摘要
糖尿病是全球性医学难题,它已成为继癌症和心脑血管疾病之后的第三大疾患,它也是全世界发病率和病死率最高的五种疾病之一。如不加以有效干预,今后30年内,我国糖尿病患病率将达到5.0-10.0%,届时全国糖尿病患者总数将逾一亿。因此,研究糖尿病的病因、发病机理和糖尿病的最佳防治方案已迫在眉睫。糖尿病是一种具有明显遗传倾向的多基因疾病,其发病机制十分复杂,环境因素和遗传因素又交互作用,共同促成了糖尿病的发生。糖尿病在临床上通常分为两大类,即I型糖尿病(胰岛素依赖性,IDDM)和U型糖尿病(非胰岛素依赖性,NIDDM),后者占所有糖尿病病例90%以上。NIDDM的基因定位策略主要有候选基因法和全基因组扫描法。候选基因法是指选定糖尿病发病过程中与糖代谢及信号传导有关的基因为研究对象,进而研究它们是否与糖尿病发病过程相关联。候选基因法简便易行,是目前乃至今后研究NIDDM的主要方法之一。然而,到目前为止,应用该方法发现的结果较少,推测NIDDM基因很可能包括许多未发现的新基因。为此,必须选用适当的方法来发现新基因。
我们在研究糖尿病的发生机制和防治策略的过程中,提出了一条新思路,即从正常的血糖自动调节的基因途径入手,先分离、克隆与血糖自动调解相关的基因,再研究这些相关基因在糖尿病状况下有何改变,为确定糖尿病相关或易感基因以及寻找防治途径提供依据。通过颈外静脉—右心房导管插管术建立了大鼠血糖自动调节模型,该模型制作简便,重复性好,人为干扰因素少。随后对该模型大鼠的骨骼肌进行的mRNA差异显示分析。
差异显示是一种用来检测哺乳细胞基因表达差异的方法。自从1992年发明该方法以来,至今已有许多条件优化和改进,逐渐发展成一个比较成熟的鉴定两种状态下的差异表达基因的方法。这些改进包括:锚定引物的数量可以从12条减少到4条;应用长引物可在严格的条件下进行PCR扩增;两步PCR法增强实验结果的可靠性。除了综合以上改进外,本文采用先通过狭缝杂交初步筛选上百条的差异条带、再克隆测序、Northern Blot杂交最后确定差异表达基因的策略。该策略由于先狭缝杂交初步筛选,既显著减少克隆测序的工作量和花费,又能保证从最初的上百条差异条带中最终通过Northern Blot杂交鉴定出最有差异表达特征的基因,从而保证实验的质量。另外,我们以整体动物代替通常的培养细胞系作为实验材料,因为细胞在培养状态下不能很好地代表机体正常的生理状态,尤其不能很好地代表由机体多组织协同参与的代谢活动例如糖代谢。
从最初的181条差异条带中,74条被狭缝杂交证实存在差异表达,其中
Diabetes is a disease difficult to treat in worldwide. It is the third disease followed cancer and cardiac disease and one of five diseases with the highest incidence and mortality. If we don't try to treat it, in the following thirty years, diabetes sufferer in China will reach 5.0-10.0% which mean the total patient number will reach one hundred million. It is necessary to do research on etiology, underlying basis and best precautionary method of diabetes as soon as possible. Diabetes is a multigenes related disease with obvious inherited tendency which has extremely complex basis. In clinical, diabetes is divided into two group: type I diabetes (IDDM) and type II diabetes (NIDDM), the latter is 90% of total diabetes patient. There are two main strategies in NIDDM gene identification: candidate gene strategy and whole genome scanning strategy. Candidate gene strategy is to select genes participating in glucose metabolism and signal transduction as candidate genes. This strategy is simple and one of main strategy in NIDDM research now. But, as yet the result discovered by this strategy is less. This leads to speculate that NIDDM genes are possible those genes have not been discovered. For this purpose, it is necessary to discover glucose metabolism related new genes with proper methods.
We have provided a new thought in the research of diabetes here: at first to cloning glucose metabolism related gene, secondly to discover how the related new gene participating into glucose metabolism, to provide basis of identify new candidate gene and of exploit new precautionary method.
Firstly, we established SD rat glucose auto-regulating model by use of Jugular Vein right atrium intubation. This model is easy to make and has good repetition, has less artificial interference. Then mRNA differential display assay had been done by the use of this model.
mRNA differential display is a method to isolate differential expressed genes from mammalian cell. There has been many modifications since this method has been established which made it a mature method. These modifications include: the number of anchor primers can reduce from 12 to 4; longer primers are used to make PCR more stringent; two-step PCR can enhance reliability. Beside we adopted these modifications, we adopted a strategy that first screening hundreds of differentially expressed bands through slot blot, then cloning and sequencing candidate cDNAs, Northern Blot ensure the differentially expressed genes at last. Because of slot blot
引文
1.Vionnet N, Hani EH, Lesage S, et al. Genetics of 2-DM in France: studies with 19 candidate genes in affected sib pairs. Diabetes, 1997,46:1062-1068
2 Liang, P. And Pardee, A. B. Differentional display of Eukaryotic Messenger RNA by means of the Polymerase chain Reaction. Science 1992; 257:967-971.
3 DeFronzo, R. A.The triumvirate: β-cell,muscle,liver: A collusion responsible for NIDDM(Lilly lecture 1987).Diabetes 1988:37:667-687.
4. Welsh J, et al. 1992 rbitrarily primed PCR fingerprinting of RNA. Nucleic Acids Res. 20(19): 4965-70
5 Peng liang, Weimin Zhu, Xiaoying Zhang et al. Differential display using one-base anchored oligo-dT primers. Nucleic Acids Research 1994:22: 5763-5764.
