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.
Historical perspective
Transcriptional coactivators are defined, broadly, as the family of coregulator molecules that interact with nuclear receptors and other transcription factors to enhance the rate of gene transcription. The existence of coactivator-like proteins was predicted in early 1970s, as some nuclear, nonhistone receptor-associated proteins were found to bind nuclear receptors and increase their interaction with DNA to enhance their transcription potential (Spelsberg et al. 1971). This crude fraction was later shown to contain many diverse coactivators; a large number of such proteins were unpredicted at the time and prevented purification. Although it was clear that steroid hormones such as estrogen can rapidly induce the new synthesis of specific mRNA and proteins (Means et al. 1972), the importance of these nuclear acceptor molecules in ligand-dependent functions was postulated to enhance nuclear receptor (NR) transcription but the concept was not proven (Yamamoto & Alberts 1975). In the interim, a series of sophisticated molecular studies unfolded, which indicated that ligand binding activates conformational changes in the steroid receptor to promote DNA-binding and transcriptional activity; anti-hormones were shown to effectively oppose such structural alterations (Allan et al. 1992). In addition to ligand-dependent functions, the steroid receptors were also found to be activated in a ligand-independent manner (Denner et al. 1990, Power et al. 1991).
In the 1990s, studies designed to elucidate the functional roles of the corepressors and coactivators were commenced again, initially in yeast (McDonnell et al. 1991a,b, Baniahmad et al. 1993). An inherent negative regulatory function for the steroid receptors was identified in steroid receptors themselves and was analyzed first in yeasts by demonstrating binding of steroid receptors to repressors such as SSN6, which when mutated allowed receptor activation of gene expression (McDonnell et al. 1992, Vegeto et al. 1992). Similar yeast studies were carried out to demonstrate ligand-mediated coactivation. These proof-of-principle yeast studies led to the definition of two classes of coregulators – coactivators and corepressors – and were followed by the biochemical discovery of a corepressor activity for TR in mammalian cells and the publications of other receptor-associated proteins in mammals (Cavailles et al. 1994, Halachmi et al. 1994, Baniahmad et al. 1995a,b). In aggregate, these studies set the stage for the first cloning of a cDNA encoding a mammalian nuclear receptor-interacting coactivator protein. This first authentic NR coactivator, termed steroid receptor coactivator 1 (SRC-1 (NCOA1)), was identified using yeast two-hybrid genetic screening employing the ligand-binding domain of the progesterone receptor (Onate et al. 1995, Xu et al. 1998). SRC-1 was the first member of the p160 family of coactivators cloned, following which two additional family members SRC-2 (NCOA2/GRIP1/TIF2; Voegel et al. 1996) and SRC-3 (NCOA3/ACTR/pCIP; Chen et al. 1997, Torchia et al. 1997) were identified. The p160 family members are closely related molecules with ∼60% homology, but are functionally distinct. In addition to the full-length SRCs, some shorter forms of SRCs were identified as well. SRC-3Δ4 is a splice isoform of SRC-3 with a deletion of exon 4 (SRC-3Δ4) and the protein lacks the N-terminal helix–loop–helix (bHLH) domain that contains a nuclear localization signal (Reiter et al. 2001, Long et al. 2010). More recently, a shorter 70 kDa isoform of SRC-1 has been identified and found to be highly elevated in human and mouse endometriotic tissues (Han et al. 2012). This 70 kDa isoform of SRC-1 is the C-terminal fragment of the full-length SRC-1, which is proteolytically cleaved by MMP9. Over the last two decades, we gained considerable knowledge about the coactivators and their impact on human health and physiology. These findings together classified a novel family of nuclear receptor coactivators that became known as the master regulators of gene regulation.
Coactivator complexome
After the discovery of the first authentic coactivator SRC-1, it was predicted that cells may have approximately five to ten coactivators and few corepressors to regulate the gene transcription. Surprisingly, more than 400 coregulators have been reported so far, substantiating their prevalent and critical role in transcriptional regulation (Lonard & O'Malley 2007). Molecular analyses by mass spectrometry identified that SRCs work in tandem with other coregulators in close association by forming large multi-subunit stable complexes. This proteomics information concerning a coactivator–protein complex also known as ‘complexome’ – identified that the complexes are in a dynamic rearrangement in an ordered manner to facilitate various reactions and subreactions in transcription. These reactions include phosphorylation, ubiquitination, methylation, and acetylation of the associated molecules in the coactivator complex, which further defines the specific affinity of the coactivators for NRs, transcription factors, and other associated molecules (Han et al. 2009). This multifunctional component of the coactivator complexome allows them to integrate different upstream environmental stimuli and to transmit to a variety of enzymatic activities at the promoter for regulating transcription.
Proteomic investigations identified the dynamic nature of a SRC-3 complex assembled on estrogen response element (ERE) in a ligand-dependent manner (Fig. 1A). The SRC-3 complex consists of several interacting partners with enzymatic activities, which include kinases, ATPases, acetyl transferases, methyl transferases as well as ubiquitin ligases, all of which contribute to the dynamic functions of the coactivators (Malovannaya et al. 2010). Recent studies on coregulator dynamics have identified some novel mechanisms for ER-regulated gene transcription, and the findings postulated a ‘three-state model’ of coactivator-dependent complex formation (Foulds et al. 2013). In the first step, ligand-bound ER on canonical EREs forms a biochemically stable ‘poised’ complex by attracting a set of coactivators and certain corepressors. Addition of ATP rapidly converts these complexes into an ‘activated’ state by the kinetic activity of DNA-dependent protein kinase (DNA-PK), which mediates phosphorylation events on coactivators and ER. Finally, DNA-PK promotes ERα-mediated transcription by phosphorylating coactivators SRC-3 and MED1 as well as dismissing corepressors RIP140 from the complex (Foulds et al. 2013). These studies unravel the dynamic events mediated by kinases on a coactivator complexome to fine-tune transcription.
(A) Coactivator-dependent complex assembly and regulation of gene transcription. Upon hormone (H) binding, the nuclear receptors (NRs) interact with steroid receptor coactivators (SRCs) and recruit them to the enhancer region of target genes. SRCs then interact with coactivator-associated arginine methyltransferase 1 (CARM1), cAMP response element-binding protein (CBP), p300 (a 300 kDa protein homologous to CBP; also known as EP300), and mediator complex (MED1) and recruit other common co-coactivators (CoCoAs) to remodel the chromatin and build up the activated transcription complex. Post-translational modifications (PTMs) 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 TATA-binding protein (TBP) and TAF (TBP-associated general transcription factors) along with RNA polymerase II (PolII). (B) Schematic 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.
