臺灣博碩士論文加值系統

利用mRNA差異呈現法 (Differential Display) 比較3T3-L1前脂肪細胞與分化成脂肪細胞基因表現之差異，我們發現56個基因在此過程中會有表現量上的差別。其中40個基因表現增加，另16個基因表現減少。這些基因的功能大致可歸類成DNA remodeling、轉錄、細胞骨架和胞外基質、胰島素/生長因子訊息傳遞因子、脂肪代謝之酵素、粒線體蛋白或基因、脂肪細胞分泌有關的各類中。在56個基因中有18個基因 (18/56= 32%) 表現受到BRL49653之調控，這些基因可能和胰島素之敏感性或阻抗性有關。
SH3P12/CAP/Ponsin即是用上述方法分離出，在3T3-L1分化時明顯增加表現且又受BRL49653影響的基因。SH3P12其蛋白質結構在N端具一sorbin homology domain (SoHo) 結構區，在C端具有三個連續之SH3 domain結構區。為瞭解其可能參與胰島素訊息傳遞而為胰島素阻抗性之基因，我們進一步描述人類SH3P12基因，經過人類基因體組織命名委員會之同意，我們稱之為SORBS1 (sorbin and SH3 domain containing 1) ，之基因選殖、染色體上之座落區域、各組織表現量和其可能之功能。在一些組織mRNA之表現觀察中，可發現SORBS1具多種transcript。由肝臟、肌肉、脂肪等、三個胰島素感受性組識中，我們分離出其主要的full-length cDNA和13個alternativly spliced exons。 其中主要的cDNA，最短的isoform具2223個鹼基會製造出約81.5 kDa之蛋白質，最長者具3879個鹼基會製造出約142.2 kDa之蛋白質。此基因座落於人類染色體10q23.3-24.1的區域，此區域與Pima印第安族群所發現與胰島素阻抗性有關的位置重疊。在人類Hep3B肝臟細胞株中，SORBS1蛋白在胰島素作用後，會由與胰島素受體相互作用的蛋白質複合體中脫離，而與c-Abl蛋白質產生互動，此作用為經由與SORBS1 蛋白C端之第三個SH3結構區結合，而SORBS1蛋白質必需有胰島素作用後可能改變結構後才能與c-Abl結合。由此推測c-Abl與SORBS1之作用可能在胰島素訊息傳遞上扮演一重要的角色。
從上述研究，我們認為SORBS1基因可能為形成胰島素阻抗性的重要基因。為了驗證其與肥胖和第2型糖尿病的遺傳性關係，我們嘗試尋找此基因的SNP。在40條染色體，各分析13,136個鹼基後，我們篩選出14個SNPs。其中2個位於蛋白質轉譯區域 (R74W和T228A)，4個雖也位於蛋白質轉譯區域但無胺基酸之改變，另8個位於intron中。經由分析202位非肥胖之正常人、113位肥胖患者和455位第2型糖尿病人之基因型，發現位於exon7之T228A SNP，其A對偶基因對肥胖和第2型糖尿病產生具預防性 (protective) 角色，而R74W SNP對疾病之產生則無關連性。經此研究顯示T228A SNP 之A228對偶基因是肥胖和第2型糖尿病產生之預防因子。此也更証實SORBS1基因在人類胰島素阻抗性相關的疾病發生上扮演一重要的角色。

To identify the expression of genes that are regulated during adipocyte differentiation, the gene expression patterns in 3T3-L1 preadipocytes and mature 3T3-L1 adipocytes were analysed with mRNA differential display. The expression of 56 genes was differentially regulated, 40 were up-regulated while 16 were down-regulated in differentiated adipocytes. DNA sequences analyses indicated that differentiation of adipocytes was associated with a complex array of gene expression involving diverse biological functions, including DNA remodeling/transcription, cytoskeletal/extracellular matrix proteins, insulin/growth factor signaling, lipid metabolism, mitochondrial functions, and adipocyte secretory proteins. Among these genes, 32 % (18 of 56) were also regulated by a PPARγ agonist, BRL49653.
SH3P12/CAP/ponsin, a gene product with a sorbin homology domain and three consecutive SH3 domains in the carboxy-terminus, was one of genes upregulated in 3T3-L1 adipogenesis and enhanced by BRL49653 treatment. Here we described the cloning, mapping, and expression of the human homologue, termed SORBS1 (sorbin and SH3 domain containing 1). Multiple transcripts of this gene with different mRNA isoforms were observed among different tissues. We had identified 13 alternatively spliced exons, which were ascertained from the full-length cDNA cloning in adipose, liver and skeletal muscle tissues. Among the major isoforms, the shortest 2,223-bp open reading frame (ORF) encodes a protein with a predicted molecular weight of 81.5 kDa, while the longest 3879-bp ORF encodes a protein of about 142.2 kDa. This gene was mapped to human chromosome 10q23.3-4, which is a candidate region for insulin resistance found in Pima Indians. In human hepatoma Hep3B cells, SORBS1 was partly dissociated from the insulin receptor complexes and bound to c-Abl protein upon insulin stimulation. This interaction with c-Abl was through the third SH3 domain and a possible conformational change of SORBS1 induced by insulin. Our data suggested c-Abl oncoprotein via SORBS1 might play a role in insulin signaling pathway.
