[76] Tamarappoo B K, Verkman A S. Defective aquaporin-2 trafficking in nephrogenic diabetes insipidus and correction by chemical chaperones[J]. J Clin Invest. 1998, 101(10): 2257-2267.
[77] Knoers N V, Deen P M. Molecular and cellular defects in nephrogenic diabetes insipidus[J]. Pediatr Nephrol.2001,16(12): 1146-1152.
[78] Oshio K, Watanabe H, Song Y, et al. Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1[J]. FASEB J.2005,19(1): 76-78.
[79] Oshio K, Song Y, Verkman A S,ET AL. Aquaporin-1 deletion reduces osmotic water permeability and cerebrospinal fluid production[J]. Acta Neurochir Suppl. 2003,86: 525-528.
[80] Manley GT, Fujimura M, Ma T, et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke [J]. Nat Med.2000,6(2): 159-163.
[81] Papadopoulos MC, Manley GT, Krishna S, et al. Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema[J]. FASEB J.2004,18(11):1291-1293.
[82] Da T, Verkman A S. Aquaporin-4 gene disruption in mice protects against impaired retinal function and cell death after ischemia[J]. Invest Ophthalmol Vis Sci.2004, 45(12): 4477-4483.
[83] Thiagarajah J R, Verkman A S. Aquaporin deletion in mice reduces corneal water permeability and delays restoration of transparency after swelling[J]. J Biol Chem. 2002,277(21): 19139-19144.
[84] Zhang D, Vetrivel L, Verkman A S. Aquaporin deletion in mice reduces intraocular pressure and aqueous fluid production[J]. J Gen Physiol.2002,119(6): 561-569.
[85] Ma T, Hara M, Sougrat R, et al. Impaired stratum corneum hydration in mice lacking epidermal water channel aquaporin-3[J]. J Biol Chem.2002,277(19): 17147-17153.
[86] Hara M, Ma T, Verkman A S. Selectively reduced glycerol in skin of aquaporin-3-deficient mice may account for impaired skin hydration, elasticity, and barrier recovery[J]. J Biol Chem.2002,277(48): 46616-46621.
[87] Hara M, Verkman A S. Glycerol replacement corrects defective skin hydration, elasticity, and barrier function in aquaporin-3-deficient mice[J]. Proc Natl Acad Sci U S A.2003,100(12): 7360-7365.
[88] Yang B, Verbavatz J M, Song Y, et al. Skeletal muscle function and water permeaility in aquaporin-4 deficient mice[J]. Am J Physiol Cell Physiol.2000,278(6): 1108-1115
[89] S. Saadoun, M.C. Papadopoulos, M. Hara-Chikuma, et al. Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption[J]. Nature. 2005,434: 786-92.
[90] S. Saadoun, M.C. Papadopoulos, H. Watanabe, D. et al. Involvement of aquaporin-4 in astroglial cell migration and glial scar formation[J]. J. Cell Sci. 2005,118: 5691-8.
[91] M. Hara-Chikuma, A.S. Verkman. Aquaporin-1 facilitates epithelial cell migration in kidney proximal tubule[J]. J. Am. Soc. Nephrol. 2006,17 :39-45.
[92] V.M. Loitto, T. Forslund, T. Sundqvist, et al. Neutrophil leukocyte motility requires directed water influx[J]. J. Leukoc. Biol. 2002,71 :212-222.
[93] V.M. Loitto, K.E. Magnusson. Hg2+ and small-sized polyethylene glycols have inverse effects on membrane permeability, while both impair neutrophil cell motility[J]. Biochem. Biophys. Res. Commun. 2004,316: 370-378.
[94] A. Harlozinska. Progress in molecular mechanisms of tumor metastasis and angiogenesis[J]. Anticancer Res. 2005,25: 3327-33.
[95] T. Bogenrieder, M. Herlyn. Axis of evil: molecular mechanisms of cancer metastasis[J]. Oncogene. 2003,22:6524-36.
[96] A. Mobasheri, R. Airley, S.M. Hewitt, et al. Heterogeneous expression of the aquaporin 1 water channel in tumors of the prostate, breast, ovary, colon and lung: a study using high density multiple human tumor tissue microarrays[J]. Int J Oncol. 2005 ,26 :1149-58.