Citation: Journal of Molecular Endocrinology 53, 2; 10.1530/JME-14-0080
Integrated mass spectrometry-based analysis of affinity-purified endogenous coregulator complexes identified a hierarchical organization of protein complexes, which exists as three discrete layers in an intrinsically tiered organization of the complexome (Malovannaya et al. 2011). These include relatively stable minimal endogenous core modules; these combine to form the variable core complex isoforms; finally, coregulator complex–complex interactions form networks. Based on the type of protein complexes formed, the coregulators can be broadly classified into two major types: type 1 represents relatively stable multi-subunit complexes consisting of conserved coactivator molecules, whereas type 2 represents context-dependent coactivators that are recruited in response to various extra-cellular stimuli (Malovannaya et al. 2011). Type 1 coregulators include mediators, corepressor–repressor element 1-silencing transcription factor (CoREST) complexes, nuclear receptor corepressors (NCOR), nucleosome remodeling and deacetylation (NuRD) complexes, and the SWI/SNF (BAF/P-BAF), whereas SRCs are prime examples of type 2 complexes. This dynamic regulation of coactivator complex assembly by the SRCs is in turn regulated by various upstream signaling events that impart post-translational modifications (PTMs) onto the coactivators (Dasgupta et al. 2014).
Signal-specific PTM codes on SRCs
The molecular recognition of the activity of SRCs depends upon the PTM codes on them. Phosphorylation, acetylation, sumoylation, ubiquitination, and methylation of the SRCs (Fig. 1B) intricately coordinate and fine-tune their activity, localization, and protein stability and dictate the interacting partner molecules used to build up the complexome.
Phosphorylation
In response to multiple upstream signaling events such as growth factor, cytokine, hormone, and nutrient signaling, PKs phosphorylate SRCs either at a single site or at multiple sites. Depending on the pattern of the phosphorylation code(s) on SRCs, they attract selective binding partners, nuclear receptors or transcription factors along with other coregulator molecules to regulate the gene transcription. In addition to exerting effects on the nuclear genome by binding directly to the NRs, steroid hormones also activate several kinases such as MAPK, JNK, AKT, and ERK1/2, which then phosphorylate NRs and coactivators to stimulate gene transcription by non-genomic signaling (Lonard & O'Malley 2007). Steroid hormone signaling phosphorylates SRC-3 at multiple residues including N-terminal Thr24, several sites in a serine/threonine-rich region, and Ser857, Ser860, and Ser867 in the receptor-interacting domain (RID; Wu et al. 2004, Yi et al. 2005, 2008, Long et al. 2012). Similarly, SRC-1 is phosphorylated on Thr1179 and Ser1185, and SRC-2 on Ser736 by MAPK, thereby increasing coactivator's affinity to NRs (Rowan et al. 2000, Gregory et al. 2004). SRC-2 has emerged as a major coactivator for glucocorticoid receptor (GR) and certain phosphorylation events on SRC-2 by casein kinase (CK) and cyclin-dependent kinase 9 dictate GR actions (Dobrovolna et al. 2012). Four major phosphorylation sites Ser469, Ser487, Ser493, and Ser499 in the N-terminal domain of SRC-2 protein promote GR-dependent transcription by facilitating recruitment of coactivator complex to native GR targets (Dobrovolna et al. 2012). SRC-3Δ4, the splicing variant of SRC-3, also is regulated by phosphorylation. But instead of a direct role in nuclear transcription, the SRC-3Δ4 is localized to the cytosol and is phosphorylated by PAK kinase, whereupon it then binds to epidermal growth factor receptor (EGFR) and transduces activity to focal adhesion kinase (FAK). Thus, phosphorylated SRC-3Δ4 acts as a critical signaling molecule to regulate the migratory potential of tumor cells by bridging the gap between EGFR and FAK (Long et al. 2010). In summary, coactivators are molecular integrators of upstream signaling events, and phospho-coded SRCs direct assembly of specific interacting partners for gene transcription.
Acetylation and methylation
Histone acetylases and deacetylases, along with methylases and demethylases, are essential components of coactivator complexes responsible for modifying chromatin. Based on their function of adding or removing histone marks, they are classified as epigenetic ‘writers’ or ‘erasers’. A number of co-coactivators including CREBBP (p300/CBP), GCN5 (KAT2A), and PCAF (KAT2B) possess intrinsic histone acetyltransferase (HAT) activity (Couture & Trievel 2006). SRCs recruit the HATs and methyl transferases such as peptidylarginine methyltransferases to remodel chromatin and regulate gene transcription. Additionally, a coactivator such as SRC-3 is in turn acetylated by p300/CBP and methylated by coactivator-associated arginine methyltransferase 1 (CARM1) at Arg1171 (Feng et al. 2006). Acetylation of SRC-3 by CBP coincides with the attenuation of hormone-induced gene transcription by enforcing the complex disassembly (Chen et al. 1997, 1999). Mechanistically, acetylation neutralizes the positive charges of two lysine residues adjacent to the ‘LXLLL’ motif of SRC-3, thereby disrupting the association of HAT complexes with the NR coactivator complex and terminating the gene transcription (Chen et al. 1999). CARM1, which activates transcription by modifying core histone tails, also promotes dissociation of coactivator complex and terminates hormone-induced transcription by methylating SRC-3 (Feng et al. 2006). In addition to the acetylases, the family of lysine deacetylases, histone deacetylases (HDACs), and sirtuin proteins also regulate gene transcription as coregulators (Lahue & Frizzell 2012). HDACs are recruited to the coregulator complex to repress gene transcription, in particular by corepressors such as NCoR. There are two classes of HDACs, classes I and IIa, the latter being relatively weak in enzymatic activity. Additionally, sirtuins, the NAD-dependent deacetylases, are also recruited to the coregulator complex and are known to modulate gene transcription.
Ubiquitination and sumoylation
Activity and stability of coactivators are regulated by ubiquitination, an enzymatic process in which 8.5 kDa small molecules named ubiquitin are systematically added by E3 ubiquitin ligase. Ubiquitination is a highly regulated process, and phosphorylation on coactivators acts as a priming event for this modification by increasing their affinity toward ubiquitin E3 ubiquitin ligase. Phosphorylation by GSK3β on SRC-3-Ser505 increases coactivator's affinity toward Fbw7α, a component of E3-ligase complex which then ubiquitinates SRC-3 on Lys723 and Lys786 (Lonard & O'Malley 2007, Wu et al. 2007). Mono-ubiquitinated SRC-3 has a higher affinity for ERα and stimulates ERα-dependent gene transcription, whereas poly-ubiquitinated SRC-3 is rapidly degraded, thereby decreasing SRC-3 protein stability. SRC-3 protein stability and activity are also regulated by specific phosphorylation codes that induce degradation of the protein known as ‘phospho-degron’ in the N-terminal domain of the protein; phosphorylation of Ser102 in the degron by CKI increases coactivator's affinity for speckle-type POZ protein (SPOP)-E3 ligase (Li et al. 2008). On the contrary, certain mutations in the SPOP protein alter the affinity of SPOP for SRC-3 imposing a SPOP-dependent regulation of SRC-3 activity and gene transcription (Geng et al. 2013). Similarly, CUL3, a member of the family of E3-ligase scaffolding proteins also modulates SRC-3 activity by binding to the Ser860-phosphorylated SRC-3 in response to retinoic acid induction (Ferry et al. 2011). Thus, PTMs on SRC-3 by phosphorylation-coupled ubiquitination modulate the activity and stability of the coactivator to control the dynamics of transcription.