6 Feng sheng Li, Elliots, Bamathan et al. Rapid method for screening and cloning cDNAs generated in differential mRNA display: application of Northern blot for affinity capturing of cDNAs. Nucleic Acid Research 1994:22 :1764-1765.
7 Maarten, H. K. Linskens, Junli Feng, WilliamH. Andrews et al. Cataloging altered gene expression in young and senescent cells using enhanced differential display. Nucleic Acids Research 1995 ;.23:3244-3251.
8 Dambrook, J., Fritsch, E. F. and Maniatis, T. (1989) Molecular Cloning: a Laboratory Manual, second edition. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
9 Feinberg, A. P. and Vogelstein, B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal. Biochem 1983;132:6- 13.
10 Peng Liang, Lidia Averboukh and Arthur B. Pardee. Distribution and cloning of eukaryotic mRNAs by means of differential display: refinements and optimization. Nucleic Acids Research 1993 ;21: 3269-75.
11 Haag, E. and Raman, V. Effects of primer choice and source of Taq DNA polymerase on the banding patterns of differential display RT-PCR. Biotechniques 1994:17(2):226-8.
12 Reeves, S. A., Rubio, M. and Louis, D. N. General method for PCR amplification and direct sequencing of mRNA differential display products. Biotechniques 1995:18(1):18-20.
13 Liang, P., Zhu, W., ZhangX., et, at. Differential display using one-base anchored oligo-dT primers. Nucleic Acids Res 1994:22(25):5763-4.
14 Fengsheng Li, Elliots. Barnathan,Katalin Kariko. Rapid method for screening and??cloning cDNAs generated in differential mRNA display: application of Northern blot for affinity capturing of cDNA. Nucleic Acids Research 1994; 22(9): 1764-1765.
15 Didier Callard, Bernard Lescure, Laurent Mazzolini. A method for the elimination of false positives generated by the mRNA differential display technique. BioTechniques 1994; 16(6): 1096-1103.
16 Xinkang Wang, Giora Z. Fenerstein. Direct Sequencing of DNA isolated from mRNA differential display. BioTechniques 1995; 18(3): 448-453.
17 Antine, E. Stenbit, Tsu-shuen Tsao, Jing Li et at. GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nature Medicine 1997; 3(10): 1096-101.
18 Fude Fang, Lu Zhou, Lian Ding et al. Modern Medical Experiment Protocol. Beijing United press of Beijing Medical University and Peking Union Medical College 1996; 8-10.
19. Hager J, Hansen L, Vaisse C, et al. A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus. Nature Genetics. 1995, 9: 299-304
20. Li11ioja S, Hott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of 2-DM. N Engl J Med, 1993, 329:1988
21. Magre J, Laurell H, Fizames C, et al. Human Hormone-sensitive lipase, genetic mapping, identification of a new dinucleotide repeat, and association with obesity and 2-DM. Diabetes 1998, 47: 284-286
22. Stifling B, Cox N, Bell G, et al. Identification of microsatellite markers near the human ob gene and linkage studies in 2-DM-affected sib pairs. Diabetes, 1995, 44: 999-1001
23. Li SR, Baromi MG, Oelbaum RS, et al. Association of genticvariant of the glucose transporter with non-insulin-dependent diabetes mellitus. Lancet, 1988, 2: 368-370
24. Baroni M, Alcolado J, Gragnoli C, et al. Affected sib-pair analysis of the GLUT1 glucose transporter gene locus in 2-DM: evidence for no linkage. Human genetics, 1994, 93: 675-680
25. Oelbaum RS, Bouloux PMG, Li SR, et al. Insulin receptor gene polymorphisms in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia, 1991, 34: 260-264
26.苗明三.实验动物和动物实验技术.北京:中国中医药出版社.1997,240-241
27.方福德,周吕,丁濂,等.现代医学实验技巧全书(下册).北京:北京医科大学协和医科大学 联合出版社,1996,654
28. Miraglia S, Godfrey W, Buck D1998 A response to AC133 hematopoietic stem cell antigen: human homologue of mouse kidney prominin or distinct member of a novel??protein family? Blood, 91(11): 4390-1
29. Weigmann A, Corbeil D, Hellwig A, Huttner WB1997 Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial ceils. Proc Nat1 Acad Sci U S A; 94(23): 12425-30
30. Corbeil D, Roper K, Weigmann A, Huttner WB1998 AC133 hematopoietic stem cell antigen: human homologue of mouse kidney prominin or distinct member of a novel protein family? Blood; 91(7): 2625-6
31. Corbeil D, Roper K, Hannah MJ, Hellwig A, Huttner WB Selective localization of the polytopic membrane protein prominin in microvilli of epithelial cellsa cumbination of apical sorting and retention in plasma membrane protrusions. J Cell Sci 1999 Apr; 112(Pt 7): 1023-33
32. Maw MR, Corbeil D, Koch J, Hellwig A, Wilson-Wheeler JC, Bridges RJ, Kumaramanickavel G, John S, Nancarrow D, Roper K, Weigmann A, Huttner WB, Denton MJ 2000 A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet Jan 1; 9(1): 27-34
33. Corbeil D, Roper K, Hellwig A, Tavian M, Miraglia S, Watt SM, Simmons PJ, Peault B, Buck DW, Huttner WB2000 The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem Feb 25; 275(8): 5512-20
34. Pasino M, Lanza T, Marotta F, Scarso L, De Biasio P, Amato S, Corcione A, Pistoia V, Mori PG Flow cytometric and functional characterization of AC133+ cells from human umbilical cord blood. Br J Haematol 2000 Mar; 108(4): 793-800