[97] Ransom, C.B. O’Neal, J.T. Sontheimer, H. Volume-activated chloride currents contribute to the resting conductance and invasive migration of human glioma cells[J]. J. Neurosci. 2001, 21: 7674-83.
[98] Mao J W, Wang L W, Sun X R, et al. Volume-activated Cl- current in migrated nasopharyngeal carcinoma cells[J]. Acta Physiologica Sinica. 2004, 56: 525-530
[99] Soroceanu, L. Manning Jr., TJ. Sontheimer, H. Modulation of glioma cell migration and invasion using Cl(-) and K(+) ion channel blockers[J]. J.Neurosci. 1999,19: 5942-54.
[100]Schwab,A. Ion channels and transporters on the move[J]. News. Physiol. Sci. 2001, 16: 29-33.
[101]Endo M., Jain, R.K. Witwer, B. et al. Water channel (aquaporin 1) expression and distribution in mammary carcinomas and glioblastomas[J]. Microvasc Res. 1999, 58: 89-98.
[102]Yang, J.H. Shi, Y.F. Cheng, et al. Expression and localization of aquaporin-5 in the epithelial ovarian tumors [J]. Gynecol Oncol. 2006,100:294-99.
[103]Moon, C. Soria, J.C. Jang, et al. Involvement of aquaporins in colorectal carcinogenesis[J]. Oncogene. 2003,22:6699-703.
[104]Mazal, P.R. Susani, M. Wrba, et al. Diagnostic significance of aquaporin-1 in liver tumors[J]. Hum. Pathol. 2005, 36: 1226-31.
[105]Warth A, Mittelbronn M, Wolburg H. Redistribution of the water channel protein aquaporin-4 and the K+ channel protein Kir4.1 differs in low- and high-grade human brain tumors[J]. Acta Neuropathol (Berl). 2005,109: 418-26.
[106]Schw ab A. Function and spatial distribution of ion channels and transporters in cell m igration[J].Am J Physiol Renal Physiol. 2001,280: F739- F747.
[107]Shimomura O. Structure of the chromophore of Aequorea green fluorescent protein[J]. FEBS Letters.1979,104 :220 – 222.
[108]Prasher D ,Echenrode V ,Wand W, et al. Primary structure of the Aequores victoria green fluorescent protein[J]. Gene.1992 ,111:229–233.
[109]Chalfie M,Ta Y,Euskirchen G, et al. Green fluorescent protein as a marker for gene expression[J]. Science.1994,263 :802–805.
[110] Wei, Hu; Chi-Lien, Cheng. Expression of Aequorea green fluorescent protein in plant cells[J]. FEBS Letters.1995,369( 2-3): 331-334.
[111] Reil?nder, Helmut; Haase, Winfried; Maul, Gabi. Functional Expression of the Aequorea Victoria Green Fluorescent Protein in Insect Cells Using the Baculovirus Expression System[J]. Biochemical and Biophysical Research Communications. 1996,219(1):14-20.
[112] Ward WW, Bokman SH. Reversible denaturation of Aequore a green-fluorescent protein:physical separation and characterization of the renatured protein[J]. Biochemistry.1982,21(19):4535-4540.
[113] YANG F, Moss LG, Phillips GN , et al. The Molecular Structure of Green Fluorescent Protein[J]. Nat Biotechnol. 1996,14 (10) : 1246-1251.
[114]Ormo M , Cubitt A B, Kallio K, et a l. Crystal Structure of the A equorea V ictoria Green Fluorescent Protein[J]. Science.1996, 273 (5280): 1392-1395.
[115]Youvan D C, M ichel-Beyerle M E. Structure and Fluorescence Mechanism of GFP[J]. Nat Biotechnol. 1996,14 (10): 1219-1220.
[116]Chalfie M , Kain S. Green fluorescent protein: properties,applications, and protocols [M ]. N ew York: W iley L iss,1998. 83.
[117]Cubitt AB, Heim R, Adams SR, et al. Understanding, improving and using green fluorescent proteins[J]. Trends Biochem Sci. 1995,20:448-455.
