APOLIPOPROTEIN-B MESSENGER-RNA-EDITING PROTEIN INDUCES HEPATOCELLULAR-CARCINOMA AND DYSPLASIA IN TRANSGENIC ANIMALS
APOLIPOPROTEIN-B MESSENGER-RNA-EDITING PROTEIN INDUCES HEPATOCELLULAR-CARCINOMA AND DYSPLASIA IN TRANSGENIC ANIMALS
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DOI：
10.1073/pnas.92.18.8483
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发表时间：
1995-08-29
影响因子：
11.1
通讯作者：
INNERARITY, TL
中科院分区：
文献类型：
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作者：
YAMANAKA, S;BALESTRA, ME;INNERARITY, TL
载脂蛋白（apo-）B mRNA编辑是胞苷的脱氨基作用，其产生新的终止密码子并产生apo-B的截短形式（apo-B48）。已经鉴定了多蛋白编辑复合物的胞苷脱氨酶催化亚基[apo-B mRNA编辑酶催化多肽1（APOBEC-1）]。我们产生了转基因兔和小鼠表达兔APOBEC-1在他们的肝脏，以确定是否肝表达将降低低密度脂蛋白胆固醇浓度。对转基因小鼠和兔肝脏的apo-B mRNA进行了广泛编辑，与对照动物相比，转基因动物的apo-B100和低密度脂蛋白浓度降低。出乎意料的是，所有的转基因小鼠和转基因兔子都有肝脏发育不良，许多转基因小鼠发展成肝细胞癌。许多小鼠肝脏增生并充满脂质。检查具有与apo-B mRNA相似的序列基序的其他肝mRNA的这种编辑类型（即，胞苷脱氨基作用）。其中之一，酪氨酸激酶，在转基因小鼠的肝脏中被编辑，但在对照组中没有。这一结果表明，其他mRNA可以被过表达的编辑酶编辑，并表明参与细胞生长和调控的肝脏mRNA的异常编辑是肿瘤发生的原因。最后，这些发现损害了APOBEC-1用于基因治疗以降低低密度脂蛋白的血浆水平的潜在用途。
Apolipoprotein (apo-) B mRNA editing is the deamination of cytidine that creates a new termination codon and produces a truncated version of apo-B (apo-B48). The cytidine deaminase catalytic subunit [apo-B mRNA-editing enzyme catalytic polypeptide 1 (APOBEC-1)] of the multiprotein editing complex has been identified. We generated transgenic rabbits and mice expressing rabbit APOBEC-1 in their livers to determine whether hepatic expression would lower low density lipoprotein cholesterol concentrations. The apo-B mRNA from the livers of the transgenic mice and rabbit was extensively edited, and the transgenic animals had reduced concentrations of apo-B100 and low density lipoproteins compared with control animals. Unexpectedly, all of the transgenic mice and a transgenic rabbit had liver dysplasia, and many transgenic mice developed hepatopcellular carcinomas. Many of the mouse livers were hyperplastic and filled with lipid. Other hepatic mRNAs with sequence motifs similar to apo-B mRNA were examined for this type of editing (i.e., cytidine deamination). One of these, tyrosine kinase, was edited in livers of transgenic mice but not of controls. This result demonstrates that other mRNAs can be edited by the overexpressed editing enzyme and suggests that aberrant editing of hepatic mRNAs involved in cell growth and regulation is the cause of the tumorigenesis. Finally, these findings compromise the potential use of APOBEC-1 for gene therapy to lower plasma levels of low density lipoproteins.