Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants
Functional characterization of Wilms tumor-suppressor WTX and tumor-associated mutants
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DOI：
10.1038/onc.2010.452
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发表时间：
2011-02
期刊：
影响因子：
8
通讯作者：
M. H. Kim;Dong-Joon Min;Michael S. Rabin;Jonathan D. Licht
中科院分区：
文献类型：
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作者：
M. H. Kim;Dong-Joon Min;Michael S. Rabin;Jonathan D. Licht
WTX，Wilms肿瘤相关的肿瘤抑制基因，存在于X染色体上，单个WTX突变可能足以促进致癌作用。与转录因子WT 1肿瘤抑制因子不同，WTX缺乏保守的功能蛋白结构域。为了研究WTX的功能，我们构建了表达WTX和肿瘤相关WTX突变体的诱导细胞系。WTX的诱导可抑制细胞生长，并导致G1/G 0期阻滞。相比之下，一个短的，肿瘤相关的截短突变体的WTX 358只有轻微的抑制细胞生长，没有一个显着的细胞周期停滞，虽然一个较长的截短突变体WTX 565的表达导致的生长抑制和细胞周期停滞到一个类似的程度，野生型WTX。像WT 1一样，WTX通过p21诱导减缓生长并引起细胞周期停滞。基因表达谱分析表明，这两种肿瘤抑制因子以相似的途径调节基因，包括那些参与控制细胞生长、细胞周期、细胞死亡、癌症和心血管系统发育的基因。当野生型WTX介导的基因表达变化与受突变体影响的基因表达变化进行比较时，WTX 565在差异调节基因中显示出55%的重叠（228个基因），而WTX 358仅调节受野生型WTX影响的两个基因，这意味着氨基酸残基358-561对WTX功能至关重要。
The WTX, Wilms tumor-associated tumor-suppressor gene, is present on the X chromosome and a single WTX mutation may be sufficient to promote carcinogenesis. Unlike the WT1 tumor suppressor, a transcription factor, WTX lacks conserved functional protein domains. To study the function of WTX, we constructed inducible cell lines expressing WTX and tumor-associated WTX mutants. Induction of WTX inhibited cell growth and caused G 1/G 0 arrest. In contrast, a short, tumor-associated truncation mutant of WTX358 only slightly inhibited cell growth without a significant cell-cycle arrest, although expression of a longer truncation mutant WTX565 led to the growth inhibition and cell-cycle arrest to a similar extent as wild-type WTX. Like WT1, WTX slowed growth and caused cell-cycle arrest through p21 induction. Gene expression profiling showed that these two tumor-suppressors regulated genes in similar pathways, including those implicated in control of the cellular growth, cell cycle, cell death, cancer and cardiovascular system development. When gene expression changes mediated by wild-type WTX were compared with those affected by mutant forms, WTX565 showed a 55% overlap (228 genes) in differentially regulated genes, whereas WTX358 regulated only two genes affected by wild-type WTX, implying that amino-acid residues 358–561 are critical for WTX function.