HNF4α reduces proliferation of kidney cells and affects genes deregulated in renal cell carcinoma
HNF4α reduces proliferation of kidney cells and affects genes deregulated in renal cell carcinoma
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DOI：
10.1038/sj.onc.1208794
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发表时间：
2005-09-22
期刊：
影响因子：
8
通讯作者：
Ryffel, GU
中科院分区：
文献类型：
--
作者：
Lucas, B;Grigo, K;Ryffel, GU
肝细胞核因子4 α（HNF 4 α）是一种组织特异性转录因子，已知可调节肝细胞和胰腺β细胞中的大量基因。虽然HNF4 α在肾脏的某些部分高度表达，但对其在该器官中的作用以及肾脏细胞中HNF4 α调节基因的了解甚少。肾细胞癌（RCC）中HNF4 α的丰度和活性经常降低，表明HNF4 α在肾细胞中具有一定的肿瘤抑制功能。为了确定HNF4 α在RCC中的潜在作用，我们使用Flp重组酶介导的基因整合来产生条件性表达野生型或突变型HNF4 α的人胚肾细胞（HEK293）。野生型HNF4 α的表达而非突变体的表达导致增殖减少和细胞形态改变。这些作用是可逆的，并且在HNF4 α的生理浓度下诱导。使用基因表达pro.通过基因芯片技术，我们确定了HNF 4 α调控的基因。有趣的是，许多由HNF4 α调控的基因在RCC微阵列研究中被证明是失调的。这些基因（ACY1、WT1、SELENBP1、COBL、EFHD1、AGXT2L1、ALDH5A1、THEM2、ABCB1、FLJ14146、CSPG2、TRIM9和HEY1）是在RCC中HNF 4 α降低时活性改变的基因的良好候选者。
Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a tissue-specific transcription factor known to regulate a large number of genes in hepatocytes and pancreatic beta cells. Although HNF4 alpha is highly expressed in some sections of the kidney, little is known about its role in this organ and about HNF4 alpha-regulated genes in the kidney cells. The abundance and activity of HNF4 alpha are frequently reduced in renal cell carcinoma (RCC) indicating some tumor suppressing function of HNF4 alpha in renal cells. To determine the potential role of HNF4 alpha in RCC, we used Flp recombinase-mediated gene integration to generate human embryonic kidney cells (HEK293) that conditionally express wild-type or mutated HNF4a. Expression of wild-type HNF4 alpha but not of the mutants led to reduction of proliferation and alterations of cell morphology. These effects were reversible and induced at physiological concentrations of HNF4 alpha. Using gene expression pro. ling by microarrays, we determined genes regulated by HNF4 alpha. Interestingly, many of the genes regulated by HNF4 alpha have been shown to be deregulated in RCC microarray studies. These genes (ACY1, WT1, SELENBP1, COBL, EFHD1, AGXT2L1, ALDH5A1, THEM2, ABCB1, FLJ14146, CSPG2, TRIM9 and HEY1) are good candidates for genes whose activity is changed upon the decrease of HNF4 alpha in RCC.