35. Gallacher L, Murdoch B, Wu DM, Karanu FN, Keeney M, Bhatia M Isolation and characterization of human CD34(-)Lin(-) and CD34(+)Lin(-) hematopoietic stem cells using cell surface markers AC133 and CD7. Blood 2000 May 1; 95(9): 2813-2820
36. Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, Rafii Expression of VEGFR-2 and AC133 by circulating human CD34(+) ceils identifies a population of functional endothelial precursors. Blood 2000 Feb 1; 95(3): 952-8
37. Rappold I, Watt SM, Kusadasi N, Rose-John S, Hatzfeld J, Ploemacher REGp130-signaling synergizes with FL and TPO for the long-term expansion of cord blood progenitors. Leukemia 1999 Dec; 13(12): 2036-48
38. Baersch G, Baumann M, Ritter J, Jurgens H, Vormoor J Expression of AC133 and CD117 on candidate normal stem cell populations in childhood B-cell precursor acute lymphoblastic leukaemia. Br J Haematol 1999 Dec; 107(3): 572-80
39. Hariharan D, Li Y, Campbell DE, Douglas SD, Starr SE, Ho W Human immunodeficiency virus infection of human placental cord blood CD34+ACI33+ stem cells and their progeny. AIDS Res Hum Retroviruses 1999 Nov 20; 15(17): 1545-52
40. Seiffert M, Cant C, Chen Z, Rappold I, Brugger W, Kanz L, Brown EJ, Ullrich A, Buhring HJ Human signal-regulatory protein is expressed on normal, but not on subsets of leukemic myeloid cells and mediates cellular adhesion involving its counterreceptor CD47. Blood 1999 Dec 1;94(11):3633-43
41. Waller CF, Martens UM, Lange W Philadelphia chromosome-positive cells are equally distributed in AC133+ and AC133- fractions of CD34+ peripheral blood progenitorcells from patients with CML. Leukemia 1999 Sep;13(9):1466-7
42. Vavrova J, Filip S, Vokurkova D, Blaha M, Vanasek J, Jebavy L Ex vivo expansion CD34+/AC133+-selected autologous peripheral blood progenitor cells (PBPC) in high-risk breast cancer patients receiving intensive chemotherapy. Hematol Cell Ther 1999 Jun;41(3):105-12
43. Buhring HJ, Seiffert M, Marxer A, Weiss B, Faul C, Kanz L, Brugger W AC133 antigen expression is not restricted to acute myeloid leukemia blasts but is also found on acute lymphoid leukemia blasts and on a subset of CD34+ B-cell precursors. Blood 1999 Jul 15;94(2):832-3
44. Buhring HJ, Seiffert M, Bock TA, SchedingS, Thiel A, Scheffold A, Kanz L, Brugger W Expression of novel surface antigens on early hematopoietic cells. Ann N Y Acad Sci 1999 Apr 30:872:25-38; discussion 38-9
45. Horn PA, Tesch H, Staib P, Kube D, Diehl V, Voliotis D Expression of AC133, a novel hematopoietic precursor antigen, on acute myeloid leukemia cells. Blood 1999 Feb 15:93(4):1435-7
46. Kratz-Albers K, Zuhlsdorp M, Leo R, Berdel WL, Buchner T, Serve H Expression of a AC133, a novel stem cell marker, on human leukemic blasts lacking CD34-antigen and on a human CD34+ leukemic line:MUTZ-2. Blood 1998 Dec 1:92(11):4485-7
47. de Wynter EA, Buck D, Hart C, Heywood R, Coutinho LH, Clayton A, Rafferty JA, Burt D, Guenechea G, Bueren JA, Gagen D, Fairbairn LJ, Lord BI, Testa NG CD34+AC133+ cells isolated from cord blood are highly enriched in long-term culture-initiating cells, NOD/SCID-repopulating cells and dendritic cell progenitors. Stem Cells 1998;16(6):387-96
48. Miraglia S, Godfrey W, Yin AH, Atkins K, Warnke R, Holden JT, Bray RA, Waller EK, Buck DW A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 1997 Dec 15:90(12):5013-21
49. Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, Olweus J, Kearney J, Buck DW AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 1997 Dec 15:90(12):5002-12
50. Identification of a novel adenylate kinase system in the brain:cloning of the fourth adenylate kinase. Brain Res Mol Brain Res. 1998. 62(2):187-19551. CDNA cloning of a chick honologue of human ATPaes complex subunit 4, quantitative tissue distribution and tertiary structure comparison of the ATPase domain to RecA. Arch Biochem Biophys. 1996. 333(1):260-266
52. Meyer-Siegler K, Mauro DJ, Seal G, Wurzer J, deRiel JK, Sirover MA A human nuclear uracil DNA glycosylase is the 37-kDa subunit of glyceraldehyde-3- phosphate dehydrogenase. Proc Natl Acad Sci U S A 1991 Oct 1;88(19):8460-4
53. Epner DE, Partin AW, Schalken JA, Isaacs JT, Coffey DS Association of glyc eraldehyde-3-phosphate dehydrogenase expression with cell motility and met astatic potential of rat prostatic adenocarcinoma. Cancer Res 1993 May 1;53 (9):1995-7
54. Sharief FS, Mohler JL, Sharief Y, Li SS Expression of human prostatic acid phosphatase and prostate specific antigen genes in neoplastic and benign tissues. Biochem Mol Biol Int 1994 Jun;33(3):567-74
55. F. S. Sharief, J. L. Mohler, et al. Expression of human prostatic acid phospha tase and prostate specific antigen genes in neoplastic and benign tissues. Biochem. Mol. Biol. Int. 33(1994) 567-574
56. Ripple MO, Wilding G Alteration of glyceraldehyde-3-phosphate dehydrogenase activity and messenger RNA content by androgen in human prostate carcino ma cells. Cancer Res 1995 Oct 1;55(19):4234-6
57. Kumagai H, Sakai H A porcine brain protein (35 K protein) which bundles mi crotubules and its identification as glyceraldehyde 3-phosphate dehydrogen ase. J Biochem (Tokyo) 1983 May;93(5):1259-69
