Belikov Sergey, Bott Laura C, Fischbeck Kenneth H, Wrange Örjan
Department of Cell and Molecular Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden.
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Biochem Biophys Rep. 2015 Jul 26;3:134-139. doi: 10.1016/j.bbrep.2015.07.014. eCollection 2015 Sep.
Expansion of a polyglutamine-encoding trinucleotide CAG repeat in the androgen receptor (AR) to more than 37 repeats is responsible for the X-linked neuromuscular disease spinal and bulbar muscular atrophy (SBMA). Here we evaluated the effect of polyglutamine length on AR function in oocytes. This allowed us to correlate the nuclear AR concentration to its capacity for specific DNA binding and transcription activation . AR variants with polyglutamine tracts containing either 25 or 64 residues were expressed in oocytes by cytoplasmic injection of the corresponding mRNAs. The intranuclear AR concentration was monitored in isolated nuclei and related to specific DNA binding as well as transcriptional induction from the hormone response element in the mouse mammary tumor virus (MMTV) promoter. The expanded AR with 64 glutamines had increased capacity for specific DNA binding and a reduced capacity for transcriptional induction as related to its DNA binding activity. The possible mechanism behind these polyglutamine-induced alterations in AR function is discussed.
雄激素受体（AR）中编码聚谷氨酰胺的三核苷酸CAG重复序列扩展至37次以上会导致X连锁神经肌肉疾病脊髓延髓肌萎缩症（SBMA）。在此，我们评估了聚谷氨酰胺长度对卵母细胞中AR功能的影响。这使我们能够将细胞核内AR浓度与其特异性DNA结合及转录激活能力相关联。通过向卵母细胞胞质注射相应的mRNA，表达了含25个或64个残基的聚谷氨酰胺片段的AR变体。在分离的细胞核中监测核内AR浓度，并将其与特异性DNA结合以及小鼠乳腺肿瘤病毒（MMTV）启动子中激素反应元件的转录诱导相关联。与具有DNA结合活性相关的是，含64个谷氨酰胺的扩展型AR具有增强的特异性DNA结合能力和降低的转录诱导能力。本文讨论了这些聚谷氨酰胺诱导的AR功能改变背后的可能机制。