[118]黄国存,朱生伟,董越梅,等. 绿色荧光蛋白及其在植物研究中的应用[J]. 植物学通报.1998 ,15(5) :24 - 30.
[119]Zolotukhin S ,Potter M,Hauswirth W W, et al . A“Humanized”green fluorescent protein cDNA adapted for high-level expression in mammalian cells[J]. Journal of Virology , 1996 ,70(7) :4646 - 4654.
[120]Heim R ,Cubitt A B ,Tsien R Y. Improved green fluorescence [J]. Nature. 1995 ,373 : 663 – 664.
[121]Heim R , Tsien RY. Engineering green fluorescent protein for improved brightness, longer wavelengths and fluorescece resonance energy transfer[J]. Curr Biol.1996 ,6:178- 182.
[122]Juan Llopis, J. Michael Mccaffey, Atsushi Miyawaki,et al. Surement of cytosolic, mitochondrial, and Golgi pH in single iving cells with green fluorescent proteins [J]. Proc. Natl. Acad. Sci. USA .1998,95: 6803–6808.
[123]Elsliger MA, Wachter RM, Hanson GT,et al. Structural and spectral response of green fluorescent protein variants to changes in pH [J]. Biochemistry 1999,38(17): 5296-5301.
[124]Wachter RM, Elsliger MA, Kallio K,et al. Structural basis of spectral shifts in the yellow-emission variants of green fluorescent protein [J]. Structure.1998,6(10): 1267-1277.
[125]Rebekka M, Wachter , S.James Remington. Sensitivity of the yellow variant of green fluorescent protein to halides and nitrate [J]. Curr.Biol.1999,9:R268-269.
[126]Luis J.V.,Galietta,Peter M.Haggie,et al. Green fluorescent protein-based halide indicators with improved chloride and iodide affinityies [J]. FEBS Letters.2001, 499:220-224.
[127]Radder H. Exploiting abstract possibilities: a critique of the concept and practice of productpatenting [J]. J Agric Environ Ethics. 2004, 17 (3) :275-291.
[128]Gordon K, Lee E, Vital J, et al. Genetic transformation of mouse milk [J]. Bio- technology .1980 ,5:1183-1187.
[129] Palmiter,R.D. et al. Dramatic growth of mice that develop from eggs microinjected with metalothionein growth hormone fusion gene[J]. Nature.1982,300: 611-615.
[130]Nagueh SF ,Chen S ,Patel R , et al. Evolution of expression of cardiac phenotypes over a 42-year period in the beta-myosin heavy chain transgenic rabbit model of human hypertrophic cardiomyopathy [J]. J Mol Cell Cardiol ,2004 ,36 (5) :663-673.
[131]Chang P ,Torres J ,Lewis RA , et al . Localization of RNAs to the Mitochondrial Cloud in Xenopus Oocytes through Entrapment and Association with Endoplasmic Reticulum[J]. Mol Biol Cell ,2004 ,15 (10): 4669-4681.
[132] Hammer, R.E., Pursel, V.G., Rexroad, C.E. Jr., et al. Production of transgenic rabbits, sheep and pigs by microinjection[J]. Nature. 1985,;315: 680–683.
[133]Koo BC ,Kwon MS ,Choi BR , et al. Retrovirus-mediated gene transfer and expression of EGFP in chicken[J] .Mol Reprod Dev ,2004 ,68 (4) :429-434
[134]Zhao J ,Liu B ,Ren WZ , et al. Production of transgenic mice by in vivo sperm atogonia-mediated gene transfer[J]. Shi Yan Sheng Wu Xue Bao. 2003 ,36(3):197-201.
[135]Lavitrano M,Camaioni A ,Fazio VM, et al . Sperm cells as vectors for introducing foreign DNA into eggs :genetic transformation of mice [J] . Cell. 1989 ,59(2) :239-241.
[136] Shiels PG, Jardine AG. Dolly, no longer the exception: telomeres and implications for transplantation[J]. Cloning Stem Cells. 2003,5(2):157-160.
[137] Kuehn BM.Goodbye. Dolly; first cloned sheep dies at six years old[J]. J Am Vet Med Assoc. 2003,222(8):1060-1061, 1065.