In addition to ubiquitination, covalent modifications by addition of a small ubiquitin-like modifier (SUMO) to the lysine residues of the coactivators have been identified. SRCs are subjected to sumoylation at two conserved lysine residues in the RID motif, which functionally enhance their interaction and affinity for NRs (Wu et al. 2006). However, sumoylations of SRC-3 on Lys723 and Lys786 were found to have a negative impact on its activity, most probably due to the competitive inhibition of ubiquitination in these sites. Nevertheless, sumoylation of coactivators provides another degree of dynamic regulation to monitor and manipulate gene transcription.
Coactivators in disease pathophysiology
Coactivators have emerged as cellular integrators of various upstream signaling pathways that transduce these signals into transcriptional outputs to regulate expression of myriad gene targets (Fig. 2). Hence, dysfunctions in coregulators are principal drivers of numerous pathologies (Lonard & O'Malley 2012). Herein, we will highlight selected examples of the clinicopathological conditions affected by the transcriptional coactivators.
Coactivator-dependent signaling regulates various biological functions, and deregulation causes diseases. Several extracellular stimuli such as growth factors epidermal growth factor (EGF) and insulin-like growth factors (IGFs), cytokines interleukin 6 (IL6) and tumor necrosis factor alpha (TNFα), 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 coactivators (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. By contrast, deregulated expression and activation of coactivators lead to a perturbed signaling pathway resulting in disease pathology.
Citation: Journal of Molecular Endocrinology 53, 2; 10.1530/JME-14-0080
Neurological disorders
Mutations in certain coregulator genes alter the epigenetic marks on chromosomes, affecting brain development and promoting onset of certain neurodevelopmental disorders (Urdinguio et al. 2009). These epigenetic dysfunctions cause moderate to severe perturbations in the transcriptomics, disrupting the neuronal growth and differentiation. Mutations in the chromatin remodeling protein ATRX (ATP-dependent helicase ATRX, X-linked helicase II) confer aberrant DNA methylating patterns in the chromatin leading to a neurodegenerative disorder named ATRX syndrome (Gibbons et al. 2008). This syndrome is an X-linked disorder confined only to the males while the female carriers manifest limited symptoms. Symptoms include mental retardation often accompanied with α-thalassemia, unusual facial appearance and urogenital defects (Gibbons et al. 1995). ATRX is a member of the Snf2 family of enzymes, which maintains nucleosome stability and regulates gene transcription by modulating the functions of chromatin remodeling transcriptional regulators, such as the polycomb-group protein EZH2 (Eisen et al. 1995). Patients with ATRX syndrome have severely compromised genetic defects due to mutated ATRX gene.
Rubinstein–Taybi syndrome (RTS) is another example of a neurological disorder associated with the dysfunction of HAT. The majority of the Rubinstein–Taybi cases are associated with mutations in the CBP gene located at chromosome 16p13.3 and some in the E1A-binding protein p300 (EP300) gene at chromosome 22q13.2 (Lonard & O'Malley 2012). In 1963, Jack Herbert Rubinstein and Hooshang Taybi described a series of cases with this syndrome demonstrating some typical features that include mental disability, distinctive facial features, and broad thumbs and toes, and are often associated with cryptorchidism in males. This disease is rare and approximately one out of 100 000–125 000 children are born with this disorder. CBP is a transcriptional coactivator that has intrinsic HAT activity and binds to the transcription factor cAMP response element-binding protein (CREB) to regulate gene transcription (Park et al. 2014). Mutation or deletion in the CBP gene severely affects HAT activity of CBP and the ability of CBP to transactivate CREB, indicating that loss of the HAT activity of CBP may cause RTS.
In Huntington's disease, transcriptional coactivator PGC1α (PPARGC1A) expression is severely impaired, and mouse genetic studies revealed that loss of PGC1α severely impairs metabolism and accentuates neurodegeneration. Huntington's disease is an autosomal dominant disorder characterized by impaired muscle coordination that leads to cognitive malfunctioning and psychiatric problems. PGC1α is a potent suppressor of reactive oxygen species (ROS) by activating the transcription of ROS defense enzymes such as superoxide dismutase 1 (SOD1), manganese SOD (SOD2), catalase, and glutathione peroxidase (Chaturvedi et al. 2009). In absence of PGC1α coactivator, the neuronal cells are extremely sensitive and vulnerable to neurotoxins leading to apoptotic death of neuronal cells and oxidative damage in the brain.
Studies using SRC knockout animals identified important roles for nuclear receptor coactivators in the coordination of neurobehavioral functions and brain development. SRC-1 is ubiquitously expressed in the human brain with more prominent presence in hippocampus, olfactory bulbs, and cortex (Meijer et al. 2000). SRC-1 is a crucial regulator of sexually dimorphic regions in the brain and coactivates GR functions to coordinate the hypothalamic–pituitary–adrenal axis of the brain. Neurobehavioral tests on Src-1−/− animals compared with WT littermates discovered some novel roles of SRC-1 in anxiety response (Stashi et al. 2013). In comparison, Src-2−/− females displayed decreased anxiety responses under certain environmental stimuli, whereas males were found to have deficits in sensorimotor gating, a neurological process which is important to understand the functional significance of attentional abnormalities. By contrast, Src-3−/− males were devoid of any noticeable neurological abnormalities; however, the females exhibit reduced exploratory activities and increased anxiety behavior (Stashi et al. 2013). Collectively, these findings establish the role of SRCs in the regulation of the CNS and coordination of neurobehavioral phenotypes in a gender-specific manner.
Cardiac development and disease
Transcriptional coactivators can play an essential role in cardiac development by regulating the mitochondrial response of the heart by broadly regulating gene expression from both nuclear and mitochondrial genomes. PGC1 has been extensively studied with respect to cardiac development and bioenergetics of the heart, and its expression was found to be repressed in numerous models of heart failure with a maladaptive energetic profile (Rowe et al. 2010). PGC1α induces expression of numerous genes in cardiac cells regulating major metabolic pathways to maintain a steady supply of ATP production. Genes induced by PGC1α include the majority of mitochondrial respiratory subunits, ATPase complexes, enzymes of fatty acid biosynthesis and transport, and key enzymes of the glycolytic and tricarboxylic acid cycle (TCA; Banke et al. 2010). In addition to metabolic pathways, PGC1α induces angiogenesis in myocytes by directly activating a broad range of angiogenic factors including vascular endothelial growth factor (VEGF) independent of the hypoxia-inducible factor pathway (Arany et al. 2008). Overexpressing PGC1α in the heart identified univocal roles of the coactivator in mitochondrial biogenesis (Lehman et al. 2000). PGC1α activates both mitochondrial as well as nuclear genes by directly transactivating transcription factors such as nuclear respiratory factor (NRF) and estrogen-related receptor (ERR) (Hock & Kralli 2009). These findings have clearly placed PGC1 as a prime regulator of metabolism in the heart, in both cardiomyocytes and cardiac cells.