58 Huitorel P, Pantaloni D Bundling of microtubules by glyceraldehyde-3-phosphate dehydrogenase and its modulation by ATP. Eur J Biochem 1985 Jul 15;150 (2):265-9
59. Caswell AH, Corbett AM Interaction of glyceraldehyde-3-phosphate dehydroge nase with isolated microsomal subfractions of skeletal muscle. J Biol Chem 1985 Jun 10:260(11):6892-8
60. Walsh JL, Keith TJ, Knull HR Glycolytic enzyme interactions with tubulin and microtubules. Biochim Biophys Acta 1989 Nov 9;999(1):64-70
61. Volker KW, Knull Hr A glycolytic enzyme binding domain on tubulin. Arch Bio chem Biophys 1997 Feb 15:338(2):237-43
62. Constantinides SM, Deal WC Jr Reversible dissociation of tetrameric rabbit muscle glyceraldehyde 3-phosphate dehydrogenase into dimers or monomers by adenosine triphosphate. J Biol Chem 1969 Oct 25:244(20):5695-702
63. G. M. Stance1, W. C. Deal Jr. Reversible dissociation of yeast glyceraldehyde 3 -phosphate dehydrogenase by adenosine triphosphate, Biochemistry 8(1969)4 005-4011
64. Oguchi M, Gerth E, Fitzgerald B, Park JH Regulation of glyceraldehyde 3-phosphate dehydrogenase by phosphocreatine and adenosine triphosphate. IV. Factors affecting in vivo control of enzymatic activity. J Biol Chem 1973 Aug 25:248(16):5571-6
65. Bartholmes P, Jaenicke R Reassociation and reactivation of yeast glycerald ehyde-3-phosphate dehydrogenase after dissociation in the presence of ATP. Eur J Biochem 1978 Jul 3;87(3):563-7
66. Kawamoto RM, Caswell AH Autophosphorylation of glyceraldehydephosphate dehydrogenase and phosphorylation of protein from skeletal muscle microsomes. Biochemistry 1986 Feb 11;25(3).-657-61
67. Wu K, Aoki C, Elste A, Rogalski-Wilk AA, Siekevitz P The synthesis of ATP by glycolytic enzymes in the postsynaptic density and the effect of endoge nously generated nitric oxide.Proc Natl Acad Sci U S A 1997 Nov 25:94(24): 13273-8
68. Duclos-Vallee JC, Capel F, Mabit H, Petit MA Phosphorylation of the hepatitis B virus core protein by glyceraldehyde-3-phosphate dehydrogenase prote in kinase activity. J Gen Virol 1998 Jul;79 ( Pt 7):1665-70
69. Engel M, Seifert M, Theisinger B, Seyfert U, Welter C Glyceraldehyde-3-phosphate dehydrogenase and Nm23-H1/nucleoside diphosphate kinase A. Two old enzymes combine for the novel Nm23 protein phosphotransferase function. J Biol Chem 1998 Aug 7;273(32):20058-65
70. Reiss N, Hermon J, Oplatka A, Naor Z Interaction of purified protein kinase C with key proteins of energy metabolism and cellular motility. Biochem Mol Biol Int 1996 Apr;38(4):711-9
71. Reiss N, Oplatka A, Hermon J, Naor Z Phosphatidylserine directs differential phosphorylation of actin and glyceraldehyde-3-phosphate dehydrogenase by protein kinase C: possible implications for regulation of actin polymeri zation. Biochem Mol Biol Int 1996 Dec;40(6):1191-200
72. Reiss N, Kanety H, Schlessinger J Five enzymes of the glycolytic pathway serve as substrates for purified epidermal-growth-factor-receptor kinase. Bi ochem J 1986 Nov 1;239(3):691-7
73. Ashmarina LI, et al. Phosphorylation of D-glyceraldehyde-3-phosphate dehydro genase by Ca2/Calmodulin dependent protein kinase II. FEBS Lett. 1988 Apr 25:231(2):413-6.
74. R.Singh, M. R. Green, Sequence-specificity binding of transfer RNA by flycera ldehyde-3-phosphate dehydrogenase, Science 259(1993)365-368
75. Zang WQ, Fieno AM, Grant RA, Yen TS Identification of glyceraldehyde-3-pho sphate dehydrogenase as a cellular protein that binds to the hepatitis B virus posttranscriptional regulatory element. Virology 1998 Aug 15:248(1):46 76. M.A. Sirover, Cell cycle regulation of DNA repair emzymes and pathways, Tran sformation of human fibroblasts: Molicular and Genetic Michanisms, CRC press, Boca Raton, 1990, pp. 29-54
77. Baxi MD, Vishwanatha JK Uracil DNA-glycosylase/glyceraldehyde-3-phosphate dehydrogenase is an Ap4A binding protein. Biochemistry 1995 Aug 1; 34(30):9700-7
78. McNulty SE, Toscano WA Jr Transcriptional regulation of glyceraldehyde-3-phosphate dehydrogenase by 2,3,7, 8-tetrachlorodibenzo-p-dioxin. Biochem Biophys Res Commun 1995 Jul 6; 212(1): 165-71
79. Ryazanov AG Glyceraldehyde-3-phosphate dehydrogenase is one of the three major RNA-binding proteins of rabbit reticulocytes. FEBS Lett 1985 Nov 11; 192(1): 131-4
80. Nagy E, Rigby WF Glyceraldehyde-3-phosphate dehydrogenase selectively binds AU-rich RNA in the NAD(+)-binding region (Rossmann fold). J Biol Chem 1995 Feb 10; 270(6): 2755-63
81. De BP, Gupta S, Zhao H, Drazba JA, Banerjee AK Specific interaction in vitro and in vivo of glyceraldehyde-3-phosphate dehydrogenase and LA protein with cis-acting RNAs of human parainfluenza virus type 3. J Biol Chem 1996 Oct 4; 271(40): 24728-35
82. Schultz DE, Hardin CC, Lemon SMSpecific interaction of glyceraldehyde 3-phosphate dehydrogenase with the 5'-nontranslated RNA of hepatitis A virus. J Biol Chem 1996 Jun 14; 271(24): 14134-42
83. Carlile GW, et al. Demonstration of a RNA-dependent nuclear interaction between the promyelocytic leukaemia protein and glyceraldehyde-3-phosphate dehydrogenase. Biochem J. 1998 Nov 1; 335(Pt 3): 691-6.
