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Minireview |
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030
Address all correspondence and requests for reprints to: Jianming Xu, Ph.D., Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: jxu{at}bcm.tmc.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONIDENTIFICATION OF THE SRC...STRUCTURAL AND FUNCTIONAL...ROLES FOR SRCs IN...BIOLOGICAL FUNCTIONS OF THE...CONCLUDING REMARKSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONIDENTIFICATION OF THE SRC...STRUCTURAL AND FUNCTIONAL...ROLES FOR SRCs IN...BIOLOGICAL FUNCTIONS OF THE...CONCLUDING REMARKSREFERENCES |
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and ERß), progesterone receptors (PR-A and PR-B), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor change their conformations, form homodimers, bind to their cognate hormone response elements (HREs), recruit coactivators, and enhance their target gene transcription (reviewed in Refs. 1 and 2). On the other hand, NRs that form heterodimers with the retinoid X receptor, such as the thyroid hormone receptor (TR), the retinoic acid receptor (RAR), and the vitamin D receptor, bind their HREs in the absence of ligands, associate with corepressors, and inhibit transcription of their target genes. After binding to their ligands, these HRE-bound receptors release the repression function through dissociation of corepressors and gain transcriptional activation function through recruitment of coactivators (reviewed in Refs. 2 and 3).
The finding that activation of one overexpressed NR could inhibit another NR’s transcriptional activity without any direct interaction or any overlapping DNA binding between these two NRs suggested that the NR transcriptional function might be mediated by limiting common coregulators (4). During the past several years, cloning methods based on protein-protein interactions between NRs and putative coregulators in the absence or presence of ligands identified a number of NR corepressors and coactivators (reviewed in Ref.2). A coactivator is usually defined according to its physical interaction with NRs in biochemical analysis and its ability to enhance NR-dependent transcription in transient transfection assays. Most individual coactivators that directly interact with NRs form distinct preexisting protein complexes with downstream intermediate factors for chromatin remodeling or for interaction with general transcription factors (Fig. 1
). These coactivator complexes can be efficiently recruited to specific promoters by ligand-activated and DNA-bound NRs or other classes of transcription factors. Since the concentration and function of each individual component in these coactivator complexes can be regulated through transcriptional control, various posttranslational modifications and degradation by multiple signaling pathways, the usage of these coactivator complexes by NRs may provide platforms for sophisticated transcriptional regulation. Among multiple coactivator complexes, the mammalian homolog of Drosophila switch defective/sucrose nonfermenter (SWI/SNF) complex containing brahma-related gene 1 and human brahma with ATPase activities can be recruited by several NRs for ATP-dependent chromatin remodeling through histone acetylation (Fig. 1) (reviewed in Ref.5). The TR-associated protein (TRAP)/vitamin D receptor interacting protein (DRIP)/activator-recruited cofactor coactivator complex consists of more than a dozen proteins and interacts with NRs in a ligand-dependent manner via a single component referred to as PPAR-binding protein/TRAP220/DRIP205. The NR-recruited TRAP/DRIP/activator-recruited cofactor complex directly interacts with general transcription factors to coactivate target gene transcription (Fig. 1) (reviewed in Ref.5). The activating signal cointegrator 2 complex contains a subset of trithorax group proteins, which can methylate histone H3 when recruited to specific chromatin regions by NRs (Fig. 1) (6). The p160 steroid receptor coactivator (SRC) complex contains acetyltransferases including the cAMP response element binding protein (CREB)-binding protein (CBP), p300, and the p300/CBP-associated factor (p/CAF) and methyltransferases including coactivator-associated arginine methyltransferase 1 and protein arginine methyltransferase 1 (PRMT1). These chromatin-remodeling enzymes (acetyltransferases and methyltransferases) are recruited to promoters though interaction between NRs and p160 SRC coactivators in a ligand-dependent manner (Fig. 1) (reviewed in Refs. 2 and 7). This minireview focuses on recent studies regarding the structural and functional characterization of the SRC family.