In addition to PGC1, expression of coactivator SRC-2 is found to be repressed in failing hearts. Genetic ablation of Src-2 identified activation of a ‘fetal gene program’ in adult mice by altering the expression of metabolic and sarcomeric genes (Reineke et al. 2012). Mechanistically, Src-2 depletion reduces the expression of several transcription factors such as GATA as well as coactivators such as PGC1α, indicating that SRC-2 is a prime regulator of the steady-state adult cardiac transcriptomic profile (Reineke et al. 2012). These studies have deciphered the importance of coactivators in cardiac functioning and how subtle changes in their expression can lead to catastrophic medical conditions.
Inflammatory diseases
The most common lung diseases including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and acute respiratory distress involve inflammatory responses coordinated by expression of multiple proinflammatory genes. Several transcriptional coactivators have been linked as the molecular regulators of inflammatory responses, of which HDACs deserve special mention (Barnes et al. 2005). Patients with asthma exhibit increased expression of HAT with simultaneous reduction in HDAC1 level in the bronchial and alveolar macrophages compared with normal airways (Cosio et al. 2004). In patients with COPD, there is a significant decrease in HDAC2 expression with a concomitant increase in HAT activity facilitating activation of NFκB and transcription of proinflammatory cytokines (Qu et al. 2013). The alveolar macrophages in COPD patients display increased release of tumor necrosis factor alpha (TNFα) and interleukin 8 (IL8) in response to stimuli, thus contributing to the adversity of the pathology. Traditional therapy includes corticosteroids that effectively suppress the transcription of proinflammatory genes by inhibiting NFκB and AP1 transcription factors (Barnes 2013).
The transcriptional coactivator SRC-3 acts as a protective factor against acute inflammatory response by repressing translation of inflammatory cytokines. Src-3−/− animals are more susceptible to endotoxic shock compared with their WT littermates with enhanced levels of proinflammatory cytokines including TNFα, IL6, and IL1β (Yu et al. 2007). Thus, it is sufficient to conclude that expression of coactivators delicately balances the inflammatory responses by modulating expression of ILs and cytokines.
Metabolic disorders and circadian biology
Coactivators are essential coordinators of whole-body energy homeostasis by modulating the expression of multiple metabolic enzymes. SRC family coactivators are prime regulators of metabolic pathways in different tissues, and genetic deletion of their expression corresponds to various physiological abnormalities and metabolic disorders (Dasgupta et al. 2014). Src-1−/− animals display reduced energy expenditure with an increased risk of developing obesity as well as a defective gluconeogenic program (Picard et al. 2002, Louet et al. 2010). Molecularly, SRC-1 coactivates CEBPα (CEBPA; CCAAT enhancer-binding proteins) to promote transcription of regulatory enzymes in the gluconeogenic pathways such as pyruvate carboxylase, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase (FBP1) (Picard et al. 2002). By contrast, Src-2−/− animals are protected from high-fat diet-induced obesity and exhibit increased insulin sensitivity, higher lipolysis, and reduced fat uptake (Picard et al. 2002). Loss of Src-2−/− also affects the hepatic glucose release due to decreased expression of glucose-6-phosphatase simulating the phenotypes observed in the genetic disorder Von Gierke's disease (Chopra et al. 2008). SRC-2 also stimulates absorption of fatty acids from the gut by activating the expression of bile salt export pump (BSEP (ABCB11)) by coactivating farnesoid X receptor (FXR (NR1H4)) under conditions of reduced energy status, thereby coordinating whole-body energy homeostasis (Chopra et al. 2011). Even in tumor cells, SRC-2 was found to modulate fatty acid biosynthesis by distinct reprogramming of metabolic functions (Dasgupta et al. 2012a). By contrast, SRC-3 participates in white adipocyte development and supports fatty acid metabolism in skeletal muscle by regulating the expression of the long-chain fatty acid transporter carnitine/acylcarnitine translocase (CACT (SLC25A20); York et al. 2012). Thus, alterations in the expression of SRCs promote global changes in numerous metabolic pathways in different tissues (York et al. 2013) to maintain the energy demands of our body, and genetic loss of their expression can lead to severe metabolic disorders (York & O'Malley 2010).
In light of this knowledge, recent studies have indicated the importance of transcriptional coactivators in circadian biology. Our recent findings have indicated that SRC-2 is a prime coordinator of circadian activities by regulating the expression of genes that regulate hepatic metabolism and diurnal rhythmicity (Stashi et al. 2014). Molecularly, SRC-2 coactivates transcription factors brain and muscle ARNT-like 1 (BMAL1/ARNTL) and circadian locomotor output cycles kaput (CLOCK), the two core components of the clock machinery (Asher & Schibler 2011). Cistromic analyses revealed that recruitment of SRC-2 to the genome overlaps with BMAL1 during the light phase targeting expression of core metabolic genes and circadian regulators. In addition, metabolomic profiling of liver metabolites from Src-2−/− and WT littermates identified severe alterations in core metabolic pathways including glycolysis, TCA, and fatty acid biosynthesis (Stashi et al. 2014). Collectively, these findings uncovered the key role of the transcriptional coactivator SRC-2 in circadian biology and its impact on various metabolic processes.
Coactivators as targets for cancer therapy
Several coactivators including PGC1, SRC family members, p300/CBP have been found to be either amplified or overexpressed in different types of cancer (Xu et al. 2009). SRCs play important roles in endocrine-related cancers such as breast, prostate, ovarian, and endometrial cancers (Lonard & O'Malley 2012) and their functions in other types of cancer are rapidly being decoded (Fig. 3). SRC-1 and SRC-3 promote ER-dependent breast cancer proliferation, as well as facilitate cancer metastasis by upregulating transcription of invasive gene signature coactivating polyoma enhancer activator 3 (PEA3 (ETV4); Qin et al. 2009, 2011). SRC-1 and SRC-3 are overexpressed in endocrine-resistant tumors such as aromatase inhibitor-resistant and tamoxifen-resistant tumors (McBryan et al. 2012). In prostate cancer, deep sequencing studies revealed SRC-2 amplification in 8% of primary tumors and 37% of metastatic tumors (Taylor et al. 2010). In addition, SRC-2 expression correlates positively with the poor survival of prostate cancer patients (Agoulnik et al. 2006, Agoulnik & Weigel 2008), and its expression is an important predictor of time-to-disease relapse (Dasgupta et al. 2012b). Recent studies have identified coactivators such as SRC-1, SRC-3, and PGC1α as regulators of bioenergetic pathways in cancer cells (Vazquez et al. 2013, Motamed et al. 2014, Zhao et al. 2014). PGC1α promotes mitochondrial oxidative phosphorylation to generate sufficient energy supporting the anabolic needs of tumor cells. In addition, recent findings have indicated that coactivators such as p300/CBP along with SRC-3 play critical roles to maintain pluripotency and an embryo stem cell state (Percharde et al. 2012, Wu et al. 2012, Chitilian et al. 2014). SRC-3 coactivates estrogen-related receptor beta (ESRRB) to enhance the expression of Oct4 (Pou5f1), Sox2, and Nanog, the master drivers of stem-cellness. Thus, it will be important to understand the role of these coactivators in ‘cancer stem cells’.