84. Skarzynski T, Moody PC, Wonacott AJ Structure of holo-glyceraldehyde-3-phosphate dehydrogenase from Bacillus stearothermophilus at 1.8 A resolution. J Mol Biol 1987 Jan 5; 193(1): 171-87
85. M. Piechaczyk. J.M. B1anchard, et al. Unusual abundance of glyceraldehyde 3-phos phate pseudogenes in vertebrate genomes, Nature 312(1984)469-471
86. Hanauer A, Mandel JL The glyceraldehyde 3 phosphate dehydrogenase gene family: structure of a human cDNA and of an X chromosome linked pseudogene; a mazing complexity of the gene family in mouse. EMBO J 1984 Nov; 3(11): 2627-33
87. Piechaczyk M, Blanchard JM, Marty L, Dani C, Panabieres F, El Sabouty S, Fort P, Post-transcriptional regulation of glyceraldehyde-3-phosphate-dehyd rogenase gene expression in rat tissues. Nucleic Acids Res 1984 Sep 25; 12(18): 6951-63
88. Cooi BL, Sirover MA Immunocytochemical localization of the base excision repair enzyme uracil DNA glycosylase in quiescent and proliferating normal human cells. Cancer Res 1989 Jun 1;49(11):3029-36
89. Meyer-Siegler K, Rahman-Mansur N, Wurzer JC, Sirover MA Proliferative depe ndent regulation of the glyceraldehyde-3-phosphate dehydrogenase/uracil DN A glycosylase gene in human cells.Carcinogenesis 1992 Nov;13(11):2127-32
90. Mansur NR, Meyer-Siegler K, Wurzer JC, Sirover MA Cell cycle regulation of the glyceraldehyde-3-phosphate dehydrogenase/uracil DNA glycosylase gene in normal human cells.Nucleic Acids Res 1993 Feb 25:21(4):993-8
91. Netzker R, Hermfisse U, Wein KH, Brand K Expression of glycolytic isozymes in rat thymocytes during cell cycle progression. Biochim Biophys Acta 1994 Dec 30:1224(3):371-6
92. Y. Gong, L. Cui.G. Y. Minuk.Comparison of glycersldehyde-3-phosphate dehydrogenase and 38s-ribosomal RNA gene expression in human hepatocellular carcinomal.Hepatology 23(1996)734-737
93. Mezquita J, Pau M, Mezquita C Several novel transcripts of glyceraldehyde-3-phosphate dehydrogenase expressed in adult chicken testis. J Cell Biochem 1998 Oct 1:71(1):127-39
94. Susor WA, Kochman M, Rutter WJ Structure determinations of FDP aldolase and the fine resolution of some glycolytic enzymes by isoelectric focusing. Ann N Y Acad Sci 1973 Jun 15:209:328-44
95. Marietta MA Nitric oxide synthase structure and mechanism. J Biol Chem 1993 Jun 15:268(17):12231-4
96. Moncada S, Palmer RM, Higgs EA Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991 Jun;43(2):109-42
97. Dimmeler S, Brune B Characterization of a nitric-oxide-catalysed ADP-ribosylation of glyceraldehyde-3-phosphate dehydrogenase. Eur J Biochem 1992 Nov 15:210(1):305-10
98. Dimmeler S, Brune B Nitric oxide preferentially stimulates auto-ADP-ribosy lation of glyceraldehyde-3-phosphate dehydrogenase compared to alcohol or lactate dehydrogenase.FEBS Lett 1993 Jan 2;315(1):21-4
99. Brune B, Lapetina EG Glyceraldehyde-3-phosphate dehydrogenase: a target for nitric oxide signaling. Adv Pharmacol 1995:34:351-60
100. Sunaga K, Takahashi H, Chuang DM, Ishitani R Glyceraldehyde-3-phosphate de hydrogenase is over-expressed during apoptotic death of neuronal cultures and is recognized by a monoclonal antibody against amyloid plaques from A1 zheimer's brain. Neurosci Lett 1995 Nov 17;200(2):133-6
101. Ishitani R, Sunaga K, Hirano A, Saunders P, Katsube N, Chuang DM Evidence that glyceraldehyde-3-phosphate dehydrogenase is involved in age-induced a poptosis in mature cerebellar neurons in culture. J Neurochem 1996 Mar;66??(3): 928-35
102 Ishitani R, Chuang DM Glyceraldehyde-3-phosphate dehydrogenase antisense oligodeoxynucleotides protect against cytosine arabinonucleoside-induced apoptosis in cultured cerebellar neurons. Proc Natl Acad Sci U S A 1996 Sep3; 93(18): 9937-41
103. Ishitani R, Kimura M, Sunaga K, Katsube N, Tanaka M, Chuang DM An antisense oligodeoxynucleotide to glyceraldehyde-3-phosphate dehydrogenase blocks age-induced apoptosis of mature cerebrocortical neurons in culture. J Pharm acol Exp Ther 1996 Jul; 278(1): 447-54.
104. Ishitani R, et al. Overexpression of glyceraldehyde-3-phosphate dehydrogen ase is involved in low K+induced apoptosis but not necrosis of cultured cerebellar granule cells. Mol Pharmacol. 1997 Apr; 51(4): 542-50.
