Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene repertoire.
Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene repertoire.
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DOI：
10.1038/onc.2009.265
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发表时间：
2009-11-26
期刊：
影响因子：
8
通讯作者：
Privalsky, M. L.
中科院分区：
文献类型：
--
作者：
Chan, I. H.;Privalsky, M. L.
甲状腺激素受体(TRs)是激素调节的转录因子，控制正常生理和发育的多个方面。在包括人肝细胞癌(HCCs)在内的某些癌症中，TRs的突变被发现频率很高。大多数肝细胞癌tr突变体在其DNA识别区域内有损伤，我们假设这些损伤在某种程度上改变了突变受体的目标基因库，对它们作为癌蛋白的功能至关重要。利用稳定的细胞转化子和表达阵列分析，我们确定了从两个不同的肝癌中分离的突变型TRs确实如假设的那样，显示了与它们的正常TR祖细胞不同的靶基因谱系。只有野生型转录因子调控的一部分基因受相应的肝细胞癌-受体突变体调控。更令人惊讶的是，肝细胞癌-tr突变体还获得了调节野生型受体不识别的额外靶基因的能力，而且不仅限于抑制，还可以激活其靶基因的子集。我们的结论是，从肝细胞癌中分离的tr突变体与其正常祖细胞相比经历了多种变化，不仅包括其转录输出的变化，还包括它们所针对的基因的变化；两者都可能导致肿瘤的发生。
Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that control multiple aspects of normal physiology and development. Mutations in TRs have been identified at high frequency in certain cancers, including human hepatocellular carcinomas (HCCs). The majority of HCC TR mutants bear lesions within their DNA recognition domains, and we have hypothesized that these lesions change the mutant receptors' target gene repertoire in a way crucial to their function as oncoproteins. Using stable cell transformants and expression array analysis, we determined that mutant TRs isolated from two different HCCs do, as hypothesized, display a target gene repertoire distinct from that of their normal TR progenitors. Only a subset of genes regulated by wild-type TRs were regulated by the corresponding HCC-TR mutants. More surprisingly, the HCC-TR mutants also gained the ability to regulate additional target genes not recognized by the wild-type receptors, and were not simply restricted to repression, but could also activate a subset of their target genes. We conclude that the TR mutants isolated from HCC have sustained multiple alterations from their normal progenitors that include not only changes in their transcriptional outputs, but also changes in the genes they target; both are likely to contribute to neoplasia.
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影响因子：
5.3
作者：
Furumoto, H;Ying, H;Cheng, SY
通讯作者：
Cheng, SY
DOI：
10.1007/bf02630890
发表时间：
1991-01-01
期刊：
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY
影响因子：
--
作者：
DARBY, IA;BOUHNIK, J;CORVOL, P
通讯作者：
CORVOL, P
影响因子：
4.8
作者：
Lin, KH;Zhu, XG;Cheng, SY
通讯作者：
Cheng, SY
影响因子：
2.1
作者：
Irizarry, RA;Hobbs, B;Speed, TP
通讯作者：
Speed, TP
影响因子：
6.6
作者：
Harvey, CB;Williams, GR
通讯作者：
Williams, GR