Graphical representation of the percentage of copy number alteration (CNA) frequency of steroid receptor coactivators (SRC-1, SRC-2, and SRC-3) across different types of cancer. Data represent various types of alterations including gene amplification, mutation, and deletion. Data generated using TCGA datasets from cBIOPortal (Cerami et al. 2012, Gao et al. 2013).
Citation: Journal of Molecular Endocrinology 53, 2; 10.1530/JME-14-0080
As SRCs have emerged as ‘master regulators’ of cancer progression and metastasis by integrating various upstream signaling pathways, therapeutic targeting of these molecules may be beneficial for treatment of cancers. High-throughput screening of a chemical library containing compounds from the NIH–Molecular Libraries Probe Production Centers Network (MLPCN) was used to identify the inhibitors blocking the intrinsic transcriptional activity of SRCs (Wang et al. 2014). The study identified a cardiac glycoside bufalin as a potent small-molecule inhibitor (SMI) for SRC-3 and SRC-1. Molecularly, bufalin and digoxin (a cardiac glycoside) blocked SRC-3 expression by directly binding to it and promoting its rapid degradation in a proteasome-dependent manner. Bufalin was extremely potent in the nanomolar scale to block the growth and proliferation of breast and lung cancer cells (Wang et al. 2014). In addition, Verrucarin A was also identified as a SMI that can selectively promote the degradation of SRC-3 protein, while affecting SRC-1 and SRC-2 to a lesser extent but having no impact on CARM1 and p300 protein levels. Verrucarin A belongs to a group of sesquiterpene found in toxins of pathogenic fungus and has potent anticancer effects by blocking tumor cell growth, proliferation, and migration–invasion (Yan et al. 2014). Thus, targeting the coactivators represents a novel way to block tumor cell growth, and future studies should identify effective small-molecule inhibitors to circumvent other pathologies as well.
Conclusion
Transcriptional coactivators have emerged as an important new class of functional proteins that participate with virtually all transcription factors and 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. Coactivators work in tandem with specific interacting partners to precisely regulate activation of genes, and loss or genetic defects lead to severe pathologies. Future studies will further broaden our understanding about these fascinating molecules in their various biological functions, and drug discovery efforts targeting coactivators may prove valuable for treatment of a variety of diseases.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.
Funding
This work was supported by the National Institutes of Health, USA (R01 HD007857/NICHD-NIH and 5P01DK059820 from NIDDK-NIH).
Author contribution statement
Both authors contributed equally to all aspects of the article.
References
Agoulnik IU & Weigel NL 2008 Androgen receptor coactivators and prostate cancer. Advances in Experimental Medicine and Biology 617 245–255. (doi:10.1007/978-0-387-69080-3_23).
Agoulnik IU, Vaid A, Nakka M, Alvarado M, Bingman WE III, Erdem H, Frolov A, Smith CL, Ayala GE & Ittmann MM et al. 2006 Androgens modulate expression of transcription intermediary factor 2, an androgen receptor coactivator whose expression level correlates with early biochemical recurrence in prostate cancer. Cancer Research 66 10594–10602. (doi:10.1158/0008-5472.CAN-06-1023).
Allan GF, Leng X, Tsai SY, Weigel NL, Edwards DP, Tsai MJ & O'Malley BW 1992 Hormone and antihormone induce distinct conformational changes which are central to steroid receptor activation. Journal of Biological Chemistry 267 19513–19520.
Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G, Cooper M, Laznik D, Chinsomboon J & Rangwala SM et al. 2008 HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature 451 1008–1012. (doi:10.1038/nature06613).
Asher G & Schibler U 2011 Crosstalk between components of circadian and metabolic cycles in mammals. Cell Metabolism 13 125–137. (doi:10.1016/j.cmet.2011.01.006).
Baniahmad A, Ha I, Reinberg D, Tsai S, Tsai MJ & O'Malley BW 1993 Interaction of human thyroid hormone receptor beta with transcription factor TFIIB may mediate target gene derepression and activation by thyroid hormone. PNAS 90 8832–8836. (doi:10.1073/pnas.90.19.8832).
Baniahmad A, Leng X, Burris TP, Tsai SY, Tsai MJ & O'Malley BW 1995a The tau 4 activation domain of the thyroid hormone receptor is required for release of a putative corepressor(s) necessary for transcriptional silencing. Molecular and Cellular Biology 15 76–86.
Baniahmad C, Nawaz Z, Baniahmad A, Gleeson MA, Tsai MJ & O'Malley BW 1995b Enhancement of human estrogen receptor activity by SPT6: a potential coactivator. Molecular Endocrinology 9 34–43.
Banke NH, Wende AR, Leone TC, O'Donnell JM, Abel ED, Kelly DP & Lewandowski ED 2010 Preferential oxidation of triacylglyceride-derived fatty acids in heart is augmented by the nuclear receptor PPARα. Circulation Research 107 233–241. (doi:10.1161/CIRCRESAHA.110.221713).
Barnes PJ 2013 Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. Journal of Allergy and Clinical Immunology 131 636–645. (doi:10.1016/j.jaci.2012.12.1564).
Barnes PJ, Adcock IM & Ito K 2005 Histone acetylation and deacetylation: importance in inflammatory lung diseases. European Respiratory Journal 25 552–563. (doi:10.1183/09031936.05.00117504).
Cavailles V, Dauvois S, Danielian PS & Parker MG 1994 Interaction of proteins with transcriptionally active estrogen receptors. PNAS 91 10009–10013. (doi:10.1073/pnas.91.21.10009).
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML & Larsson E et al. 2012 The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discovery 2 401–404.
Chaturvedi RK, Adhihetty P, Shukla S, Hennessy T, Calingasan N, Yang L, Starkov A, Kiaei M, Cannella M & Sassone J et al. 2009 Impaired PGC-1α function in muscle in Huntington's disease. Human Molecular Genetics 18 3048–3065. (doi:10.1093/hmg/ddp243).
Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y & Evans RM 1997 Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90 569–580. (doi:10.1016/S0092-8674(00)80516-4).
Chen H, Lin RJ, Xie W, Wilpitz D & Evans RM 1999 Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase. Cell 98 675–686. (doi:10.1016/S0092-8674(00)80054-9).
Chitilian JM, Thillainadesan G, Manias JL, Chang WY, Walker E, Isovic M, Stanford WL & Torchia J 2014 Critical components of the pluripotency network are targets for the p300/CBP interacting protein (p/CIP) in embryonic stem cells. Stem Cells 32 204–215. (doi:10.1002/stem.1564).