105. Sawa A, Khan AA, Hester LD, Snyder SH Glyceraldehyde-3-phosphate dehydroge nase: nuclear translocation participates in neuronal and nonneuronal cell death. Proc Nat1 Acad Sci USA 1997 Oct 14; 94(21): 11669-74
106. Saunders PA, Chalecka-Franaszek E, Chuang DM Subcellular distribution of glyceraldehyde-3-phosphate dehydrogenase in cerebellar granule cells undergoing cytosine arabinoside-induced apoptosis. J Neurochem 1997 Nov; 69(5): 1820-8
107. Ishitani R, et al. Nuclear localization of overexpressed glyceraldehyde-3-p hosphate dehydrogenase in cultured cerebellar neurons undergoing apoptosis. Mol Pharmacol. 1998 Apr; 53(4): 701-7.
108. Nomura Y, Uehara T, Nakazawa M Neuronal apoptosis by glial NO: involvement of inhibition of glyceraldehyde-3-phosphate dehydrogenase. Hum Cell 1996 Sep; 9(3): 205-14
109. Holmes DI, Wahab NA, Mason RM. 1999. Cloning and characterization of ZNF236, aglucose-regulated Kurppe1-1ike zinc-finger gene mapping to human chromosome 18q22-q23. Genomics 1999; 60(1): 105-9
110. Huang X, Eriksson KF, Xaag A, et al. 1999. Insulin-regulated mitochondrial gene experssion is addociated with glucose flux in human skeletal muscle. Diabetes 48(8): 1508-14.
111. Condorelli G, Vigliotta G, Iavarone C, et al. 1998 PED/PEA-15 gene controls glucose transport and is overexpressed in type 2 diabetes mellitus. EMBO J17(14): 3858-3866
112. Schulze H, Schuler A, Stuber D, Dobeli H, Langen H, Huber G Rat brain glyc eraldehyde-3-phosphate dehydrogenase interacts with the recombinant cytopl asmic domain of Alzheimer's beta-amyloid precursor protein. J Neurochem 1993 May; 60(5): 1915-22
113. Burke JR, Enghild JJ, Martin ME, Jou YS, Myers RM, Roses AD, Vance JM, Str??ittmatter WJ Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH.Nat Med 1996 Mar;2(3):347-50
114. Koshy B, Matilla T, Burright EN, Merry DE, Fischbeck KH, Orr HT, Zoghbi HY Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene produ cts interact with glyceraldehyde-3-phosphate dehydrogenase. Hum Mol Genet 1 996 Sep;5(9):1311-8
1. Durkop H, Latza U, Hummel M, et al. Cell 1992 Feb 7; 68(3): 421-427
2. Quach TT, Rong Y, Belin MF, et al. Brain Res Mol Brain Rcs 1997 Jun; 46(1-2): 329-332
3. Turcci O, Schmitt H, Fadlc N, et al. H Biol Chem 1997 Mar 7; 272(10): 6416-6422
4. Rich SS. Disbctcs 1995 Feb; 44(2): 139-140
5. Nichols WC, Seligsohn U, Zivelin A, et al. J Clin Invest 1997, Feb 15; 99(4): 596-601
7. Virtaneva K, Miao J, Traskelin AL, et al. Am J Hum Genet 1996 Jun; 55(6): 1247-1253
8. Laporte J, Hu LJ, Kretz C, et al. Nat Genet 1996 Jun; 13(2): 175-182
9. Egco A, Mazzocdo M, Sotgia F, et al. HumGenct 1998 Mar; 102(3): 289-293
10. Sirotldn H, Morrow B, Saint-Jore B, et al. Genomics 1997 Jun 1; 42(2): 245-251
11. Mueller HW, Michel A, Heckel D, et al. Hum Genct 1997 Dec; 101(2): 190-197
12. Comincini S, Drisaldi B, Ferretti L. Mamm Gcnomc 1997 Jul; 8(7): 486-490
13. Chen H, Chrast R, Rossier C. et al. Genome Res 1996 Aug: 6(8): 747-760
14. Datson NA, van de Vosse E, Dauwerse HG, et al. Nucleic Acids Res 1996 Mar 15; 24(6): 1105-1111
15. Datson NA, Duyk GM, Van Ommen JB, et al. Nucleic Acids Res 1994 Ost 11; 22(20): 4148-4152
16. Hamsguchi M, Sakamoto H, Tsuruta H, et al. PNAS 1992 Oct 15; 89(20): 9779-9783
17. Krizman DB. Gcnct Eng (NY) 1996; 18: 49-56
18. Duyk GM, Kim SW, Myers RM, et al. PNAS 1990 Nov; 87(22): 8995-8999
19. Schuler GDScicncc 1996; 274:540
20. Gabor Miklos LGCell 1996; 86:521
21. Rastan SNaturc Gcnct 1997; 16:113
22. Banfi SNature Genet 1996; 13:167
23. Bassctt Jr DENature 1996: 379:589
24. Nces M, van Wijingaarden E, Bakos E, et al. Oncogene 1995 May 14; 16(19): 2447-2458
25. Thakkcr-varia S,Elkabcs S,Schick C, et al. Brain Res Mol Brain Res 1998 May; 56(1-2): 99-10726. Autieri MV, Feuerstein GZ, Yue TL, et al. Lab Invest 1995 Jun 72(6): 656-661
27. Burger AM, Zheng X, Li H, et al. Oncogene 1998 May 14: 16(19): 2459-2467
28, Tawe WN, Eschbach ML, Walter Rd, et al. Nucleic Acids Res 1998 Apr1; 26(7): 1721-1627
29. Dandoy-Dron F, Guillo F, Benboudjema L, et al. J Biol Chem 1998 Mar 27; 273(13): 7691-7697
30. Holmes DI, Abdel Wahab N, Mason RM. Biochem Biophys Res Commun 1997 Sep 8; 238(1): 179-184
31. Diatchenko L, Lan YF, Campbell AP, et al. PNAS 1996 Jun 11; 93(12): 6025-6030