To explore the genetic role of SORBS1 in human obesity and type 2 diabetes, we investigated the nucleotide polymorphisms in the SORBS1 gene with molecular scanning. After scanning for a total of 13,136 base pairs in each of 40 chromosomes, we have identified 14 single nucleotide polymorphisms (SNPs) in the human SORBS1 gene. Among them, 2 affected amino acid coding (R74W and T228A), 4 occurred within exons but did not affect amino acid coding, and the remaining 8 occurred within introns, which were located outside of the consensus region of the splicing mechanism. Further studies in 202 non-obese, 113 obese and 455 subjects with type 2 diabetes revealed that the A-allele of the T228A polymorphism in exon 7 exerted a protective role for both obesity (relative risk: 0.466, 95% CI 0.265-0.821) and diabetes (relative risk: 0.668, 95% CI 0.472-0.945). Neither allele of the R74W polymorphism was associated with obesity or diabetes. In conclusion, our results suggest that the A228 allele of the T228A polymorphism of the SORBS1 gene is a protective factor for both obesity and diabetes, and also imply that the SORBS1 gene plays an important role in the pathogenesis of human disorders with insulin resistance.

封面
中文摘要
英文摘要(Abstract)
縮寫（Abreviations)
導論
糖尿病(Diabetes Melitus)
糖尿病與胰島素阻抗性(Insulin Resistance)
胰島素阻抗性成因研究
胰島素阻抗性與肥胖(Obesity)
第一章、脂肪細胞胰島素作用相關基因之篩選-SH3P12、CCR4之研究
一、前言
Mrna Differential Display
3T3-L1 adipogenesis
PPARr
二、材料與方法
3T3-L1 細胞株之培養
Oil red染色法
mRNA差異呈現法
北方雜交分析法
Reverse transcription-PCR (RT-PCR)之分析法
三、結果
3T3-L1脂肪分化中差異表想基因的確認
分離出的基因在3T3-L1分化過程表現的型態
分化表現基因的功能分析
BRL49653與基因的表現
CCR4、SH3P12的基因表現
四、討論
第二章、人類SORBS1基因染色體定位與肝細胞中胰島素傳遞訊息之角色
一、前言
二、材料與方法
SORBS1的EST選殖法
以RT-PCR選殖出SORBS1 cDNA
含多種組織的北方轉漬分析
BAC質體的選殖和FISH
Hep3B細胞之培養和萃取
GST fusion蛋白質的製備
三、結果
SORBS1 cDNA選殖和序列分析
SORBS1的基因結構
SORBS1的組織分佈表現
SORBS1在人類染色體的位置
SORBS1、c-Ab1和胰島素受體之相互作用
四、討論
第三章、人類SORBS1基因之SNP與肥胖和第２型糖尿病之關連性
一、前言
SNP
二、材料與方法
樣品(Subject)
樣本的生化和外表型特性
篩選SNP的策略
變異的篩選
PCR-RELP的T229A變異判斷
DHPLC的R74W變異判斷
三、結果
SORBS1 SNP的篩選
T228A的表現型(phenotypes)研究
T228A多樣性與糖尿病和肥胖關連性
四、討論
第四章、總結與展望
參考文獻
圖表
圖1-1A CC4、SH3P12表現量與C/EBPa，C/EBPB，C/EBPr所做的比較
圖1-1B RT-PCR分析基因的表現量．3T3T1脂肪分化各基因每一天的表現量
圖1-1C RT-PCR分析基因的表現量．CC4、SH3P12表現量與PPARr所做的比較
圖1-2 CCR4和SH3P12在第六天分化的脂肪細胞受RRL49653的影響
圖1-3 SHEP12 alternativly spliced exon DNA序列
表1-1 總結由DD方法篩選出3T3L1脂肪細胞分化的基因
表1-2 篩選出3T3L1脂肪細胞分化的基因功能分類
表1-3 BRL49653的影響
表1-4 用於RT-PCR的引子資料
圖2-1 SORBSI Cdna的EST選殖
圖2-2A SORBS1的脂肪、肝臟、肌肉中Mrna表現狀況
圖2-2B SORBS1選殖
圖2-2C SORBS1 gene exon7 and exon30 DNA序列
圖2-3A SORBS1 cDNA序列
圖2-3B SORBS1 alternativly sliced exons DNA序列
圖2-4 SORBS1的基因結構
圖2-5 SORBS1 mRNA的組織分佈
圖2-6 SORBS1的FISH實驗
圖2-7A ArgBP2A與含H exn之SORBS1的蛋白質所做的比對
圖2-8B c-Cb1,Sos1,c-Ab1 PXXP motif的序列比對
圖2-8 SORBS1與胰島素受體的相互作用情形
圖2-9A SORBS1與c-Ab1相互作用情形-免疫沉澱法實驗
圖2-9B SORBS1與c-Ab1相互作用情形-GST融含蛋白質之pull down實驗
表2-1 SORBS1基因exon/intron的結構
圖3-1 SORBS1的基因結構和１４個SNP位置