Chopra AR, Louet JF, Saha P, An J, Demayo F, Xu J, York B, Karpen S, Finegold M & Moore D et al. 2008 Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease. Science 322 1395–1399. (doi:10.1126/science.1164847).
Chopra AR, Kommagani R, Saha P, Louet JF, Salazar C, Song J, Jeong J, Finegold M, Viollet B & DeMayo F et al. 2011 Cellular energy depletion resets whole-body energy by promoting coactivator-mediated dietary fuel absorption. Cell Metabolism 13 35–43. (doi:10.1016/j.cmet.2010.12.001).
Cosio BG, Mann B, Ito K, Jazrawi E, Barnes PJ, Chung KF & Adcock IM 2004 Histone acetylase and deacetylase activity in alveolar macrophages and blood monocytes in asthma. American Journal of Respiratory and Critical Care Medicine 170 141–147. (doi:10.1164/rccm.200305-659OC).
Couture JF & Trievel RC 2006 Histone-modifying enzymes: encrypting an enigmatic epigenetic code. Current Opinion in Structural Biology 16 753–760. (doi:10.1016/j.sbi.2006.10.002).
Dasgupta S, Zhang B, Louet JF & O'Malley BW 2012a Steroid receptor coactivator-2 mediates oncogenic reprogramming of cancer cell metabolism. Cancer Research 72 Abstract nr 5153 (Proceedings: AACR 103rd Annual Meeting 2012, Mar 31–Apr 4, 2012; Chicago, IL, USA) doi:10.1158/1538-7445.AM2012-5153).
Dasgupta S, Srinidhi S & Vishwanatha JK 2012b Oncogenic activation in prostate cancer progression and metastasis: molecular insights and future challenges. Journal of Carcinogenesis 11 4. (doi:10.4103/1477-3163.93001).
Dasgupta S, Lonard DM & O'Malley BW 2014 Nuclear receptor coactivators: master regulators of human health and disease. Annual Review of Medicine 65 279–292. (doi:10.1146/annurev-med-051812-145316).
Denner LA, Weigel NL, Maxwell BL, Schrader WT & O'Malley BW 1990 Regulation of progesterone receptor-mediated transcription by phosphorylation. Science 250 1740–1743. (doi:10.1126/science.2176746).
Dobrovolna J, Chinenov Y, Kennedy MA, Liu B & Rogatsky I 2012 Glucocorticoid-dependent phosphorylation of the transcriptional coregulator GRIP1. Molecular and Cellular Biology 32 730–739. (doi:10.1128/MCB.06473-11).
Eisen JA, Sweder KS & Hanawalt PC 1995 Evolution of the SNF2 family of proteins: subfamilies with distinct sequences and functions. Nucleic Acids Research 23 2715–2723. (doi:10.1093/nar/23.14.2715).
Feng Q, Yi P, Wong J & O'Malley BW 2006 Signaling within a coactivator complex: methylation of SRC-3/AIB1 is a molecular switch for complex disassembly. Molecular and Cellular Biology 26 7846–7857. (doi:10.1128/MCB.00568-06).
Ferry C, Gaouar S, Fischer B, Boeglin M, Paul N, Samarut E, Piskunov A, Pankotai-Bodo G, Brino L & Rochette-Egly C 2011 Cullin 3 mediates SRC-3 ubiquitination and degradation to control the retinoic acid response. PNAS 108 20603–20608. (doi:10.1073/pnas.1102572108).
Foulds CE, Feng Q, Ding C, Bailey S, Hunsaker TL, Malovannaya A, Hamilton RA, Gates LA, Zhang Z & Li C et al. 2013 Proteomic analysis of coregulators bound to ERα on DNA and nucleosomes reveals coregulator dynamics. Molecular Cell 51 185–199. (doi:10.1016/j.molcel.2013.06.007).
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R & Larsson E et al. 2013 Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Science Signaling 6 (269) pl1. (doi:10.1126/scisignal.2004088).
Geng C, He B, Xu L, Barbieri CE, Eedunuri VK, Chew SA, Zimmermann M, Bond R, Shou J & Li C et al. 2013 Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover. PNAS 110 6997–7002. (doi:10.1073/pnas.1304502110).
Gibbons RJ, Brueton L, Buckle VJ, Burn J, Clayton-Smith J, Davison BC, Gardner RJ, Homfray T, Kearney L & Kingston HM 1995 Clinical and hematologic aspects of the X-linked α-thalassemia/mental retardation syndrome (ATR-X). American Journal of Medical Genetics 55 288–299. (doi:10.1002/ajmg.1320550309).
Gibbons RJ, Wada T, Fisher CA, Malik N, Mitson MJ, Steensma DP, Fryer A, Goudie DR, Krantz ID & Traeger-Synodinos J 2008 Mutations in the chromatin-associated protein ATRX. Human Mutation 29 796–802. (doi:10.1002/humu.20734).
Gregory CW, Fei X, Ponguta LA, He B, Bill HM, French FS & Wilson EM 2004 Epidermal growth factor increases coactivation of the androgen receptor in recurrent prostate cancer. Journal of Biological Chemistry 279 7119–7130. (doi:10.1074/jbc.M307649200).
Halachmi S, Marden E, Martin G, MacKay H, Abbondanza C & Brown M 1994 Estrogen receptor-associated proteins: possible mediators of hormone-induced transcription. Science 264 1455–1458. (doi:10.1126/science.8197458).
Han SJ, Lonard DM & O'Malley BW 2009 Multi-modulation of nuclear receptor coactivators through posttranslational modifications. Trends in Endocrinology and Metabolism 20 8–15. (doi:10.1016/j.tem.2008.10.001).
Han SJ, Hawkins SM, Begum K, Jung SY, Kovanci E, Qin J, Lydon JP, DeMayo FJ & O'Malley BW 2012 A new isoform of steroid receptor coactivator-1 is crucial for pathogenic progression of endometriosis. Nature Medicine 18 1102–1111. (doi:10.1038/nm.2826).
Hock MB & Kralli A 2009 Transcriptional control of mitochondrial biogenesis and function. Annual Review of Physiology 71 177–203. (doi:10.1146/annurev.physiol.010908.163119).
Lahue RS & Frizzell A 2012 Histone deacetylase complexes as caretakers of genome stability. Epigenetics 7 806–810. (doi:10.4161/epi.20922).
Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM & Kelly DP 2000 Peroxisome proliferator-activated receptor γ coactivator-1 promotes cardiac mitochondrial biogenesis. Journal of Clinical Investigation 106 847–856. (doi:10.1172/JCI10268).
Li C, Liang YY, Feng XH, Tsai SY, Tsai MJ & O'Malley BW 2008 Essential phosphatases and a phospho-degron are critical for regulation of SRC-3/AIB1 coactivator function and turnover. Molecular Cell 31 835–849. (doi:10.1016/j.molcel.2008.07.019).