32. Dagerib L, Salmeron S, Patri S, et al. Leukemia 1998 Mar; 12(3): 326-332
33. Cao J, Cai X, Zheng L, et al. J Cancer Res Clin Oncol 1997; 123(8): 447-451
34. Swendeman SL, La Quaglia MP. Semin Pediatr Surg 1996 Aug; 5(3): 149-154
35. Dron M, Manuelidis L. J Neurovirol 1996 Aug; 2(4): 240-248
36. Baldocchi RA, Tartaglia KE, Bryda EC, et al. Genomics 1996 Apt 15; 33(2): 193-198
37. Vande woude S, Richt JA, Zink MC, et al. Science 1990 Nov 30; 250(4985); 1278-1281
38. Behrens J, Nature 382: 638-642
39. da Costa LT, PNAS 1993: 4192-4196
40. Fridell1RA, PNAS 1993: 4421-4424
41. Ohno HScience 269: 1872-1875
42. Shen ZGenomics 36: 271-279
43. Hubank M, Nucleic Acid Res 1994 22: 5640-5648
44. Charles C, PNAS 1997 94: 2507-2512
45. Pennisi EScience 1996 272:1736
46. Brown POScience 1995 270:467
47. Wiegant J, Kalle W, Mullerders, et al. Hum Mol Genet 1992 1: 587-591
48. Heng HH, Squire J, Tsui LC. PNAS 1992 89: 9509-9613
49. Fidlerova H, Senger G, Kost M, et al. Cytogenet Cell Genet 1994; 65: 203-5
50. ParraJ, Windle B. Nat Genet 1993; 5: 17-21
51. Houseal TW, Dackowski WR, Landes GM, et al. Cytometry 1994; 15: 193-198
52. Heiskanen M, Karhu R, Hellsten E, et al. Biotechniques 1994; 17: 928-929
53. Heiskanen M, Hellsten E, Kallioniemi OP, et al. Genomics 1995; 30: 31-36
54. Palotie A. Heiskanen M, Laan M, et al. Ann Med 1996; 28: 101-106
55. Saeed Tavazoie, George M Church. Nature Bietechnology 1998 Jun 16: 566-57156. Scherer PE, Bickel PE, Kotler M, et al. Nature Biotechnology 1998 Jun 16: 581-556
57. Tashiro K, Tada H, Heilker R, et al. Science 1993 261: 600-603
58. Klein RD, Gu Q, Goddard A, et al. PNAS 1996 93: 7108-7113
59. Matthew WD, Sandrosk AW Jr. J Immunological Methods 1987 100: 73-82
60. Brooks PC, Lin JM, French DL, et al. J Cell Biol 1993 122: 1351-1359
61. de Kruif J, Terstappen L, Boel E. et al. PNAS 1995 92: 3938-3942
62. Van Ewijk W, de Kruif J, Germeraad WT, et al. PNAS 1997 94: 3903-39081. Wan JS, Sharp SJ, Pooirier GM, et al. 1996. Cloning differentially expressed mRNAs. Nature Biotechnol 14: 1685-1691.
2. Adams MD, Kelley JM, Gocayne JD, et al. 1991. Complementary DNA sequencing: expressed sequence tags and human genome project. Science 252: 1651-1656.
3. Adams MD, Dubnick M, Kerlavage AR, et al. 1992. Sequence identification of 2,375 human brain genes. Nature 355: 632-634.
4. Adams MD, Kerlavage AR, Fields C, Venter JC. 1993a. 3,400 new expressed sequence tags identify diversity of transcripts in human brain. Nat Genet 4: 256-267.
5. Carulli JP, Artinger M, Swain PM, et al. 1998. High throughput analysis of differential gene expressioin. J Cell Biochem Suppl 30-31: 286-296.
6. Walker MG, Volkmuth W, Klingler TM. 1999. Pharmaceutical target discovery using Guilt-by-Association: schizophrenia and Parkinson's disease genes. Proceeedings of the Seventh International Conference on Intelligent Systems for Molecular Biology (ISMB). Cambridge, MA: MIT Press. p 282-286.
7. Marra M, Hillier L, Kucaba T, Allen M, Barstead R, beck C, Blistain A, et al. 1999. An Encyclopedia of mouse genes. Nat GENET 21: 191-194.
8. Bonaldo MF, Lennon G, Sorares MB. 1996. Normalization and subtraction: two approaches to facilitate gene discovery. Genome Res 6: 791-806.
9. Khan J, Bittner ML, Chert Y, et al. 1999. DNA microarray technology: theanticipated impact on the study of human disease. Biochem Biophys Acta 1423:M17-M28.
10.duggan DJ, Bittner M, Chen Y, Meltzer )P, Trent JM. 1999. Expression profiling using cDNA microarrays. Nat GENet 21 (1 Suppl): 10-14.
11.Brown PO,Botstein K. 1999. Exploring the new world of the genome with DNA microarrays Nat Genet 21 (1 Suppl):33-37.
12.Bowtell DD. 1999. Options availabel-from start to finish-for otaining expression data by microarray. Nat Genet 21(1 Suppl):25-32.
13.Lockhart DJ, Dong H, Byrne MC,et al. 1996. Expression montioring by hubridization to high-density oligonucleotide arrays. Nat Biotechnol 14:1675- 1680.
14.Lipshutz RJ, Fodor SP, Gingeras TR, Lockhart DJ. 1999.High densitry synthetic oligonucleotide arrays. Nat Genet 21 (1 Suppl):20-24.
15.Ermolaeva O, Rastogi M, Pruitt KD, Schuler GD,et al. 1998. Data management and analysis for gene expression arrays. Nat Genet 20:19-23.