圖3-2A 非糖尿病樣品依SORBS1基因型所做的BMI分析
圖3-2B 非糖尿病樣品依SORBS1基因型所做的HMOA-IR分析
表3-1 SORBS1 SNP尋找的引子資料
表3-2 20位分析個體中SORBS1基因的變異和對偶基因頻率
表3-3 各樣本組的T228A基因型比率
附錄：與本論文相關之已發表文章

Adams, M., Reginato, M. J., Shao, D., Lazar, M. A. & Chatterjee, V. K. (1997). Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site. J Biol Chem 272(8), 5128-32.
Agami, R., Blandino, G., Oren, M. & Shaul, Y. (1999). Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis [see comments]. Nature 399(6738), 809-13.
Ahmad, F., Considine, R. V. & Goldstein, B. J. (1995). Increased abundance of the receptor-type protein-tyrosine phosphatase LAR accounts for the elevated insulin receptor dephosphorylating activity in adipose tissue of obese human subjects. J Clin Invest 95(6), 2806-12.
Alzaid, A. A., Sobki, S. & De Silva, V. (1994). Prevalence of microalbuminuria in Saudi Arabians with non-insulin-dependent diabetes mellitus: a clinic-based study. Diabetes Res Clin Pract 26(2), 115-20.
Arita, Y., Kihara, S., Ouchi, N., Takahashi, M., Maeda, K., Miyagawa, J., Hotta, K., Shimomura, I., Nakamura, T., Miyaoka, K., Kuriyama, H., Nishida, M., Yamashita, S., Okubo, K., Matsubara, K., Muraguchi, M., Ohmoto, Y., Funahashi, T. & Matsuzawa, Y. (1999). Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257(1), 79-83.
Ashar, H. R., Fejzo, M. S., Tkachenko, A., Zhou, X., Fletcher, J. A., Weremowicz, S., Morton, C. C. & Chada, K. (1995). Disruption of the architectural factor HMGI-C: DNA-binding AT hook motifs fused in lipomas to distinct transcriptional regulatory domains. Cell 82(1), 57-65.
Bandyopadhyay, G., Standaert, M. L., Zhao, L., Yu, B., Avignon, A., Galloway, L., Karnam, P., Moscat, J. & Farese, R. V. (1997). Activation of protein kinase C (alpha, beta, and zeta) by insulin in 3T3/L1 cells. Transfection studies suggest a role for PKC-zeta in glucose transport. J Biol Chem 272(4), 2551-8.
Baumann, C. A., Chokshi, N., Saltiel, A. R. & Ribon, V. (2000a). Cloning and characterization of a functional peroxisome proliferator activator receptor-gamma-responsive element in the promoter of the CAP gene. J Biol Chem 275(13), 9131-5.
Baumann, C. A., Ribon, V., Kanzaki, M., Thurmond, D. C., Mora, S., Shigematsu, S., Bickel, P. E., Pessin, J. E. & Saltiel, A. R. (2000b). CAP defines a second signalling pathway required for insulin-stimulated glucose transport [In Process Citation]. Nature 407(6801), 202-7.
Birchenall-Roberts, M. C., Yoo, Y. D., Bertolette, D. C., 3rd, Lee, K. H., Turley, J. M., Bang, O. S., Ruscetti, F. W. & Kim, S. J. (1997). The p120-v-Abl protein interacts with E2F-1 and regulates E2F-1 transcriptional activity. J Biol Chem 272(14), 8905-11.
Black, K., Qu, X., Seale, J. P. & Donnelly, R. (1998). Metabolic effects of thioctic acid in rodent models of insulin resistance and diabetes. Clin Exp Pharmacol Physiol 25(9), 712-4.