[138] Williams N. Death of Dolly marks cloning milestone[J]. Curr Biol. 2003;13(6):R209- -210
[139]Gerald D ,Fischbach and Ruth L , et al . Stem cells: science ,policy ,and ethics[J]. J Clin Invest ,2004 ,114(10) :1364-1370.
[140]Thomas KR , Capecchi MR. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells[J]. Cell. 1987 ,51 :503-512.
[141]Doetschman T , Gregg RG, Maeda N , et al. Targeted correction of a mutant HPRT gene in mouse embryonic stem cells[J]. Nature. 1987,330:576-578.
[142]Koller BH , Smithies O. Inactivating the beta microglobin locus in mouse embryonic stem cells by homologous recombination[J]. Proc Natl Acad Sci USA .1989,86:8932- -8935.
[143]Mansour SL , Thomas KR , Deng C , et al. Introduction of a lacZ reporter gene into the mouse intlocus by homologous recombination[J]. Proc Natl Acad Sci USA. 1990,87:7688-7692.
[144]Capecchi MR. Targeted gene replacement[J]. Scientific American .1994, 270(3):52-59.
[145]Orban PC , Chui D , Marth JD. Tissue and site-specific DNA recombine-tion in transgenic mice[J]. Proc Natl Acad Sci USA.1992,89 :6861-6865.
[146]Lakso M,Pichel JG, Gorman JR , et al. Efficient in vivo manipulation of mouse enomic sequences at the zygote stage [J]. Proc Natl Acad Sci USA. 1996,93:5860-5865.
[147]Thomson AJ , Mcwhir J. Biomedical and agricultural applications of animal transgenesis[J]. Mol Biotechnol. 2004 ,27 (3):231-244.
[148]Soudais C , Bielinska M, Heikinheimo M, et al. Targeted mutagenesis of the transcription factor GATA24 gene in mouse embryonic stem cells dis-rupts visceral endoderm differentiation in vitro[J]. Development.1995,121:3877-3888.
[149]Smih F , Rouet P , Romanienko PJ , et al. Double-strand breaks at the target locus stimulate gene targeting in embryonic stem cells[J]. Nucleic Ac-ids Res, 1995,23 :5012-5019.
[150]Piedrahita JA. Gene targeting in domestic species: a new beginning[J]. Transgenic Res. 2000,9(425):261-262.
[151]Friedrich G, Soriano P. Promoter traps in embryonic stem cells: a genetic screen to identify and mutate developmental genes in mice [J]. Genes Dev. 1991,5(9): 1513-1523.
[152]Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain[J]. Nat Genet.1999,21(1):70-71.
[153]Brain P. Zambrowicz, Akira Imamoto, Steve Fiering,et al. Disruption of overlapping transcripts in the ROSA bgeo 26 gene trap strain leads to widespread expression of b-galactosidase inmouse embryos and hematopoietic cells[J]. Proc. Natl. Acad. Sci. USA. 1997,94:3789–3794.
[154] Lai KM, Gonzalez M;,Poueymirou WT,et al. Conditional activation of akt in adult skeletal muscle induces rapid hypertrophy[J]. Mol Cell Biol. 2004,24(21):9295-9304
[155]Vooijs M, Jonkers J, Berns A. A highly efficient ligand-regulated Cre recombinase mouse line shows that LoxP recombination is position dependent[J]. EMBO Rep. 2001 ,2(4):292-297.
[156]Bex A, Vooijs M, Horenblas S,et al. Controlling gene expression in the urothelium using transgenic mice with inducible bladder specific Cre-lox recombination[J].J Urol .2002 ,168(6):2641-2644.
[157]Srinivas S, Watanabe T, Lin CS,et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus[J].BMC Dev Biol.2001,1(1):4
[158]Mouse Genome Informatics (MGI), Information obtained from the NIH Mouse Knockout Inventory, 2004.
[159]Mao X, Fujiwara Y, Chapdelaine A,et al. Activation of EGFP expression by cre-mediated excision in a new ROSA26 reporter mouse strain[J].Blood. 2001,97(1):324-326.
[160]Kisseberth WC, Brettingen NT, Lohse JK,et al. Ubiquitous expression of marker transgenes in mice and rats[J]. Dev Biol. 1999,214(1):128-138.
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