Molecular analysis of novel PDZ domain-containing gene encoding autoantigen of autoimmune enteropathy
Molecular analysis of novel PDZ domain-containing gene encoding autoantigen of autoimmune enteropathy
批准号:
10470052
负责人:
MORIUCHI Tetsuya
金额:
$4.1万
依托单位:
依托单位国家:
日本
项目类别:
Grant-in-Aid for Scientific Research (B)
财政年份:
1998
资助国家:
日本
项目状态:
已结题
起止时间:
1998 至 1999
中文摘要
LEC大鼠是一种突变株,其肝炎和肝癌自发发展的发生率极高。利用酵母为基础的检测,将p53基因转录本突变体的比例作为红色集落进行评分,我们在LEC大鼠的肝脏中检测到频繁的突变。其中大多数(50-65%)是由于插入一个额外的腺嘌呤(A)而引起的移码突变,所有的A插入都出现在含有6个连续腺嘌呤的区域。额外的腺嘌呤插入几乎全部在mRNA (cDNA)中发现,特别是在3个(A)6序列(4,7,8外显子)中位于最5'侧(外显子4)的(A)6序列中,而很少在相应基因组DNA部分的克隆中发现。利用SP6 RNA聚合酶人工合成的p53 mRNA在2个克隆的第7外显子和1个克隆的第8外显子中插入了一个额外的腺嘌呤,但在12个克隆的第4外显子中没有插入。总体上占转录mRNA的1.6%,表明外显子4 (A)6的腺嘌呤插入是一种体内现象,而不是逆转录过程中的伪影。急性肝炎期A针的发生率急剧上升,达到20%左右,慢性肝炎期恢复到控制水平,肿瘤期又略有上升。其突变率与血清AST水平相关(r = 0.96, p<0.00 1),与肝脏铜和8-羟基脱氧鸟苷含量无关。乙醇处理培养的肝源性细胞也增加了(A)6通道的转录滑移率,共同表明非特异性细胞损伤是导致转录突变比例增加的原因。这些结果表明,细胞损伤降低了转录保真度,从而进一步增强了细胞功能的损伤。
英文摘要
The LEC rat is a mutant strain in which hepatitis and hepatoma spontaneously develop at an extremely high incidence. Using a yeast-based assay which scores the ratio of mutants in p53 gene transcripts as red colonies, we detected frequent mutations in the liver of LEC rats. The majority of them (50-65%) were frameshift mutations caused by insertion of an extra adenine (A) and all the A insertions were found in the regions containing 6 consecutive adenines. Insertions of an extra adenine were found almost exclusively in the mRNA (cDNA), especlally in the (A)6 tract located in the most 5'-side (exon 4) among the three (A)6 tracts (exon 4, 7, and 8), and rarely in the clones of the corresponding genomic DNA part. Artifrcially synthesized p53 mRNA with the use of SP6 RNA polymerase gave insertions of an extra adenine in two clones in exon 7 and one in exon 8, but none in exon 4 out of 1 2 analyzed clones recovered from red colonies; overall accounting for 1.6% of the transcribed mRNA, indicating that the adenine insertion in exon4 (A)6 tract was an in vivo phenomenon rather than an artifact in reverse-transcription. The incidence of A insertion sharply increased up to about 20% in acute hepatitis stage, returned to control level in chronic hepatitis stage, and increased again slightly in neoplastic stage. The mutation rate correlated with serum AST level (r = 0.96, p<0.00 1) but not with contents of copper and 8-hydroxydeoxyguanosine in the liver of LEC rats. Ethanol treatment of cultured liver-derived cells also increased the rate of transcriptlonal slippage at the (A)6 tract, together suggesting that non-specific cellular damage is responsible to the increased ratios of the transcriptional mutations. These results suggest that cellular damage reduces transcriptional fidelity, thereby further enhancing the impairment of cellular functions.
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守内哲也: "Inflammatory cell-mediated tumour progression and minisatellite mutation cor-relate with the decrease of antioxidative enzymes in murine fibrosarcoma cells." Br J Cancer. 79. 377-385 (1999)
Tetsuya Moriuchi:“炎症细胞介导的肿瘤进展和小卫星突变与鼠纤维肉瘤细胞中抗氧化酶的减少相关。” 79. 377-385 (1999)
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通讯作者:
Ba, Y., Tonoki, H., Tada, M., Nakata, D., Hamada, J. and Monuchi, T.: "Transcriptional slippage of p53 gene enhanced by cellular damage in rat liver : monitoring the slippage by a yeast functional assay."Mutation Res.. (in press).
Ba, Y.、Tonoki, H.、Tada, M.、Nakata, D.、Hamada, J. 和 Monuchi, T.:“大鼠肝脏细胞损伤增强 p53 基因的转录滑移:通过酵母监测滑移
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浜田淳一: "Unsaturated fatty acid feeding prevent the development of acute hepatitis in Long-Evans Cinnamon (LEC) rats"Anticancer Res.. (印刷中).
Junichi Hamada:“不饱和脂肪酸喂养可预防 Long-Evans Cinnamon (LEC) 大鼠发生急性肝炎”Anticancer Res..(出版中)。
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守内哲也: "Inhibitory effects of malotilate on invasion and metastasis of rat mammary carcinoma cells by modifying the functions of vascular endothelial cells." Br J Cancer. 77. 1371-1377 (1998)
Tetsuya Moriuchi:“马洛替酯通过改变血管内皮细胞的功能来抑制大鼠乳腺癌细胞的侵袭和转移。” Br J Cancer. 77. 1371-1377 (1998)
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浜田淳一: "Selective transendothelial migration of hematopoietic progenitor cells:a role in homing of progenitor cells." Blood. 93・1. 149-156 (1999)
Junichi Hamada:“造血祖细胞的选择性跨内皮迁移:祖细胞归巢的作用。” 149-156(1999)。
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共 21 条
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