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Nuclear receptor coregulators: modulators of pathology and therapeutic targets

Abstract

The nuclear receptor superfamily includes transcription factors that transduce steroid, thyroid and retinoid hormones and other ligands in conjunction with coregulators. To date, over 350 coregulators have been reported in the literature, and advances in proteomic analyses of coregulator protein complexes have revealed that a far greater number of coregulator-interacting proteins also exist. Coregulator dysfunction has been implicated in diverse pathological states, genetic syndromes and cancer. A hallmark of disease related to the disruption of normal coregulator function is the pleiotropic effect on animal physiology, which is frequently manifested as the dysregulation of metabolic and neurological systems. Coregulators have broad physiological and pathological functions that make them promising new drug targets for diseases such as hormone-dependent cancers. Advances in proteomics, genomics and transcriptomics have provided novel insights into the biology of coregulators at a system-wide level and will lead the way to a new understanding of how coregulators can be evaluated in the context of complex and multifaceted genetic factors, hormones, diet, the environment and stress. Ultimately, better knowledge of the associations that exist between coregulator function and human diseases is expected to expand the indications for the use of future coregulator-targeted drugs.

Key Points

  • Coregulators interact with nuclear receptors and other transcription factors to alter chromatin and stimulate (coactivators) or repress (corepressors) gene expression

  • Over 350 coregulators have been identified in the literature, but proteomic studies indicate that this number is a gross underestimate

  • Many coregulators have been implicated in the physiology of reproduction, energy metabolism, inherited human genetic diseases and cancer

  • Coregulators are receiving increasing attention as important drug targets for diseases including cancer, inflammatory disorders and genetic syndromes related to their dysfunction

  • Proteomic, genomic and transcriptomic characterization of coregulators will enable their physiological and pathological roles to be better realized in the context of diverse endocrine, environmental, dietary and stress conditions

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Figure 1: Coregulator-targeted drugs are predicted to overcome cancer cell resistance to chemotherapy.

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Lonard, D., O'Malley, B. Nuclear receptor coregulators: modulators of pathology and therapeutic targets. Nat Rev Endocrinol 8, 598–604 (2012). https://doi.org/10.1038/nrendo.2012.100

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