Lonard DM & O'Malley BW 2007 Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation. Molecular Cell 27 691–700. (doi:10.1016/j.molcel.2007.08.012).
Lonard DM & O'Malley BW 2012 Nuclear receptor coregulators: modulators of pathology and therapeutic targets. Nature Reviews. Endocrinology 8 598–604. (doi:10.1038/nrendo.2012.100).
Long W, Yi P, Amazit L, LaMarca HL, Ashcroft F, Kumar R, Mancini MA, Tsai SY, Tsai MJ & O'Malley BW 2010 SRC-3Δ4 mediates the interaction of EGFR with FAK to promote cell migration. Molecular Cell 37 321–332. (doi:10.1016/j.molcel.2010.01.004).
Long W, Foulds CE, Qin J, Liu J, Ding C, Lonard DM, Solis LM, Wistuba II, Qin J & Tsai SY et al. 2012 ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion. Journal of Clinical Investigation 122 1869–1880. (doi:10.1172/JCI61492).
Louet JF, Chopra AR, Sagen JV, An J, York B, Tannour-Louet M, Saha PK, Stevens RD, Wenner BR & Ilkayeva OR et al. 2010 The coactivator SRC-1 is an essential coordinator of hepatic glucose production. Cell Metabolism 12 606–618. (doi:10.1016/j.cmet.2010.11.009).
Malovannaya A, Li Y, Bulynko Y, Jung SY, Wang Y, Lanz RB, O'Malley BW & Qin J 2010 Streamlined analysis schema for high-throughput identification of endogenous protein complexes. PNAS 107 2431–2436. (doi:10.1073/pnas.0912599106).
Malovannaya A, Lanz RB, Jung SY, Bulynko Y, Le NT, Chan DW, Ding C, Shi Y, Yucer N & Krenciute G et al. 2011 Analysis of the human endogenous coregulator complexome. Cell 145 787–799. (doi:10.1016/j.cell.2011.05.006).
McBryan J, Theissen SM, Byrne C, Hughes E, Cocchiglia S, Sande S, O'Hara J, Tibbitts P, Hill AD & Young LS 2012 Metastatic progression with resistance to aromatase inhibitors is driven by the steroid receptor coactivator SRC-1. Cancer Research 72 548–559. (doi:10.1158/0008-5472.CAN-11-2073).
McDonnell DP, Nawaz Z & O'Malley BW 1991a In situ distinction between steroid receptor binding and transactivation at a target gene. Molecular and Cellular Biology 11 4350–4355.
McDonnell DP, Nawaz Z, Densmore C, Weigel NL, Pham TA, Clark JH & O'Malley BW 1991b High level expression of biologically active estrogen receptor in Saccharomyces cerevisiae. Journal of Steroid Biochemistry and Molecular Biology 39 291–297. (doi:10.1016/0960-0760(91)90038-7).
McDonnell DP, Vegeto E & O'Malley BW 1992 Identification of a negative regulatory function for steroid receptors. PNAS 89 10563–10567. (doi:10.1073/pnas.89.22.10563).
Means AR, Comstock JP, Rosenfeld GC & O'Malley BW 1972 Ovalbumin messenger RNA of chick oviduct: partial characterization, estrogen dependence, and translation in vitro. PNAS 69 1146–1150. (doi:10.1073/pnas.69.5.1146).
Meijer OC, Steenbergen PJ & De Kloet ER 2000 Differential expression and regional distribution of steroid receptor coactivators SRC-1 and SRC-2 in brain and pituitary. Endocrinology 141 2192–2199. (doi:10.1210/endo.141.6.7489).
Motamed M, Rajapakshe KI, Hartig SM, Coarfa C, Moses RE, Lonard DM & O'Malley BW 2014 Steroid receptor coactivator 1 is an integrator of glucose and NAD(+)/NADH homeostasis. Molecular Endocrinology 28 395–405. (doi:10.1210/me.2013-1404).
Onate SA, Tsai SY, Tsai MJ & O'Malley BW 1995 Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270 1354–1357. (doi:10.1126/science.270.5240.1354).
Park E, Kim Y, Ryu H, Kowall NW, Lee J & Ryu H 2014 Epigenetic mechanisms of Rubinstein–Taybi syndrome. Neuromolecular Medicine 16 16–24. (doi:10.1007/s12017-013-8285-3).
Percharde M, Lavial F, Ng JH, Kumar V, Tomaz RA, Martin N, Yeo JC, Gil J, Prabhakar S & Ng HH et al. 2012 Ncoa3 functions as an essential Esrrb coactivator to sustain embryonic stem cell self-renewal and reprogramming. Genes and Development 26 2286–2298. (doi:10.1101/gad.195545.112).
Picard F, Gehin M, Annicotte J, Rocchi S, Champy MF, O'Malley BW, Chambon P & Auwerx J 2002 SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell 111 931–941. (doi:10.1016/S0092-8674(02)01169-8).
Power RF, Mani SK, Codina J, Conneely OM & O'Malley BW 1991 Dopaminergic and ligand-independent activation of steroid hormone receptors. Science 254 1636–1639. (doi:10.1126/science.1749936).
Qin L, Liu Z, Chen H & Xu J 2009 The steroid receptor coactivator-1 regulates twist expression and promotes breast cancer metastasis. Cancer Research 69 3819–3827. (doi:10.1158/0008-5472.CAN-08-4389).
Qin L, Chen X, Wu Y, Feng Z, He T, Wang L, Liao L & Xu J 2011 Steroid receptor coactivator-1 upregulates integrin α(5) expression to promote breast cancer cell adhesion and migration. Cancer Research 71 1742–1751. (doi:10.1158/0008-5472.CAN-10-3453).
Qu Y, Yang Y, Ma D, He L & Xiao W 2013 Expression level of histone deacetylase 2 correlates with occurring of chronic obstructive pulmonary diseases. Molecular Biology Reports 40 3995–4000. (doi:10.1007/s11033-012-2477-z).
Reineke EL, York B, Stashi E, Chen X, Tsimelzon A, Xu J, Newgard CB, Taffet GE, Taegtmeyer H & Entman ML et al. 2012 SRC-2 coactivator deficiency decreases functional reserve in response to pressure overload of mouse heart. PLoS ONE 7 e53395. (doi:10.1371/journal.pone.0053395).
Reiter R, Wellstein A & Riegel AT 2001 An isoform of the coactivator AIB1 that increases hormone and growth factor sensitivity is overexpressed in breast cancer. Journal of Biological Chemistry 276 39736–39741. (doi:10.1074/jbc.M104744200).
Rowan BG, Garrison N, Weigel NL & O'Malley BW 2000 8-Bromo-cyclic AMP, induces phosphorylation of two sites in SRC-1 that facilitate ligand-independent activation of the chicken progesterone receptor and are critical for functional cooperation between SRC-1 and CREB binding protein. Molecular and Cellular Biology 20 8720–8730. (doi:10.1128/MCB.20.23.8720-8730.2000).
