Diverse roles of androgen receptor (AR) domains in AR-mediated signaling.
Diverse roles of androgen receptor (AR) domains in AR-mediated signaling.
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DOI：
10.1621/nrs.06008
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发表时间：
2008-06-27
期刊：
影响因子：
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通讯作者：
Haelens A
中科院分区：
文献类型：
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作者：
Claessens F;Denayer S;Van Tilborgh N;Kerkhofs S;Helsen C;Haelens A
雄激素控制男性的性发育和成年男性表型的维持。它们对生殖器官、肌肉、骨骼、大脑和皮肤等靶器官的影响非常不同。这在一定程度上是因为不同类型的细胞对雄激素刺激的反应不同，即使所有这些反应都是由相同的细胞内雄激素受体介导的。为了理解这些组织和细胞特异性的雄激素读数，我们必须了解雄激素受体(NR3C4)转录激活机制的许多不同步骤。像所有的核受体一样，类固醇受体有一个中心DNA结合域，通过铰链区与配体结合域相连。此外，所有类固醇受体都有一个相对较大的氨基末端结构域。尽管雄激素受体与其他核受体在总体结构上具有同源性，但它有几个特定的特征，这里将对其进行讨论。这种受体可以结合两种类型的雄激素反应元件(ARE)：一种类似于经典的GRE/PRE型元件，另一种类型更分化和更有选择性的ARE。激素结合结构域具有低的内在反式激活特性，这一特征与该结构域对典型的LxxLL共激活剂的低亲和力相关。对于雄激素受体，转录激活包括在氨基末端区域和铰链区的不同区域选择性地招募辅助激活子。最后，雄激素受体的氨基末端结构域和配体结合域之间由配体诱导的相互作用似乎涉及到其转录因子功能的许多方面。本文综述了雄激素受体结构域内结构-功能关系的研究现状，并试图将不同结构域、亚结构域和基序参与雄激素受体作为转录因子的功能与组织和细胞特异性读出相结合。
Androgens control male sexual development and maintenance of the adult male phenotype. They have very divergent effects on their target organs like the reproductive organs, muscle, bone, brain and skin. This is explained in part by the fact that different cell types respond differently to androgen stimulus, even when all these responses are mediated by the same intracellular androgen receptor. To understand these tissue- and cell-specific readouts of androgens, we have to learn the many different steps in the transcription activation mechanisms of the androgen receptor (NR3C4). Like all nuclear receptors, the steroid receptors have a central DNA-binding domain connected to a ligand-binding domain by a hinge region. In addition, all steroid receptors have a relatively large amino-terminal domain. Despite the overall structural homology with other nuclear receptors, the androgen receptor has several specific characteristics which will be discussed here. This receptor can bind two types of androgen response elements (AREs): one type being similar to the classical GRE/PRE-type elements, the other type being the more divergent and more selective AREs. The hormone-binding domain has low intrinsic transactivation properties, a feature that correlates with the low affinity of this domain for the canonical LxxLL-bearing coactivators. For the androgen receptor, transcriptional activation involves the alternative recruitment of coactivators to different regions in the amino-terminal domain, as well as the hinge region. Finally, a very strong ligand-induced interaction between the amino-terminal domain and the ligand-binding domain of the androgen receptor seems to be involved in many aspects of its function as a transcription factor. This review describes the current knowledge on the structure-function relationships within the domains of the androgen receptor and tries to integrate the involvement of different domains, subdomains and motifs in the functioning of this receptor as a transcription factor with tissue- and cell-specific readouts.