Calles-Escandon, J., Mirza, S. A., Sobel, B. E. & Schneider, D. J. (1998). Induction of hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia increases plasminogen activator inhibitor 1 in blood in normal human subjects. Diabetes 47(2), 290-3.
Chao, L., Marcus-Samuels, B., Mason, M. M., Moitra, J., Vinson, C., Arioglu, E., Gavrilova, O. & Reitman, M. L. (2000). Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones. J Clin Invest 106(10), 1221-8.
Chapman, A. B., Knight, D. M., Dieckmann, B. S. & Ringold, G. M. (1984). Analysis of gene expression during differentiation of adipogenic cells in culture and hormonal control of the developmental program. J Biol Chem 259(24), 15548-55.
Chiang, S. H., Baumann, C. A., Kanzaki, M., Thurmond, D. C., Watson, R. T., Neudauer, C. L., Macara, I. G., Pessin, J. E. & Saltiel, A. R. (2001). Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature 410(6831), 944-8.
Chiu, K. C. & McCarthy, J. E. (1997). The insertion allele at the angiotensin I-converting enzyme gene locus is associated with insulin resistance. Metabolism 46(4), 395-9.
Chuang, L. M., Myers, M. G., Jr., Backer, J. M., Shoelson, S. E., White, M. F., Birnbaum, M. J. & Kahn, C. R. (1993). Insulin-stimulated oocyte maturation requires insulin receptor substrate 1 and interaction with the SH2 domains of phosphatidylinositol 3-kinase. Mol Cell Biol 13(11), 6653-60.
Cianflone, K. M., Sniderman, A. D., Walsh, M. J., Vu, H. T., Gagnon, J. & Rodriguez, M. A. (1989). Purification and characterization of acylation stimulating protein. J Biol Chem 264(1), 426-30.
Clarke, S. L., Robinson, C. E. & Gimble, J. M. (1997). CAAT/enhancer binding proteins directly modulate transcription from the peroxisome proliferator-activated receptor gamma 2 promoter. Biochem Biophys Res Commun 240(1), 99-103.
Cole, S. A., Aston, C. E., Hamman, R. F. & Ferrell, R. E. (1993). Association of a PvuII RFLP at the lipoprotein lipase locus with fasting insulin levels in Hispanic men. Genet Epidemiol 10(3), 177-88.
Considine, R. V., Nyce, M. R., Allen, L. E., Morales, L. M., Triester, S., Serrano, J., Colberg, J., Lanza-Jacoby, S. & Caro, J. F. (1995). Protein kinase C is increased in the liver of humans and rats with non-insulin-dependent diabetes mellitus: an alteration not due to hyperglycemia. J Clin Invest 95(6), 2938-44.
Czech, M. P. & Corvera, S. (1999). Signaling mechanisms that regulate glucose transport. J Biol Chem 274(4), 1865-8.
Dai, Z. & Pendergast, A. M. (1995). Abi-2, a novel SH3-containing protein interacts with the c-Abl tyrosine kinase and modulates c-Abl transforming activity. Genes Dev 9(21), 2569-82.
Day, C. (1999). Thiazolidinediones: a new class of antidiabetic drugs. Diabet Med 16(3), 179-92.
DeFronzo, R. A. (1992). Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview. Diabetologia 35(4), 389-97.
DeFronzo, R. A., Bonadonna, R. C. & Ferrannini, E. (1992). Pathogenesis of NIDDM. A balanced overview. Diabetes Care 15(3), 318-68.
Denis, C. L. (1984). Identification of new genes involved in the regulation of yeast alcohol dehydrogenase II. Genetics 108(4), 833-44.
Dichtl, W., Ares, M. P., Stollenwerk, M., Giachelli, C. M., Scatena, M., Hamsten, A., Eriksson, P. & Nilsson, J. (2000). In vivo stimulation of vascular plasminogen activator inhibitor-1 production by very low-density lipoprotein involves transcription factor binding to a VLDL-responsive element. Thromb Haemost 84(4), 706-11.
Dowell, P., Ishmael, J. E., Avram, D., Peterson, V. J., Nevrivy, D. J. & Leid, M. (1999). Identification of nuclear receptor corepressor as a peroxisome proliferator-activated receptor alpha interacting protein. J Biol Chem 274(22), 15901-7.
Drake, P. G. & Posner, B. I. (1998). Insulin receptor-associated protein tyrosine phosphatase(s): role in insulin action. Mol Cell Biochem 182(1-2), 79-89.
Draper, M. P., Salvadore, C. & Denis, C. L. (1995). Identification of a mouse protein whose homolog in Saccharomyces cerevisiae is a component of the CCR4 transcriptional regulatory complex. Mol Cell Biol 15(7), 3487-95.
Dreyer, C., Krey, G., Keller, H., Givel, F., Helftenbein, G. & Wahli, W. (1992). Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68(5), 879-87.
