Regulation by Progestins, Corticosteroids, and RU486 of Transcriptional Activation of Elephant Shark and Human Progesterone Receptors: An Evolutionary Perspective
Regulation by Progestins, Corticosteroids, and RU486 of Transcriptional Activation of Elephant Shark and Human Progesterone Receptors: An Evolutionary Perspective
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孕激素、皮质类固醇和 RU486 对象鲨和人类孕酮受体转录激活的调节：进化视角
DOI：
10.1021/acsptsci.1c00191
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Baker Michael E.
中科院分区：
文献类型：
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作者：
Lin Xiaozhi;Takagi Wataru;Hyodo Susumu;Ijiri Shigeho;Katsu Yoshinao;Baker Michael E.
我们研究了象鲨中黄体酮受体（PR）的黄体酮和皮质类固醇激活，象鲨是一种属于最古老的颌脊椎动物群的软骨鱼。与人类PR的比较揭示了人类PR的类固醇激活演化。在1 nM的类固醇下，象鲨PR被黄体酮、17-羟基黄体酮、20β-羟基黄体酮、11-脱氧皮质酮（21-羟基黄体酮）和11-脱氧皮质醇激活。相比而言，人类PR在1 nM类固醇激活，仅被黄体酮和11-脱氧皮质酮激活，表明人类PR在进化过程中增加了黄体酮和皮质类固醇的特异性。人类PR的重要临床拮抗剂RU486没有抑制象鲨PR的黄体酮激活，象鲨PR中的Cys-528与人类PR中的Gly-722相对应。证实了Cys-528在象鲨PR中的重要性，RU486抑制了Cys528Gly突变体PR的孕酮激活。为了研究gys -722在人PR和Cys-528在象鲨PR中的生理相关性，我们研究了Gly722Cys人PR和Cys528Gly象鲨PR的类固醇激活。11-脱氧皮质醇对人类Gly722Cys PR的激活增加，而皮质酮的激活减少，这可能在选择与人类甘氨酸-722 PR相对应的突变时很重要，这种突变首先在鸭嘴兽PR中进化出来，一种基础哺乳动物。
We investigated progestin and corticosteroid activation of the progesterone receptor (PR) from elephant shark, a cartilaginous fish belonging to the oldest group of jawed vertebrates. Comparison with the human PR provides insights into the evolution of steroid activation of the human PR. At 1 nM steroid, the elephant shark PR is activated by progesterone, 17-hydroxy-progesterone, 20β-hydroxy-progesterone, 11-deoxycorticosterone (21-hydroxyprogesterone), and 11-deoxycortisol. The human PR, in comparison, is activated at 1 nM steroid, only by progesterone and 11-deoxycorticosterone, indicating increased progestin and corticosteroid specificity during the evolution of the human PR. RU486, an important clinical antagonist of the human PR, did not inhibit progesterone activation of the elephant shark PR. Cys-528 in the elephant shark PR corresponds to Gly-722 in the human PR, which is essential for RU486 inhibition of the human PR. Confirming the importance of Cys-528 in the elephant shark PR, RU486 inhibited progesterone activation of the Cys528Gly mutant PR. To investigate the physiological relevance of Gly-722 in the human PR and Cys-528 in the elephant shark PR, we studied steroid activation of the Gly722Cys human PR and Cys528Gly elephant shark PR. Compared to the wild-type human PR, there was an increase in the activation of human Gly722Cys PR by11-deoxycortisol and a decrease in activation by corticosterone, which may have been important in selection for the mutation corresponding to the human glycine-722 PR that first evolved in the platypus PR, a basal mammal.