Silodosin inhibits noradrenaline-activated transcription factors Elk1 and SRF in human prostate smooth muscle.
Silodosin inhibits noradrenaline-activated transcription factors Elk1 and SRF in human prostate smooth muscle.
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DOI：
10.1371/journal.pone.0050904
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Gratzke C
中科院分区：
文献类型：
--
作者：
Hennenberg M;Strittmatter F;Beckmann C;Rutz B;Füllhase C;Waidelich R;Montorsi F;Hedlund P;Andersson KE;Stief CG;Gratzke C
转录因子Elk1和血清反应因子（SRF）是各种细胞类型中细胞周期和表型的中心调节因子。Elk1通过磷酸化（丝氨酸-383）激活，而SRF的激活需要其辅助因子心肌素。Elk1和SRF的激活导致与启动子区域的特定DNA序列结合，并且可能由不同器官的肾上腺素能受体激活诱导。研究肾上腺素能刺激对人前列腺Elk1和SRF的影响，以及高选择性α 1a -肾上腺素受体拮抗剂西洛多辛对转录因子激活的影响。前列腺组织取自接受根治性前列腺切除术的患者。Western blot和免疫组化检测Elk1、SRF和心肌素的表达。双免疫荧光染色研究共定位。采用磷酸化特异性抗体进行Western blot分析，检测去甲肾上腺素（NA-）和苯肾上腺素（PE-）诱导的Elk1磷酸化。通过电泳迁移位移法（EMSA）研究na诱导的Elk1和SRF活化。在每个患者的组织基质细胞中观察到Elk1、SRF和心肌素的免疫反应性。在荧光染色中，SRF与心肌素和α-平滑肌肌动蛋白（αSMA）共定位。用PE（10µM）或NA（30µM）刺激前列腺组织增加Elk1丝氨酸-383位点的磷酸化。通过EMSA证实了na诱导的Elk1激活，其中观察到na诱导的Elk1与DNA序列TTTGCAAAATGCAGGAATTGTTTTCACAGT结合。同样，NA导致SRF与SRF特异性DNA序列CCATATTAGGCCATATTAGG结合。在前列腺组织中应用西洛多辛（3µM）可降低na刺激组织中Elk1和SRF的活性。西洛多辛阻断了两种转录因子Elk1和SRF的激活，这是由去甲肾上腺素在人前列腺中诱导的。α - 1肾上腺素受体的作用可能超越平滑肌收缩，包括转录调节功能。
The transcription factors Elk1 and serum response factor (SRF) are central regulators of cell cycle and phenotype in various cell types. Elk1 is activated by phosphorylation (serine-383), while activation of SRF requires its co-factor, myocardin. Activation of Elk1 and SRF results in binding to specific DNA sequences in promoter regions, and may be induced by adrenergic receptor activation in different organs. To examine the effects of adrenergic stimulation on Elk1 and SRF in the human prostate and the ability of the highly selective α1A-adrenoceptor antagonist, silodosin, on transcription factor activation. Prostate tissue was obtained from patients undergoing radical prostatectomy. Expression of Elk1, SRF, and myocardin was estimated by Western blot and immunohistochemistry. Colocalizations were studied by double immunofluorescence staining. Noradrenaline- (NA-) and phenylephrine- (PE-) induced phosphorylation of Elk1 was assessed by Western blot analysis using a phospho-specific antibody. NA-induced activation of Elk1 and SRF was investigated by electrophoretic mobility shift assay (EMSA). Immunoreactivity for Elk1, SRF, and myocardin was observed in stromal cells of tissues from each patient. In fluorescence stainings, SRF colocalized with myocardin and α-smooth muscle actin (αSMA). Stimulation of prostate tissues with PE (10 µM) or NA (30 µM) increased the phosphorylation of Elk1 at serine-383. NA-induced Elk1 activation was confirmed by EMSA, where a NA-induced binding of Elk1 to the DNA sequence TTTGCAAAATGCAGGAATTGTTTTCACAGT was observed. Similarly, NA caused SRF binding to the SRF-specific DNA sequence CCATATTAGGCCATATTAGG. Application of silodosin (3 µM) to prostate tissues reduced the activity of Elk1 and SRF in NA-stimulated tissues. Silodosin blocks the activation of the two transcription factors, Elk1 and SRF, which is induced by noradrenaline in the human prostate. A role of α1-adrenoceptors beyond smooth muscle contraction may be considered, which includes a function in transcriptional regulation.
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