Duggirala, R., Blangero, J., Almasy, L., Arya, R., Dyer, T. D., Williams, K. L., Leach, R. J., O''Connell, P. & Stern, M. P. (2001). A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans. Am J Hum Genet 68(5), 1149-64.
Edmondson, D. G. & Olson, E. N. (1993). Helix-loop-helix proteins as regulators of muscle-specific transcription. J Biol Chem 268(2), 755-8.
el Mugamer, I. T., Ali Zayat, A. S., Hossain, M. M. & Pugh, R. N. (1995). Diabetes, obesity and hypertension in urban and rural people of bedouin origin in the United Arab Emirates. J Trop Med Hyg 98(6), 407-15.
Elchebly, M., Payette, P., Michaliszyn, E., Cromlish, W., Collins, S., Loy, A. L., Normandin, D., Cheng, A., Himms-Hagen, J., Chan, C. C., Ramachandran, C., Gresser, M. J., Tremblay, M. L. & Kennedy, B. P. (1999). Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283(5407), 1544-8.
Eriksson, P., Nilsson, L., Karpe, F. & Hamsten, A. (1998). Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia. Arterioscler Thromb Vasc Biol 18(1), 20-6.
Feng, W., Ribeiro, R. C., Wagner, R. L., Nguyen, H., Apriletti, J. W., Fletterick, R. J., Baxter, J. D., Kushner, P. J. & West, B. L. (1998). Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science 280(5370), 1747-9.
Fernandez-Real, J. M., Gutierrez, C., Ricart, W., Casamitjana, R., Fernandez-Castaner, M., Vendrell, J., Richart, C. & Soler, J. (1997). The TNF-alpha gene Nco I polymorphism influences the relationship among insulin resistance, percent body fat, and increased serum leptin levels. Diabetes 46(9), 1468-72.
Forman, B. M., Tontonoz, P., Chen, J., Brun, R. P., Spiegelman, B. M. & Evans, R. M. (1995). 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83(5), 803-12.
Goldfine, I. D., Maddux, B. A., Youngren, J. F., Frittitta, L., Trischitta, V. & Dohm, G. L. (1998). Membrane glycoprotein PC-1 and insulin resistance. Mol Cell Biochem 182(1-2), 177-84.
Goldstein, B. J., Ahmad, F., Ding, W., Li, P. M. & Zhang, W. R. (1998). Regulation of the insulin signalling pathway by cellular protein-tyrosine phosphatases. Mol Cell Biochem 182(1-2), 91-9.
Green, H. & Kehinde, O. (1975). An established preadipose cell line and its differentiation in culture. II. Factors affecting the adipose conversion. Cell 5(1), 19-27.
Green, H. & Kehinde, O. (1979). Formation of normally differentiated subcutaneous fat pads by an established preadipose cell line. J Cell Physiol 101(1), 169-71.
Greenwalt, D. E., Scheck, S. H. & Rhinehart-Jones, T. (1995). Heart CD36 expression is increased in murine models of diabetes and in mice fed a high fat diet. J Clin Invest 96(3), 1382-8.
Guller, S., Allen, D. L., Corin, R. E., Lockwood, C. J. & Sonenberg, M. (1992). Growth hormone and fibronectin expression in 3T3 preadipose cells. Endocrinology 130(5), 2609-16.
Halle, M., Berg, A., Northoff, H. & Keul, J. (1998). Importance of TNF-alpha and leptin in obesity and insulin resistance: a hypothesis on the impact of physical exercise. Exerc Immunol Rev 4, 77-94.
Hata, H., Mitsui, H., Liu, H., Bai, Y., Denis, C. L., Shimizu, Y. & Sakai, A. (1998). Dhh1p, a putative RNA helicase, associates with the general transcription factors Pop2p and Ccr4p from Saccharomyces cerevisiae. Genetics 148(2), 571-9.
Horikawa, Y., Oda, N., Cox, N. J., Li, X., Orho-Melander, M., Hara, M., Hinokio, Y., Lindner, T. H., Mashima, H., Schwarz, P. E., del Bosque-Plata, L., Oda, Y., Yoshiuchi, I., Colilla, S., Polonsky, K. S., Wei, S., Concannon, P., Iwasaki, N., Schulze, J., Baier, L. J., Bogardus, C., Groop, L., Boerwinkle, E., Hanis, C. L. & Bell, G. I. (2000). Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26(2), 163-75.
Hotamisligil, G. S. & Spiegelman, B. M. (1994). Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 43(11), 1271-8.
Hu, E., Liang, P. & Spiegelman, B. M. (1996). AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem 271(18), 10697-703.