16 Gress TM, Hoheisel JD, Lennon GG, Zehetner G, Lehrach H Hybridization fingerprinting of high-density cDNA-library arrays with cDNA pools derived from whole tissues.Mamm Genome 1992;3(11):609-19
17 Lennon GG, Lehrach H Hybridization analyses of arrayed cDNA libraries.Trends Genet 1991 Oct;7(10):314-7
18 Nguyen C, Rocha D, Granjeaud S, Baldit M, Bernard K, Naquet P, Jordan BR Differential gene expression in the murine thymus assayed by quantitative hybridization of arrayed cDNA clones.Genomics 1995 Sep l;29(l):207-16
19 Takahashi N, Hashida H, Zhao N, Misumi Y, Sakaki Y High-density cDNA filter analysis of the expression profiles of the genes preferentially expressed in human brain.Gene 1995 Oct 27; 164(2):219-27
20 Shalon D, Smith SJ, Brown PO A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridization.Genome Res 1996 Jul;6(7):639-45
21 Ferguson JA, Boles TC, Adams CP, Walt DR A fiber-optic DNA biosensor microarray for the analysis of gene expression. Nat Biotechnol 1996 Dec;14(13):1681-4
22 Liang P, et al. 1992 Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. Science;257(5072):967-71.
23 Welsh J, et al. 1992 rbitrarily primed PCR fingerprinting of RNA. Nucleic Acids Res. 20(19):4965-70
24 Hubank M, Schatz DG Identifying differences in mRNA expression by representational difference analysis of cDNA. Nucleic Acids Res 1994 Dec 25;22(25):5640-8
25 Lisitsyn NA, Lisitsina NM, Dalbagni G, Barker P, Sanchez CA, Gnarra J, Linehan WM, Reid BJ, Wigler MH Comparative genomic analysis of tumors: detection of DNA losses and amplification. Proc Natl Acad Sci U S A 1995 Jan 3;92(l):151-5
26 Braun BS, Frieden R, Lessnick SL, May WA, Denny CT Identification of target genes for the Ewing's sarcoma EWS/FLI fusion protein by representational difference analysis. Mol Cell Biol 1995 Aug;15(8):4623-30
27 Hino.O Kobayashi E.Nishizawa, Y et al. J.Cancer Res.Clin. Oncol. 121(9-10)1995 602-605
28 Tsuchiya H, Tsuchiya Y.Kobayashi Y.et al. Jpn,J,Cancer Res 85(11)(1994) 1099- 1104
29 Wan JS, Sharp SJ, Poirier GM, Wagaman PC, Chambers J, Pyati J, Hom YL, Galindo JE, Huvar A, Peterson PA, Jackson MR, Erlander MG Cloning differentially expressed mRNAs. Nat Biotechnol 1996 Dec; 14(13): 1685-91
30 Lisitsyn NA Representational difference analysis: finding the differences between genomes. Trends Genet 1995 Aug;11(8):303-7
31 Velculescu VE, Zhang L, Vogelstein B, Kinzler KW Serial analysis of gene expression. Science 1995 Oct 20;270(5235):484-7
32.Zhang L, Zhou W, Velculescu VE,et al. 1997.Gene expression profiles in normal and cancer cells. Science 276:1268-1272.
33.Uchiyama CM, Zhu J, Carroll RS, et al. 1995. Differential display of messenger ribonucleic acid: a useful technique for analyzing differential gene expression in human brain tumors. Neurosurgery 37:464-469.
34 Liang P, Pardee AB 1995Recent advances in differential display.Curr Opin Immunol Apr;7(2):274-80
35 McClelland M, Mathieu-Daude F, Welsh J 1995RNA fingerprinting and differential display using arbitrarily primed PCR. Trends Genet; 11(6):242-6
36 McClelland M, Honeycutt R, Mathieu-Daude F, Vogt T, Welsh J 1997Fingerprinting by arbitrarily primed PCR. Methods Mol Biol;85:13-24
37 Zhao S, Ooi SL, Pardee AB New primer strategy improves precision of
differential display. Biotechniques 1995 May;18(5):842-6, 848, 850
38 Linskens MH, Feng J, Andrews WH, Enlow BE, Saati SM, Tonkin LA, Funk WD, Villeponteau B Cataloging altered gene expression in young and senescent cells using enhanced differential display. Nucleic Acids Res 1995 Aug 25;23(16):3244-51
39 Wang X, Feuerstein GZ Direct sequencing of DNA isolated from mRNA differential display. Biotechniques 1995 Mar;18(3):448-53
40 Chen SL, Maroulakou IG, Green JE, Romano-Spica V, Modi W, Lautenberger J, Bhat NK Isolation and characterization of a novel gene expressed in multiple cancers. Oncogene 1996 Feb 15;12(4):741-51
41 Zhang H, Zhang R, Liang P Differential screening of gene expression difference enriched by differential display. Nucleic Acids Res 1996 Jun 15;24(12):2454-5
42 Galindo JE, Poirier GMC Guo H,et al.DNA markers: Protocols, Application and Overviews, 1997
43 Kato K 1996RNA fingerprinting by molecular indexing. Nucleic Acids Res ;24(2):394-5
44 Suzuki H, et al. 1996 Restriction landmark cDNA scanning (RLCS): a novel cDNA display system using two-dimensional gel electrophoresis. Nucleic Acids Res.24(2):289-94
45 Ivanova NB, Belyavsky AV Identification of differentially expressed genes by restriction endonuclease-based gene expression fingerprinting. Nucleic Acids Res 1995 Aug 11;23(15):2954-8
46 Matz M, Usman N, Shagin D, Bogdanova E, Lukyanov S Ordered differential display: a simple method for systematic comparison of gene expression profiles. Nucleic Acids Res 1997 Jun 15;25(12):2541-2