Intracellular receptors and signal transducers and activators of transcription superfamilies : novel targets for small-molecule drug discovery

• Published in: Journal of medicinal chemistry Vol. 38; no. 25; pp. 4855 - 4874
• Main Authors: ROSEN, J, DAY, A, JONES, T. K, JONES, E. T. T, NADZAN, A. M, STEIN, R. B
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 08-12-1995
• Subjects: Base Sequence; Biological and medical sciences; DNA; Gene Expression Regulation; General pharmacology; Humans; Medical sciences; Miscellaneous; Molecular Sequence Data; Pharmacology. Drug treatments; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction; Structure-Activity Relationship; Transcription Factors - metabolism; Transcription, Genetic; Agonist; Androgen; Transcription; Steroid hormone; Cytokine; Estrogen; Review; Retinol; Signal transduction; Perspective; Antagonist; Intracellular; Progesterone; Sex steroid hormone; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00025a001

The proliferation and differentiation of mammalian cells is modulated by a number of specific signal molecules that regulate gene expression. Among these signals are (i) the steroid hormones (e.g., glucocorticoids, mineralocorticoids, estrogens, progestins, and androgens), chemical messengers produced by the body in response to a variety of stimuli; (ii) small-molecule hormones including thyroid hormone, calcitriol (a vitamin D sub(3) metabolite), and the retinoids; and (iii) the cytokine superfamily of protein molecules that affect cells of the immune and other systems. The definition of biochemical events that mediate signal transduction in response to steroid hormones and small-molecule hormones has advanced rapidly, beginning in 1985 with the first cloning of an intracellular receptor (IR). Molecular biological techniques enabled subsequent cloning and characterization of receptors for each of the steroid and small-molecule hormones. This dramatically enhanced understanding of hormone action and led to a number of unifying insights concerning the receptors and their ligands. The IRs are closely related members of a protein superfamily that have apparently diverged from a common ancestral gene. The presence of a specific IR within a cell enables that cell to respond to the hormone cognate to that IR. The IRs share a common mechanism of action, since they in general remain latent inside target cells until exposed to their specific ligands, which activate them as transcription factors producing specific changes in gene expression. Cytokines are a large and diverse family of circulating polypeptides produced by many different cell types. The understanding of the biochemical events by which some of the cytokines achieve their distinctive biological effects has increased significantly since 1992. There is a surprising degree of underlying similarity in the pathways of cytokine signal transduction, explained by the discovery of a family of latent cytosolic proteins, termed signal transducers and activators of transcription (STATs), that mediate signal transduction for the majority of the cytokines. This newly defined STAT protein superfamily acts to mediate specific changes in gene expression and consequently cell function following exposure to most cytokines.