Huxtable, S. J., Saker, P. J., Haddad, L., Walker, M., Frayling, T. M., Levy, J. C., Hitman, G. A., O''Rahilly, S., Hattersley, A. T. & McCarthy, M. I. (2000). Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles. Diabetes 49(1), 126-30.
Ikematsu, N., Yoshida, Y., Kawamura-Tsuzuku, J., Ohsugi, M., Onda, M., Hirai, M., Fujimoto, J. & Yamamoto, T. (1999). Tob2, a novel anti-proliferative Tob/BTG1 family member, associates with a component of the CCR4 transcriptional regulatory complex capable of binding cyclin-dependent kinases [In Process Citation]. Oncogene 18(52), 7432-41.
Imagawa, M., Tsuchiya, T. & Nishihara, T. (1999). Identification of inducible genes at the early stage of adipocyte differentiation of 3T3-L1 cells. Biochem Biophys Res Commun 254(2), 299-305.
Kahn, C. R., Flier, J. S., Bar, R. S., Archer, J. A., Gorden, P., Martin, M. M. & Roth, J. (1976). The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med 294(14), 739-45.
Kim, Y. B., Nikoulina, S. E., Ciaraldi, T. P., Henry, R. R. & Kahn, B. B. (1999). Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J Clin Invest 104(6), 733-41.
Klein, J., Fasshauer, M., Ito, M., Lowell, B. B., Benito, M. & Kahn, C. R. (1999). beta(3)-adrenergic stimulation differentially inhibits insulin signaling and decreases insulin-induced glucose uptake in brown adipocytes. J Biol Chem 274(49), 34795-802.
Kohn, A. D., Summers, S. A., Birnbaum, M. J. & Roth, R. A. (1996). Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem 271(49), 31372-8.
Koleske, A. J., Gifford, A. M., Scott, M. L., Nee, M., Bronson, R. T., Miczek, K. A. & Baltimore, D. (1998). Essential roles for the Abl and Arg tyrosine kinases in neurulation. Neuron 21(6), 1259-72.
Krook, A. & O''Rahilly, S. (1996). Homozygous mutation in the insulin receptor. Clin Endocrinol (Oxf) 45(2), 237-8.
Kruglyak, L. (1999). Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 22(2), 139-44.
Kruh, G. D., Perego, R., Miki, T. & Aaronson, S. A. (1990). The complete coding sequence of arg defines the Abelson subfamily of cytoplasmic tyrosine kinases. Proc Natl Acad Sci U S A 87(15), 5802-6.
Kurakin, A., Hoffman, N. G. & Kay, B. K. (1998). Molecular recognition properties of the C-terminal Sh3 domain of the Cbl associated protein, Cap. J Pept Res 52(5), 331-7.
Lander, E. S. & Schork, N. J. (1994). Genetic dissection of complex traits. Science 265(5181), 2037-48.
Lanier, L. M. & Gertler, F. B. (2000). From Abl to actin: Abl tyrosine kinase and associated proteins in growth cone motility. Curr Opin Neurobiol 10(1), 80-7.
Lee, C. G., Morse, H. C., 3rd, Kay, B. K. & Kozak, C. A. (1999). Genetic mapping of eight SH3 domain genes on seven mouse chromosomes. Mamm Genome 10(4), 402-4.
Lewis, G. F. & Steiner, G. (1996). Acute effects of insulin in the control of VLDL production in humans. Implications for the insulin-resistant state. Diabetes Care 19(4), 390-3.
Lewis, J. M., Baskaran, R., Taagepera, S., Schwartz, M. A. & Wang, J. Y. (1996). Integrin regulation of c-Abl tyrosine kinase activity and cytoplasmic- nuclear transport. Proc Natl Acad Sci U S A 93(26), 15174-9.
Lin, F. T. & Lane, M. D. (1994). CCAAT/enhancer binding protein alpha is sufficient to initiate the 3T3-L1 adipocyte differentiation program. Proc Natl Acad Sci U S A 91(19), 8757-61.
Lin, W. H., Huang, C. J., Liu, M. W., Chang, H. M., Chen, Y. J., Tai, T. Y. & Chuang, L. M. (2001). Cloning, Mapping, and Characterization of the Human Sorbin and SH3 Domain Containing 1 (SORBS1) Gene: A Protein Associated with c-Abl during Insulin Signaling in the Hepatoma Cell Line Hep3B. Genomics 74(1), 12-20.
Lin, W. S., Chang, H. M., Tai, T. Y. & Chuang, L. M. (1999). Effect of thiazolidinedione on gene expression in NIH3T3-L1 adipocytes. Diabetes 48:(suppl 1), A217.
