Alternatively spliced androgen receptor variants.
Alternatively spliced androgen receptor variants.
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DOI：
10.1530/erc-11-0141
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发表时间：
2011-10
影响因子：
3.9
通讯作者：
Tindall DJ
中科院分区：
文献类型：
--
作者：
Dehm SM;Tindall DJ
选择性剪接是从有限的一组基因中增加功能多样性的重要机制。在不同的病理条件下，这一过程的去调节是常见的。雄激素受体(AR)是一种类固醇受体转录因子，具有对正常男性发育以及正常和癌前列腺组织的生长和存活至关重要的功能。对雄激素不敏感综合征(AIS)和前列腺癌(PCa)AR功能的研究表明，AIS的AR功能丧失，而PCa的AR功能获得改变。在过去的二十年里，在各种AIS患者中发现了AR基因的改变，这种改变扰乱了正常的AR剪接模式，并产生了功能障碍的AR蛋白变体。最近，AR剪接模式的改变被认为是前列腺癌进展和对雄激素耗竭治疗产生抵抗的机制之一。一些研究已经描述了编码截短的AR亚型的选择性剪接转录本的合成，这些AR亚型缺乏配体结合域，而配体结合域是雄激素耗竭的最终目标。这些截短的AR亚型中的许多都是构成活性的、配体无关的转录因子，可以支持AR靶基因的雄激素非依赖性表达，以及PCa细胞的雄激素非依赖性生长。在这篇综述中，我们将总结已发现的各种选择性剪接AR变异体，重点介绍它们在AIS和PCa的病理状态中的作用和来源。
Alternative splicing is an important mechanism for increasing functional diversity from a limited set of genes. De-regulation of this process is common in diverse pathologic conditions. The androgen receptor (AR) is a steroid receptor transcription factor with functions critical for normal male development as well as the growth and survival of normal and cancerous prostate tissue. Studies of AR function in androgen insensitivity syndrome (AIS) and prostate cancer (PCa) have demonstrated loss-of-function AR alterations in AIS, and gain-of-function AR alterations in PCa. Over the past two decades, AR gene alterations have been identified in various individuals with AIS, which disrupt normal AR splicing patterns and yield dysfunctional AR protein variants. More recently, altered AR splicing patterns have been identified as a mechanism of PCa progression and resistance to androgen-depletion therapy. Several studies have described the synthesis of alternatively spliced transcripts encoding truncated AR isoforms that lack the ligand-binding domain, which is the ultimate target of androgen depletion. Many of these truncated AR isoforms function as constitutively active, ligand-independent transcription factors that can support androgen-independent expression of AR target genes, as well as the androgen-independent growth of PCa cells. In this review, we will summarize the various alternatively spliced AR variants that have been discovered, with a focus on their role and origin in the pathologic conditions of AIS and PCa.