Intracellular glucocorticoid signaling: a formerly simple system turns stochastic.
Intracellular glucocorticoid signaling: a formerly simple system turns stochastic.
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DOI：
10.1126/stke.3042005pe48
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发表时间：
2005-10-04
期刊：
影响因子：
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通讯作者：
Kino, Tomoshige
中科院分区：
文献类型：
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作者：
Chrousos, George P;Kino, Tomoshige
糖皮质激素对维持所有高等生物的基础和应激相关的体内平衡起着重要作用。这些类固醇在生理学上的主要作用与它们在病理学上的显著贡献完全匹配。糖皮质激素影响约20%的人类基因组表达，其作用几乎不影响任何器官或组织。多年来，我们认为糖皮质激素的许多作用是由单一受体分子介导的：经典的糖皮质激素受体（GR）异构体α，一种复杂的多功能结构域蛋白，作为配体依赖的转录因子。然而，GR基因通过两个不同的末端外显子（9alpha和9beta）编码两个3'剪接变体GRalpha和GRbeta，每个变体mRNA从至少8个起始位点翻译成多个GRalpha和可能的GRbeta亚型，总计至少16个GR单体和256个不同的同源或异源二聚体。翻译的grα亚型可能在靶组织中产生变化，具有不同的内在转录活性，并影响糖皮质激素应答基因的不同补体。可能在假定的GRbeta翻译异构体之间也存在表达和功能差异。不同数量的多个GR单体和二聚体的存在以及在数量和质量上不同的转录活性表明糖皮质激素信号系统具有高度的随机性。
Glucocorticoids contribute fundamentally to the maintenance of basal and stress-related homeostasis in all higher organisms. The major roles of these steroids in physiology are amply matched by their remarkable contributions to pathology. Glucocorticoids influence about 20% of the expressed human genome, and their effects spare almost no organs or tissues. For many years we thought that the numerous actions of glucocorticoids were mediated by a single receptor molecule: the classic glucocorticoid receptor (GR) isoform alpha, a complex, multifunctional domain protein, operating as a ligand-dependent transcription factor. The GR gene, however, encodes two 3' splicing variants, GRalpha and GRbeta, from alternative use of two distinct terminal exons (9alpha and 9beta), and each variant mRNA is translated from at least eight initiation sites into multiple GRalpha and possibly GRbeta isoforms, amounting to a minimum of 16 GR monomers and 256 different homo- or heterodimers. The translational GRalpha isoforms may be produced variably in target tissues, have varying intrinsic transcriptional activities, and influence different complements of glucocorticoid-responsive genes. It is likely that expression and functional differences might also be present between the putative GRbeta translational isoforms. The presence of multiple GR monomers and dimers in different quantities with quantitatively and qualitatively different transcriptional activities suggests that the glucocorticoid signaling system is highly stochastic.