Liu, H. Y., Badarinarayana, V., Audino, D. C., Rappsilber, J., Mann, M. & Denis, C. L. (1998). The NOT proteins are part of the CCR4 transcriptional complex and affect gene expression both positively and negatively. Embo J 17(4), 1096-106.
Liu, H. Y., Toyn, J. H., Chiang, Y. C., Draper, M. P., Johnston, L. H. & Denis, C. L. (1997). DBF2, a cell cycle-regulated protein kinase, is physically and functionally associated with the CCR4 transcriptional regulatory complex. Embo J 16(17), 5289-98.
Mandai, K., Nakanishi, H., Satoh, A., Takahashi, K., Satoh, K., Nishioka, H., Mizoguchi, A. & Takai, Y. (1999). Ponsin/SH3P12: an l-afadin- and vinculin-binding protein localized at cell-cell and cell-matrix adherens junctions. J Cell Biol 144(5), 1001-17.
Mattioni, T., Jackson, P. K., Bchini-Hooft van Huijsduijnen, O. & Picard, D. (1995). Cell cycle arrest by tyrosine kinase Abl involves altered early mitogenic response. Oncogene 10(7), 1325-33.
McCarthy, M. & Menzel, S. (2001). The genetics of type 2 diabetes. Br J Clin Pharmacol 51(3), 195-9.
Meza-Zepeda, L. A., Berner, J. M., Henriksen, J., South, A. P., Pedeutour, F., Dahlberg, A. B., Godager, L. H., Nizetic, D., Forus, A. & Myklebost, O. (2001). Ectopic
sequences from truncated HMGIC in liposarcomas are derived from various amplified chromosomal regions. Genes Chromosomes Cancer 31(3), 264-73.
Moller, D. E. (2000). Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends Endocrinol Metab 11(6), 212-7.
Musaiger, A. O. (1992). Diabetes mellitus in Bahrain: an overview. Diabet Med 9(6), 574-8.
Nolte, R. T., Wisely, G. B., Westin, S., Cobb, J. E., Lambert, M. H., Kurokawa, R., Rosenfeld, M. G., Willson, T. M., Glass, C. K. & Milburn, M. V. (1998). Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 395(6698), 137-43.
Okuno, M., Arimoto, E., Ikenobu, Y., Nishihara, T. & Imagawa, M. (2001). Dual DNA-binding specificity of peroxisome-proliferator-activated receptor gamma controlled by heterodimer formation with retinoid X receptor alpha. Biochem J 353(Pt 2), 193-8.
Olefsky, J., Farquhar, J. W. & Reaven, G. (1973). Relationship between fasting plasma insulin level and resistance to insulin-mediated glucose uptake in normal and diabetic subjects. Diabetes 22(7), 507-13.
Peraldi, P. & Spiegelman, B. (1998). TNF-alpha and insulin resistance: summary and future prospects. Mol Cell Biochem 182(1-2), 169-75.
Permana, P. A., Luczy-Bachman, G. & Bogardus, C. (1999). Protein targeting to glycogen/PPP1R5: screening of coding and flanking genomic regions for polymorphisms and association analysis with insulin action in Pima Indians. Biochem Biophys Res Commun 258(1), 184-6.
Plattner, R., Kadlec, L., DeMali, K. A., Kazlauskas, A. & Pendergast, A. M. (1999). c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF. Genes Dev 13(18), 2400-11.
Pratley, R. E., Thompson, D. B., Prochazka, M., Baier, L., Mott, D., Ravussin, E., Sakul, H., Ehm, M. G., Burns, D. K., Foroud, T., Garvey, W. T., Hanson, R. L., Knowler, W. C., Bennett, P. H. & Bogardus, C. (1998). An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. J Clin Invest 101(8), 1757-64.
Previato, L., Parrott, C. L., Santamarina-Fojo, S. & Brewer, H. B., Jr. (1991). Transcriptional regulation of the human lipoprotein lipase gene in 3T3- L1 adipocytes. J Biol Chem 266(28), 18958-63.
Prochazka, M., Lillioja, S., Tait, J. F., Knowler, W. C., Mott, D. M., Spraul, M., Bennett, P. H. & Bogardus, C. (1993). Linkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians. Diabetes 42(4), 514-9.
Reaven, G. M. (1993). Role of insulin resistance in human disease (syndrome X): an expanded definition. Annu Rev Med 44, 121-31.
Ren, R., Ye, Z. S. & Baltimore, D. (1994). Abl protein-tyrosine kinase selects the Crk adapter as a substrate using SH3-binding sites. Genes Dev 8(7), 783-95.
Ribon, V., Herrera, R., Kay, B. K. & Saltiel, A. R. (1998a). A role for CAP, a novel, multifunctional Src homology 3 domain- containing protein in formation of actin stress fibers and focal adhesions. J Biol Chem 273(7), 4073-80.