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IDENTIFICATION OF THE SRC FAMILY |
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TOPABSTRACTINTRODUCTIONIDENTIFICATION OF THE SRC...STRUCTURAL AND FUNCTIONAL...ROLES FOR SRCs IN...BIOLOGICAL FUNCTIONS OF THE...CONCLUDING REMARKSREFERENCES |
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B (NF-B) (21), and interferon- and cAMP regulatory element-binding protein (CREB) (13). Therefore, when experimentally expressed in cultured cells, each member of the SRC family seems to serve as a general coactivator for multiple NRs and a limited number of other transcription factors. Conversely, the transcriptional activity of a specific NR can be mediated by any member of the SRC family. This functional relationship defined by in vitro experiments among various NRs and SRCs may provide a basic explanation for functional redundancy among members of the SRC family when they are coexpressed in vivo.
The amino acid sequences and biological functions of all known SRC-related proteins are evolutionarily related and relatively conserved among different species (Fig. 2). The quail SRC-1 is 75% identical to mammalian SRC-1 proteins and highly expressed in steroid-sensitive brain regions (22). Except human and rodents, SRC-2 homologous proteins were also identified in zebrafish (zTIF2, GenBank NP_571852) and frog (xTIF2) (23). Overexpression of the NR- or CBP-binding domains of xTIF2 interfered with the biological function of xTIF2 and caused ectopic expression of Xenopus Brachyury and MyoD genes and severe developmental defects such as loss of head structures, shortened trunks, and open blastopores (23). These data suggest the existence of a NR pathway in frog that requires xTIF2 and CBP to regulate gene expression during development. SRC-3-related proteins were also identified in fruit fly and frog. In Drosophila, a coactivator for the ecdysone receptor, termed Taiman, was identified by a genetic approach and found sharing certain sequence homology to SRC-3. The highest level of amino acid sequence identity was found in the N-terminal basic helix-loop-helix (bHLH) domain of Taiman, which was 48% identical and 71% similar between amplified in breast cancer-1 and Taiman. Mutation of the Taiman gene caused defects in the migration of the border cells in the Drosophila ovary, and the mutant cells exhibited abnormal accumulation of E-cadherin, ß-catenin, and focal adhesion kinase. These findings suggest that Taiman may have a potential role in regulation of invasive cell behavior similar to the metastasis of cancer cells (24). The Xenopus SRC-3 (xSRC-3) is 72% identical to mammalian SRC-3. It was demonstrated that xSRC-3 can interact with and coactivate mammalian NRs such as retinoid X receptor, RAR, and TR (25), suggesting that the coactivator function of SRC family members in the frog is similar to that in mammals.
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STRUCTURAL AND FUNCTIONAL DOMAINS OF THE SRC FAMILY |
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TOPABSTRACTINTRODUCTIONIDENTIFICATION OF THE SRC...STRUCTURAL AND FUNCTIONAL...ROLES FOR SRCs IN...BIOLOGICAL FUNCTIONS OF THE...CONCLUDING REMARKSREFERENCES |
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). Their most conserved N-terminal bHLH/Per/Ah receptor nuclear translocator (ARNT)/Sim domain was originally identified in Drosophila proteins (Per and Sim), where it is involved in DNA binding and heterodimerization between proteins containing these motifs (26). Although the bHLH/Per/ARNT/Sim domain in SRC-1 is not obligatory for coactivation of NRs in transfection assays (8), at least one study has shown that this domain is important for interaction of SRC-2 with myogenic factors including myogenin and MEF-2C (27). The relatively conserved central region of the SRC family members contains three LXXLL (L, leucine; X, any amino acid) motifs that are responsible for interaction with ligand-bound NRs (L1–L3 in Fig. 3) (13, 16, 28, 29). The LXXLL motif forms an amphipathic -helix that binds a hydrophobic cleft formed in ligand-binding domains of NRs after binding ligands (30). Interestingly, distinct LXXLL motifs and contextual sequences exhibit differential binding affinity for different NRs, suggesting NRs have a preference for one LXXLL motif over another in the same coactivator or for one coactivator molecule over another. However, single mutation of any one of these three LXXLL motifs does not completely abolish the interaction of SRC members with NRs, suggesting that multiple LXXLL motifs are involved in the high-affinity binding of SRCs to NRs (reviewed in Ref.31).
