FUNCTIONS OF (1,3) FUCOSYLTRANFERASE GENE FAMILY

(1,3)岩藻糖基转移酶基因家族的功能

• 批准号: 2458009
• 负责人: BRENT W WESTON
• 金额: $ 7.48万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-06 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2458009
• 关键词: adenocarcinoma; breast neoplasms; carbohydrate metabolism; cell adhesion; colon neoplasms; cytokine; enzyme activity; enzyme mechanism; genetic mapping; genetic regulatory element; genetic transcription; hexosyltransferase; human genetic material tag; human tissue; leukocyte adhesion molecules; metastasis; molecular cloning; northern blottings; oligosaccharides; polymerase chain reaction; receptor binding; selectins; southern blotting; vascular endothelium

Metastasis of cancer cells via the bloodstream significantly affects the diagnosis, treatment, and prognosis of most human malignancies. Interaction of tumor cells with the microvasculature depends on many factors, but metastatic invasion clearly requires arrest and adherence of the cell to endothelium, followed by migration and/or proliferation. Activation of endothelial cells by cytokines increases adhesion of some human melanoma and adenocarcinoma cells in vitro by a process distinct from integrin-mediated interactions. Recent experiments have shown that the fucosylated structure sialyl Lewis x can mediate adhesion of leukocytes to E-selectin (ELAM-1) and P-selectin (GMP-140/PADGEM) expressed by human endothelial cells. A related glycan, sialyl Lewis a, can also serve as a ligand for E-selectin. These carbohydrate moieties were originally described as oncodevelopmental antigens associated with some of the same malignant cells now shown to adhere to cytokine-activated endothelium. Genetic and biochemical data suggest the presence of at least six alpha(1,3)fucosyltransferase (FT) genes in humans capable of generating these related glycans. Although tissue specific expression has been demonstrated for fucosylated oligosaccharide antigens and multiple alpha(1,3)FT activities, molecular mechanisms that determine this process are not well understood. We have isolated and characterized four human alpha(1,3)FT genes, which will now be used for experiments outlined in the following specific aims: 1. Isolate and characterize remaining alpha(1,3) and alpha(1,4)FT gene(s). 2. Determine the physical maps of alpha(1,3)FT loci on human chromosomes. 3. Determine normal expression patterns of alpha(1,3)FT transcripts in human tissues. 4. Examine expression of alpha(1,3)FT transcripts in human adenocarcinoma cells capable of adhering to cytokine-activated endothelium. Demonstrate the specific alpha(1,3) or alpha(1,4) FT gene(s) involved, correlate with FT activity and oligosaccharide ligand expression, add assess selectin receptor binding. Defining the molecular basis of carbohydrate glycan expression in malignant cell adhesion events may link observations about metastasis and FT regulatory mechanisms.

癌细胞通过血流的转移显著影响 大多数人类恶性肿瘤的诊断、治疗和预后。 肿瘤细胞与微血管系统的相互作用依赖于许多 因素，但转移性侵袭显然需要阻止和坚持 细胞迁移到内皮细胞，随后发生迁移和/或增殖。 细胞因子激活内皮细胞可增加某些细胞的粘附性 人黑色素瘤和腺癌细胞在体外通过不同的过程 来自整合素介导的相互作用。最近的实验表明， 岩藻糖化结构唾液酸基Lewis x可介导黏附 白细胞对E-选择素(ELAM-1)和P-选择素(GMP-140/PADGEM)的作用 由人内皮细胞表达。一种相关的多糖，唾液酸路易斯a， 也可以作为E-选择素的配体。这些碳水化合物部分 最初被描述为肿瘤发育抗原，与 一些同样的恶性细胞现在被证明与细胞因子激活的黏附 内皮细胞。 遗传和生化数据表明，至少有六种 人类α(1，3)岩藻糖基转移酶(FT)基因 这些相关的多聚糖。尽管组织特异性表达已经被 对岩藻糖化寡糖抗原和多个 α(1，3)FT活性，决定这一过程的分子机制 都没有被很好地理解。 我们已经分离并鉴定了四个人类α(1，3)FT基因，它们是 现在将用于下列具体目标中概述的实验： 1.分离和鉴定了剩余的α(1，3)和α(1，4)FT基因(S)。 2.确定α(1，3)FT基因座在人类染色体上的物理图谱。 3.确定α(1，3)FT转录本的正常表达模式 人体组织。4.检测人α(1，3)FT转录本的表达 腺癌细胞可黏附于细胞因子激活 内皮细胞。展示特定的α(1，3)或α(1，4)FT基因(S) 参与，与FT活性和寡糖配体相关 表达，添加评估选择素受体结合。定义分子 糖链在恶性细胞黏附事件中表达的基础 可能将有关转移的观察与FT的调节机制联系起来。

项目成果

Expression of human alpha(1,3)fucosyltransferase antisense sequences inhibits selectin-mediated adhesion and liver metastasis of colon carcinoma cells.

人α(1,3)岩藻糖基转移酶反义序列的表达抑制选择素介导的结肠癌细胞粘附和肝转移。

• 发表时间: 1999
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Weston,BW;Hiller,KM;Mayben,JP;Manousos,GA;Bendt,KM;Liu,R;CusackJr,JC
• 通讯作者: CusackJr,JC

Transfection of alpha(1,3)fucosyltransferase antisense sequences impairs the proliferative and tumorigenic ability of human colon carcinoma cells.

• 发表时间: 2000
• 期刊: Molecular carcinogenesis
• 影响因子: 4.6
• 作者: K. Hiller;J. P. Mayben;K. Bendt;G. Manousos;K. Senger;H. Cameron;B. Weston