Transcriptional coregulators: emerging roles of SRC family of coactivators in disease pathology

Abstract

Transcriptional coactivators have evolved as an important new class of functional proteins that participate with virtually all transcription factors and nuclear receptors (NRs) to intricately regulate gene expression in response to a wide variety of environmental cues. Recent findings have highlighted that coactivators are important for almost all biological functions, and consequently, genetic defects can lead to severe pathologies. Drug discovery efforts targeting coactivators may prove valuable for treatment of a variety of diseases.

Keywords: hormone receptors; nuclear receptors; transcription; transcription factors.

Figure 1

(A) Coactivator dependent complex assembly and regulation of gene transcription. Upon hormone (H) binding, the nuclear receptors (NR) interact with steroid receptor coactivators (SRC) and recruit them to the enhancer region of target genes. SRC coactivators then interact with co-activator-associated arginine methyl transferase 1 (CARM1), cyclic AMP response element-binding protein (CBP), p300 (a 300 kDa protein homologous to CBP; also known as EP300), mediator complex (MED1) and recruit other common co-coactivators (CoCoAs) to remodel the chromatin and build up the activated transcription complex. Post-translational modifications (PTM) on SRCs such as phosphorylation (P), acetylation (Ac), and methylation (Me) also regulate the coactivator complex association, and modulate the assembly of general transcription factors such as TBP (TATA-binding protein) and TAF (TBP-associated general transcription factors) along with RNA polymerase II (Pol II). (b) Schematic representation of the molecular structural domains and a comprehensive map of known PTM codes on SRC-3 along with the type of modifications, residues modified, and enzymes imparting the code.

Figure 2

Coactivator dependent signaling regulates various biological functions, and deregulation causes diseases. Several extracellular stimuli such as growth factors- EGF (epidermal growth factor) and IGF (insulin-like growth factors); cytokines- IL-6 (interlukein-6) and TNFα (tumor necrosis factor-α) and steroid hormones trigger downstream signaling pathway activating coactivator-dependent complex assembly. In addition, alterations in the energy status (ATP/ADP ratio), nutrient signaling, and cellular stress can also promote coactivator recruitment on target gene promoters. Coactivators such as steroid receptor activators (SRCs) then bind to nuclear receptors (NRs) or several other transcription factors to stimulate gene transcription. This coactivator dependent gene activation is highly selective, and intricately regulated by several mechanisms (described in the text) stimulating specific cellular functions. In contrast, deregulated expression and activation of coactivators lead to perturbed signaling pathway resulting in disease pathology.

Figure 3

Graphical representation of percentage of copy number alteration (CNA) frequency of Steroid receptor coactivators (SRC-1, SRC-2 and SRC-3) across different types of cancer. Data represents various types of alterations including gene amplification, mutation, and deletion. Data generated using TCGA datasets from cBIOPortal [Cerami et al. Cancer Discov. 2012 & Gao et al. Sci. Signal. 2013.]