Specific expression and regulation of the new melanoma inhibitory activity-related gene MIA2 in hepatocytes
Specific expression and regulation of the new melanoma inhibitory activity-related gene MIA2 in hepatocytes
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DOI：
10.1074/jbc.m212639200
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发表时间：
2003-04-25
影响因子：
4.8
通讯作者：
Hellerbrand, C
中科院分区：
文献类型：
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作者：
Bosserhoff, AK;Moser, M;Hellerbrand, C
通过GenBank（TM）检索鉴定了编码黑色素瘤抑制活性（MIA）同源蛋白的新人类基因MIA 2。MIA 2与MIA、OTOR和TANGO一起属于新的MIA基因家族，具有重要的结构特征、在核苷酸和蛋白质水平上的显著同源性以及相似的基因组结构。原位杂交，逆转录酶-PCR，和北方印迹提出了一个高度组织特异性的MIA 2在肝脏中的表达模式。启动子研究分析MIA 2的转录调控揭示了HNF-1结合位点在位置-236控制肝细胞特异性表达。该位点的突变导致HepG 2细胞中启动子活性的完全丧失。在MIA，2启动子中检测到的其他位点是SMAD和STAT 3的共有结合位点。因此，通过用白细胞介素-6、转化生长因子-β和来自活化的肝星状细胞的条件培养基处理，发生了MIA 2 mRNA表达的刺激。根据这些结果，发现MIA 2 mRNA在慢性丙型肝炎感染患者的肝组织中与对照组相比增加。重度纤维化或炎症患者的MIA 2 mRNA水平显著高于不太严重的纤维化或炎症患者。总之，我们的数据表明，MIA 2代表了一种潜在的新型急性期蛋白，MIA 2表达对肝损伤有反应。在更严重的慢性肝病中增加的转录表明MIA 2可以作为肝病活动性和严重程度的标志物。
The novel human gene MIA2 encoding a melanoma inhibitory activity (MIA) homologous protein was identified by a GenBank(TM) search. MIA2, together with MIA, OTOR, and TANGO, belongs to the novel MIA gene family sharing important structural features, significant homology at both the nucleotide and protein levels, and similar genomic organization. In situ hybridization, reverse transcriptase-PCR, and Northern blots presented a highly tissue-specific MIA2 expression pattern in the liver. Promoter studies analyzing transcriptional regulation of MIA2 revealed an HNF-1-binding site at position -236 controlling hepatocyte-specific expression. Mutation of the site led to a complete loss of promoter activity in HepG2 cell. Further sites detected in the MIA,2 promoter were consensus binding sites for SMAD and STAT3, Consistently, stimulation of MIA2 mRNA expression occurred by treatment with interleukin-6, transforming growth factor-beta, and conditioned medium from activated hepatic stellate cells. In accordance with these results, MIA2 mRNA was found to be increased in liver tissue of patients with chronic hepatitis C infection compared with controls. MIA2 mRNA levels were significantly higher in patients with severe fibrosis or inflammation than in patients with less severe fibrosis or inflammation. In summary our data indicate that MIA2 represents a potential novel acute phase protein and MIA2 expression responds to liver damage. The increased transcription in more severe chronic liver disease suggests that MIA2 may serve as a marker of hepatic disease activity and severity.