Aberrant transcription from an unrelated promoter can result in MDR-1 expression following drug selection in vitro and in relapsed lymphoma samples.
Aberrant transcription from an unrelated promoter can result in MDR-1 expression following drug selection in vitro and in relapsed lymphoma samples.
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不相关启动子的异常转录可能导致体外药物选择和复发性淋巴瘤样本中 MDR-1 的表达。
DOI：
10.1158/0008-5472.can-04-1349
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发表时间：
2005
期刊：
影响因子：
11.2
通讯作者：
Lee,Jong-Seok
中科院分区：
文献类型：
--
作者：
Huff,LynMickley;Wang,Zheng;Iglesias,Angel;Fojo,Tito;Lee,Jong-Seok
癌症治疗中耐药性的发展仍然是一个主要问题。多药耐药的标志是对多种结构上不相关的化合物的交叉耐药。MDR-1基因编码的P-糖蛋白介导的耐药机制被广泛研究。以前的研究提出两个启动子控制MDR-1基因的表达，分别命名为上游启动子和下游启动子。在这篇文章中，我们提供的证据表明，转录本起源于假定的上游启动子ofMDR-1实际上是异常的转录本，其表达是由附近的基因组序列，其中包括一个人内源性逆转录病毒长末端重复序列（LTR）的调控。这种LTR的表达发生在所有细胞中。我们发现，在药物选择后，特别是在基因扩增发生的情况下，MDR-1转录物可以开始在逆转录病毒LTR附近，转录方向与通常的LTR转录相反。由于这些异常MDR-1转录本（AMT）的表达主要存在于耐药细胞系中，因此我们得出结论，耐药的发展或伴随的药物暴露可能在这种现象的激活或表达AMT的细胞的选择中起作用。从复发性淋巴瘤患者获得的肿瘤样品中类似的异常转录物的证明表明，这种现象也可能发生在临床上。（Cancer Res 2005; 65（24）：11694-703）
The development of drug resistance in the treatment of cancer remains a major problem. The hallmark of multidrug resistance is cross-resistance to multiple structurally unrelated compounds. TheMDR-1gene encoding P-glycoprotein mediates one of the most extensively studied mechanisms of drug resistance. Previous studies led to the proposal that two promoters control expression of theMDR-1gene, and these were designated the upstream and downstream promoters. In the present article, we provide evidence that transcripts originating from the putative upstream promoter ofMDR-1are in fact aberrant transcripts whose expression is regulated by nearby genomic sequences that include a human endogenous retroviral long terminal repeat (LTR). Expression of this LTR occurs in all cells. We show that following drug selection, especially in cases where gene amplification has occurred,MDR-1transcripts can begin near this retroviral LTR with transcription proceeding in the direction opposite of the usual LTR transcription. Because expression of these aberrantMDR-1transcripts (AMT) is found primarily in drug-resistant cell lines, we conclude that the development of drug resistance or the attendant drug exposure might have a role in the activation of this phenomenon or the selection of cells expressing AMTs. Demonstration of similar aberrant transcripts in tumor samples obtained from patients with relapsed lymphoma suggests that this phenomenon may also occur clinically. (Cancer Res 2005; 65(24): 11694-703)