Inhibition of Heat Shock Factor 1 Enhances Repressive Molecular Mechanisms on the POMC Promoter
Inhibition of Heat Shock Factor 1 Enhances Repressive Molecular Mechanisms on the POMC Promoter
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抑制热休克因子 1 增强 POMC 启动子的抑制分子机制
DOI：
10.1159/000500200
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发表时间：
2019
影响因子：
4.1
通讯作者：
Stalla GK
中科院分区：
文献类型：
--
作者：
Ciato D;Monteserin Garcia JL;Papst L;D'Annunzio S;Hristov M;Tichomirowa MA;Belaya Z;Rozhinskaya L;Buchfelder M;Theodoropoulou M;Paez‐Pereda M;Stalla GK
库欣病(CD)是由分泌促肾上腺皮质激素(ACTH)的垂体肿瘤引起的。目的：(1)探讨热休克蛋白1(HSF1)的表达与CD的临床特征和激素/放射学特征的关系，以及(2)探讨抑制HSF1作为CD治疗靶点的作用。方法采用免疫印迹法检测8例CD肿瘤组织中总HSF1和pSer326 HSF1的表达，并与正常脑垂体HSF1状态进行比较。我们通过免疫组织化学筛选了45例CD患者的HSF1，并将HSF1免疫反应评分与现有的临床数据相关联。我们用RNA干扰和HSF1抑制剂KRIBB11在AtT-20细胞和四种原代培养的人皮质激素肿瘤细胞中评估了HSF1沉默的效果。结果表明，与正常脑垂体瘤相比，HSF1蛋白在CD肿瘤中高表达和转录活性。HSF1的免疫反应评分与疾病的典型临床特征无关。HSF1抑制可降低AtT-20细胞中前阿片黑素皮质素(POMC)的转录。HSF1抑制剂KRIBB11在原代细胞培养中抑制了75%的人CD肿瘤的ACTH合成。这种对POMC转录的抑制作用是通过糖皮质激素受体的增加以及对Nurr77/Nurr1和AP-1转录活性的抑制来实现的。结论HSF1对POMC的转录具有调控作用。HSF1的药理学靶向可能是控制CD中ACTH过度分泌的一种有前途的治疗选择。
BackgroundCushing’s disease (CD) is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. They express high levels of heat shock protein 90 and heat shock factor 1 (HSF1) in comparison to the normal tissue counterpart, indicating activated cellular stress.AimsOur objectives were:(1) to correlate HSF1 expression with clinical features and hormonal/radiological findings of CD, and (2) to investigate the effects of HSF1 inhibition as a target for CD treatment.Patients/MethodsWe examined the expression of total and pSer 326 HSF1 (marker for its transcriptional activation) by Western blot on eight human CD tumours and compared to the HSF1 status of normal pituitary. We screened a cohort of 45 patients with CD for HSF1 by immunohistochemistry and correlated the HSF1 immunoreactivity score with the available clinical data. We evaluated the effects of HSF1 silencing with RNA interference and the HSF1 inhibitor KRIBB11 in AtT-20 cells and four primary cultures of human corticotroph tumours.ResultsWe show that HSF1 protein is highly expressed and transcriptionally active in CD tumours in comparison to normal pituitary. The immunoreactivity score for HSF1 did not correlate with the typical clinical features of the disease. HSF1 inhibition reduced proopiomelanocortin (Pomc) transcription in AtT-20 cells. The HSF1 inhibitor KRIBB11 suppressed ACTH synthesis from 75% of human CD tumours in primary cell culture. This inhibitory action on Pomc transcription was mediated by increased glucocorticoid receptor and suppressed Nurr77/Nurr1 and AP-1 transcriptional activities.ConclusionsThese data show that HSF1 regulates POMC transcription. Pharmacological targeting of HSF1 may be a promising treatment option for the control of excess ACTH secretion in CD.
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影响因子：
5.2
作者：
Scheschowitsch K;Leite JA;Assreuy J
通讯作者：
Assreuy J
激动剂激活的糖皮质激素受体在体内抑制热休克因子 1 与热休克蛋白 70 启动子的结合。
DOI：
10.1210/me.2003-0215
发表时间：
2004
期刊：
Molecular endocrinology (Baltimore, Md.)
影响因子：
--
作者：
Wadekar,SubhagyaA;Li,Dapei;Sánchez,EdwinR
通讯作者：
Sánchez,EdwinR
DOI：
10.1016/s0021-9258(18)48448-7
发表时间：
1992-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
E. R. Sánchez
通讯作者：
E. R. Sánchez
库欣病先于全身糖皮质激素抵抗：新型显性失活糖皮质激素受体突变的临床后果。
DOI：
--
发表时间：
1996
期刊：
Proceedings of the Association of American Physicians
影响因子：
--
作者：
M. Karl;S. Lamberts;J. Koper;D. Katz;N. Huizenga;T. Kino;B. Haddad;M. Hughes;G. Chrousos
通讯作者：
G. Chrousos
影响因子：
5.3
作者：
Galliher-Beckley, Amy Jo;Williams, Jason Grant;Cidlowski, John Anthony
通讯作者：
Cidlowski, John Anthony