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) (12, 15, 32). Interestingly, the AD1 domain also contains three LXXLL/LXXLL-like motifs (L4–L6 in Fig. 3); mutation of one or more of these motifs impairs the interaction of SRCs with the general transcriptional cointegrators, CBP and p300, as well as the activation function of SRCs, indicating that the major role of AD1 is to recruit acetyltransferases including CBP/p300 and p/CAF for chromatin remodeling (Fig. 1) (29, 33). The second transcriptional activation domain (AD2) is located at the C terminus of SRC proteins (Fig. 3). AD2 is responsible for interaction with histone methyltransferases, coactivator-associated arginine methyltransferase 1 and PRMT1 (34, 35). Recruitment of these histone methyltransferases to an enhancer/promoter by SRC coactivators may also be critical for NR- directed local chromatin remodeling and assembly of the transcriptional machinery around the promoter (Fig. 1). |
ROLES FOR SRCs IN CHROMATIN REMODELING AND TRANSCRIPTIONAL ACTIVATION |
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TOPABSTRACTINTRODUCTIONIDENTIFICATION OF THE SRC...STRUCTURAL AND FUNCTIONAL...ROLES FOR SRCs IN...BIOLOGICAL FUNCTIONS OF THE...CONCLUDING REMARKSREFERENCES |
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Instead, SRCs may play major roles in the chromatin remodeling and the assembly of general transcription factors through direct and indirect recruitments of other coactivators. Accumulated data support a sequential molecular mechanism for SRC function. First, the SRC preexisting complexes containing CBP, p300, p/CAF, CARM-1, and PRMT1 (specific components may be cell type dependent) are recruited to the chromatin environment through ligand binding-triggered direct interactions between NRs and SRCs, which results in site-specific acetylations and methylations of specific histones (10, 33, 34, 35, 38, 39, 40, 41, 42, 43). Second, the SWI/SNF chromatin-remodeling complex is recruited to the chromatin through direct or indirect interactions with CBP/p300, and the recruitment is stabilized by the CBP/p300-acetylated histone tails. The SWI/SNF complex contains ATPase and causes specific histone acetylations in an ATP-dependent manner, which results in changes of DNA topology (5, 44, 45). Third, the TRAP mediator complex can be recruited to the chromatin through interactions with SRC/CBP/p300 complex or direct interactions with NRs. Recent studies also showed that the recruitment of the TRAP complex by p300 is partially dependent on histone acetylation. The TRAP complex directly communicates with the basal transcriptional machinery and facilitates the initiation of gene expression (40, 45, 46, 47, 48, 49). Fourth, the entire process of NR-induced coactivator recruitment, assembly of transcription machinery, and initiation of transcription is dynamic and may happen in a cyclic fashion. For example, the ER transcription complex appears to repeatedly cycle onto and off of target promoters in the presence of estrogen. The cycling is probably regulated by phosphorylation of the pol II C terminus, exchange of coactivators such as exchange of p300 for CBP, and covalent modifications of coregulators such as phosphorylation and acetylation of SRCs (40, 50, 51).
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BIOLOGICAL FUNCTIONS OF THE SRC FAMILY |
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TOPABSTRACTINTRODUCTIONIDENTIFICATION OF THE SRC...STRUCTURAL AND FUNCTIONAL...ROLES FOR SRCs IN...BIOLOGICAL FUNCTIONS OF THE...CONCLUDING REMARKSREFERENCES |
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). For each SRC member, both aspects will be discussed.
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Despite these tissue-specific expression patterns in neuronal cells, no known human disease has been specifically linked to a genetic defect of the SRC-1 gene at this time. Likewise, mice lacking functional SRC-1 protein exhibited normal growth and fertility. However, genetic models provided important clues for partial resistance to steroid hormones due to the loss of SRC-1 function. For example, the estrogen-induced uterine growth and the estrogen- and progesterone-dependent uterine decidual response were decreased in ovariectomized female SRC-1-/- mice. Mammary gland ductal side branching and alveolar formation were also reduced in ovariectomized female SRC-1-/- mice treated with estrogen and progesterone. A similar partial response was observed from testosterone-stimulated prostate growth in the castrated male SRC-1-/- mice (56). These observations indicate that SRC-1 serves as one of the in vivo coactivators to mediate a part of the transcriptional activity for steroid receptors.