Rowe GC, Jiang A & Arany Z 2010 PGC-1 coactivators in cardiac development and disease. Circulation Research 107 825–838. (doi:10.1161/CIRCRESAHA.110.223818).
Spelsberg TC, Steggles AW & O'Malley BW 1971 Progesterone-binding components of chick oviduct. 3. chromatin acceptor sites. Journal of Biological Chemistry 246 4188–4197.
Stashi E, Wang L, Mani SK, York B & O'Malley BW 2013 Research resource: Loss of the steroid receptor coactivators confers neurobehavioral consequences. Molecular Endocrinology 27 1776–1787. (doi:10.1210/me.2013-1192).
Stashi E, Lanz RB, Mao J, Michailidis G, Zhu B, Kettner NM, Putluri N, Reineke EL, Reineke LC & Dasgupta S et al. 2014 SRC-2 is an essential coactivator for orchestrating metabolism and circadian rhythm. Cell Reports 6 633–645. (doi:10.1016/j.celrep.2014.01.027).
Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E & Reva B et al. 2010 Integrative genomic profiling of human prostate cancer. Cancer Cell 18 11–22. (doi:10.1016/j.ccr.2010.05.026).
Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK & Rosenfeld MG 1997 The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387 677–684. (doi:10.1038/42652).
Urdinguio RG, Sanchez-Mut JV & Esteller M 2009 Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurology 8 1056–1072. (doi:10.1016/S1474-4422(09)70262-5).
Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, Clish CB, Granter SR, Widlund HR & Spiegelman BM et al. 2013 PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23 287–301. (doi:10.1016/j.ccr.2012.11.020).
Vegeto E, Allan GF, Schrader WT, Tsai MJ, McDonnell DP & O'Malley BW 1992 The mechanism of RU486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor. Cell 69 703–713. (doi:10.1016/0092-8674(92)90234-4).
Voegel JJ, Heine MJ, Zechel C, Chambon P & Gronemeyer H 1996 TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO Journal 15 3667–3675.
Wang Y, Lonard DM, Yu Y, Chow DC, Palzkill TG, Wang J, Qi R, Matzuk AJ, Song X & Madoux F et al. 2014 Bufalin is a potent small-molecule inhibitor of the steroid receptor coactivators SRC-3 and SRC-1. Cancer Research 74 1506–1517. (doi:10.1158/0008-5472.CAN-13-2939).
Wu RC, Qin J, Yi P, Wong J, Tsai SY, Tsai MJ & O'Malley BW 2004 Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic responses to multiple cellular signaling pathways. Molecular Cell 15 937–949. (doi:10.1016/j.molcel.2004.08.019).
Wu H, Sun L, Zhang Y, Chen Y, Shi B, Li R, Wang Y, Liang J, Fan D & Wu G et al. 2006 Coordinated regulation of AIB1 transcriptional activity by sumoylation and phosphorylation. Journal of Biological Chemistry 281 21848–21856. (doi:10.1074/jbc.M603772200).
Wu RC, Feng Q, Lonard DM & O'Malley BW 2007 SRC-3 coactivator functional lifetime is regulated by a phospho-dependent ubiquitin time clock. Cell 129 1125–1140. (doi:10.1016/j.cell.2007.04.039).
Wu Z, Yang M, Liu H, Guo H, Wang Y, Cheng H & Chen L 2012 Role of nuclear receptor coactivator 3 (Ncoa3) in pluripotency maintenance. Journal of Biological Chemistry 287 38295–38304. (doi:10.1074/jbc.M112.373092).
Xu J, Qiu Y, DeMayo FJ, Tsai SY, Tsai MJ & O'Malley BW 1998 Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science 279 1922–1925. (doi:10.1126/science.279.5358.1922).
Xu J, Wu RC & O'Malley BW 2009 Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family. Nature Reviews. Cancer 9 615–630. (doi:10.1038/nrc2695).
Yamamoto K & Alberts B 1975 The interaction of estradiol-receptor protein with the genome: an argument for the existence of undetected specific sites. Cell 4 301–310. (doi:10.1016/0092-8674(75)90150-6).
Yan F, Yu Y, Chow DC, Palzkill T, Madoux F, Hodder P, Chase P, Griffin PR, O'Malley BW & Lonard DM 2014 Identification of Verrucarin A as a potent and selective steroid receptor coactivator-3 small molecule inhibitor. PLoS ONE 9 e95243. (doi:10.1371/journal.pone.0095243).
Yi P, Wu RC, Sandquist J, Wong J, Tsai SY, Tsai MJ, Means AR & O'Malley BW 2005 Peptidyl-prolyl isomerase 1 (Pin1) serves as a coactivator of steroid receptor by regulating the activity of phosphorylated steroid receptor coactivator 3 (SRC-3/AIB1). Molecular and Cellular Biology 25 9687–9699. (doi:10.1128/MCB.25.21.9687-9699.2005).
Yi P, Feng Q, Amazit L, Lonard DM, Tsai SY, Tsai MJ & O'Malley BW 2008 Atypical protein kinase C regulates dual pathways for degradation of the oncogenic coactivator SRC-3/AIB1. Molecular Cell 29 465–476. (doi:10.1016/j.molcel.2007.12.030).
York B & O'Malley BW 2010 Steroid receptor coactivator (SRC) family: masters of systems biology. Journal of Biological Chemistry 285 38743–38750. (doi:10.1074/jbc.R110.193367).
York B, Reineke EL, Sagen JV, Nikolai BC, Zhou S, Louet JF, Chopra AR, Chen X, Reed G & Noebels J et al. 2012 Ablation of steroid receptor coactivator-3 resembles the human CACT metabolic myopathy. Cell Metabolism 15 752–763. (doi:10.1016/j.cmet.2012.03.020).
York B, Sagen JV, Tsimelzon A, Louet JF, Chopra AR, Reineke EL, Zhou S, Stevens RD, Wenner BR & Ilkayeva O et al. 2013 Research resource: tissue- and pathway-specific metabolomic profiles of the steroid receptor coactivator (SRC) family. Molecular Endocrinology 27 366–380. (doi:10.1210/me.2012-1324).
Yu C, York B, Wang S, Feng Q, Xu J & O'Malley BW 2007 An essential function of the SRC-3 coactivator in suppression of cytokine mRNA translation and inflammatory response. Molecular Cell 25 765–778. (doi:10.1016/j.molcel.2007.01.025).
Zhao W, Chang C, Cui Y, Zhao X, Yang J, Shen L, Zhou J, Hou Z, Zhang Z & Ye C et al. 2014 Steroid receptor coactivator-3 regulates glucose metabolism in bladder cancer cells through coactivation of hypoxia inducible-factor 1α. Journal of Biological Chemistry 289 11219–11229. (doi:10.1074/jbc.M113.535989).
(S Dasgupta and B W O'Malley contributed equally to this work)