Ribon, V., Printen, J. A., Hoffman, N. G., Kay, B. K. & Saltiel, A. R. (1998b). A novel, multifuntional c-Cbl binding protein in insulin receptor signaling in 3T3-L1 adipocytes. Mol Cell Biol 18(2), 872-9.
Ribon, V. & Saltiel, A. R. (1997). Insulin stimulates tyrosine phosphorylation of the proto-oncogene product of c-Cbl in 3T3-L1 adipocytes. Biochem J 324(Pt 3), 839-45.
Rondinone, C. M., Wang, L. M., Lonnroth, P., Wesslau, C., Pierce, J. H. & Smith, U. (1997). Insulin receptor substrate (IRS) 1 is reduced and IRS-2 is the main docking protein for phosphatidylinositol 3-kinase in adipocytes from subjects with non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A 94(8), 4171-5.
Shi, Y., Alin, K. & Goff, S. P. (1995). Abl-interactor-1, a novel SH3 protein binding to the carboxy-terminal portion of the Abl protein, suppresses v-abl transforming activity. Genes Dev 9(21), 2583-97.
Smith, J. M., Katz, S. & Mayer, B. J. (1999). Activation of the Abl tyrosine kinase in vivo by Src homology 3 domains from the Src homology 2/Src homology 3 adaptor Nck. J Biol Chem 274(39), 27956-62.
Sparks, A. B., Hoffman, N. G., McConnell, S. J., Fowlkes, D. M. & Kay, B. K. (1996). Cloning of ligand targets: systematic isolation of SH3 domain- containing proteins. Nat Biotechnol 14(6), 741-4.
Spiegelman, B. M. & Ginty, C. A. (1983). Fibronectin modulation of cell shape and lipogenic gene expression in 3T3-adipocytes. Cell 35(3 Pt 2), 657-66.
Steppan, C. M., Bailey, S. T., Bhat, S., Brown, E. J., Banerjee, R. R., Wright, C. M., Patel, H. R., Ahima, R. S. & Lazar, M. A. (2001). The hormone resistin links obesity to diabetes. Nature 409(6818), 307-12.
Student, A. K., Hsu, R. Y. & Lane, M. D. (1980). Induction of fatty acid synthetase synthesis in differentiating 3T3-L1 preadipocytes. J Biol Chem 255(10), 4745-50.
Takahashi, T., Nagai, N., Oda, H., Ohama, K., Kamada, N. & Miyagawa, K. (2001). Evidence for RAD51L1/HMGIC fusion in the pathogenesis of uterine leiomyoma. Genes Chromosomes Cancer 30(2), 196-201.
Taylor, S. I. & Arioglu, E. (1998). Syndromes associated with insulin resistance and acanthosis nigricans. J Basic Clin Physiol Pharmacol 9(2-4), 419-39.
Timothy, J., Lafuente, D., Chakrabarty, A., Saxena, A. & Marks, P. (1999). Meningioma recurrence at a different site masquerading as a subdural hematoma. Case report. J Neurosurg 91(3), 496-8.
Wang, B., Golemis, E. A. & Kruh, G. D. (1997). ArgBP2, a multiple Src homology 3 domain-containing, Arg/Abl- interacting protein, is phosphorylated in v-Abl-transformed cells and localized in stress fibers and cardiocyte Z-disks. J Biol Chem 272(28), 17542-50.
Wang, J. Y. (1993). Abl tyrosine kinase in signal transduction and cell-cycle regulation. Curr Opin Genet Dev 3(1), 35-43.
Werman, A., Hollenberg, A., Solanes, G., Bjorbaek, C., Vidal-Puig, A. J. & Flier, J. S. (1997). Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor gamma (PPARgamma). Differential activity of PPARgamma1 and -2 isoforms and influence of insulin. J Biol Chem 272(32), 20230-5.
Widen, E., Lehto, M., Kanninen, T., Walston, J., Shuldiner, A. R. & Groop, L. C. (1995). Association of a polymorphism in the beta 3-adrenergic-receptor gene with features of the insulin resistance syndrome in Finns. N Engl J Med 333(6), 348-51.
Zhou, X., Benson, K. F., Przybysz, K., Liu, J., Hou, Y., Cherath, L. & Chada, K. (1996). Genomic structure and expression of the murine Hmgi-c gene. Nucleic Acids Res 24(20), 4071-7.
Zhu, X., McKenzie, C. A., Forrester, T., Nickerson, D. A., Broeckel, U., Schunkert, H., Doering, A., Jacob, H. J., Cooper, R. S. & Rieder, M. J. (2000). Localization of a small genomic region associated with elevated ACE. Am J Hum Genet 67(5), 1144-53.