Butt T R, Karathanasis S K
Department of Molecular Virology and Host Defense, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939, USA.
Gene Expr. 1995;4(6):319-36.
Many traditional drugs target cell surface receptors. Medicinal chemists and pharmacologists have not ventured into the field of transcription regulation due to the fear that drugs that interfere with transcription regulation may not be selective or efficacious. The past 5 years have seen some exciting developments in the field of signal transduction in general, and transcription regulation in particular. Our understanding of mechanisms of regulated and basal transcription is advanced to a degree that it should be possible to selectively modulate a target gene directly. In this review we have argued that sufficient diversity exists in the combinatorial interplay of the transcription factors to offer opportunities for selective therapeutic intervention. We have focused our attention on transcriptional factors that play a role in three different therapeutic areas: osteoporosis, immune modulation, and cardiovascular diseases. Human estrogen receptor is considered as a model transcription factor. The role of estrogen in bone remodeling is discussed. Opportunities for tissue-specific modulation of estrogen receptors are described. For selective immune modulation, we have discussed the role of NF-AT (nuclear factors for activated T cells) transcription factors in interleukin-2 gene regulation. The last section focuses on the transcriptional mechanisms conferring tissue specificity in regulated expression of the apoAI gene, a major component of HDL, in liver. We have highlighted opportunities for rational development of transcription-based drugs useful for raising HDL plasma levels and atherosclerosis prevention.
许多传统药物作用于细胞表面受体。药物化学家和药理学家一直未涉足转录调控领域，因为担心干扰转录调控的药物可能缺乏选择性或疗效不佳。总体而言，过去5年信号转导领域，尤其是转录调控领域取得了一些令人振奋的进展。我们对调控转录和基础转录机制的理解已经达到了一定程度，使得直接选择性地调节靶基因成为可能。在这篇综述中，我们认为转录因子的组合相互作用中存在足够的多样性，为选择性治疗干预提供了机会。我们将注意力集中在参与三个不同治疗领域的转录因子上：骨质疏松症、免疫调节和心血管疾病。人类雌激素受体被视为一种典型的转录因子。讨论了雌激素在骨重塑中的作用。描述了组织特异性调节雌激素受体的机会。对于选择性免疫调节，我们讨论了活化T细胞核因子（NF-AT）转录因子在白细胞介素-2基因调控中的作用。最后一部分重点关注在肝脏中调控载脂蛋白AI（HDL的主要成分）基因表达时赋予组织特异性的转录机制。我们强调了合理开发基于转录的药物以提高血浆HDL水平和预防动脉粥样硬化的机会。