SRC-1 plays an important role in brain development and function. At birth, the gonads of male rats produce testosterone that is converted into dihydrotestosterone and estradiol in the brain. The dihydrotestosterone activates AR and results in behavioral masculinization (increase in male-typical behaviors). Estradiol activates ER and results in development of the sexually dimorphic nucleus (SDN) and behavioral defeminization (decrease in female-typical behaviors) in male rats. Infusion of testosterone into brains of female rats at the neonatal stage also results in a larger SDN and development of male sexual behavior in the adult. Interestingly, down-regulation of SRC-1 by infusion of antisense oligodeoxynucleotides (ODNs) into the androgen-treated hypothalamus of female rats at the neonatal stage significantly reduced the SDN volume and blocked behavioral defeminization. Accordingly, male and androgen-infused female rats treated with SRC-1 antisense at the neonatal stage displayed significantly higher levels of female sexual behaviors. In contrast, SRC-1 antisense treatment did not affect the masculinizing actions of neonatal testosterone treatment on male sexual behavior. These results suggest that SRC-1 plays an important role in ER-mediated SND development and behavioral defeminization but not in AR-mediated behavioral masculinization during sexual differentiation of the rat brain (59). Furthermore, infusion of antisense ODNs to SRC-1 and SRC-2 into the adult rodent brain inhibits ER-dependent PR synthesis in the ventromedial nucleus and blocks female reproductive behaviors. Intriguingly, SRC-1 knockout mice exhibit nearly normal female reproductive behaviors (60). The paradoxical observations on sexual behaviors between SRC-1 antisense-treated rodents and SRC-1 knockout mice could be due to the temporal differences in SRC-1 depletion. During development, the SRC-1 knockout mice may adapt a genetic compensatory mechanism such as up-regulation of other coactivators for maintenance of fundamental biological functions. Indeed, the level of SRC-2 mRNA is slightly elevated in the brain of SRC-1-/- mice (56). In contrast, when SRC-1 is down-regulated by acute administration of SRC-1 antisense, it could be possible that the genetic compensation has not yet been adapted before the effects of SRC-1 on sexual behaviors are observed.
In addition, SRC-1 is expressed at higher levels than other SRC family members in the cerebellar PCs, and mice lacking SRC-1 exhibit a delay in PC development during embryonic development and neonatal stages. Interestingly, the recovery of PC development by postnatal d 10 in SRC-1-/- mice correlates with an earlier and higher expression of SRC-2, suggesting a mechanism of genetic compensation from other SRC family members during development. The adult SRC-1 knockout mice also exhibit moderate motor learning dysfunction, probably due to the lack of SRC-1 in PCs or the delayed maturation of PCs (58). Since TRs and the retinoid-related orphan nuclear receptor play important roles in PC development, SRC-1 and SRC-2 may be required for normal function of retinoid-related orphan nuclear receptor and TRs in PC development and function.
Partial resistance to TH was also observed in SRC-1-/- mice as evidenced by elevated serum T3 and T4 THs and TSH. These studies demonstrated that SRC-1 is required for efficient down-regulation of TSH by T3, supporting the hypothesis that resistance to TH in humans can be caused by a defective TR coactivator such as SRC-1 (61). Interestingly, SRC-1 may be involved not only in transcriptional activation by liganded TRs, but also in the repression by liganded or unliganded TRs. For example, suppression of TSHß expression by T3 was attenuated in SRC-1 knockout mice (62). Intriguingly, multiple observations have suggested that the usage of SRC-1 by different TR isoforms is tissue specific. First, SRC-1 is important for both TR- and TRß-mediated body growth since both TR/SRC-1 and TRß/SRC-1 double-knockout mice exhibit more severe growth retardation than either TR or TRß single-knockout mice. Second, SRC-1 partially mediates the TH effects on heart rates by TR and TRß. Third, hypersensitivity to TH seen in TR null mice, as demonstrated by overexpression of a TH-regulated gene, 5' deoiodinase, in the liver, is abolished in SRC-1-/- mice, suggesting that the hypersensitivity in TR null mice is due to TRß function enhanced by SRC-1 (63). Fourth, SRC-1 is required for normal down-regulation of TSH by both TR and TRß in the pituitary. In the absence of TR, SRC-1 expression is elevated in the pituitary, suggesting that the excess amount of SRC-1 in TR null mice may superactivate TRß and cause TH hypersensitivity for down-regulation of TSH (64).
The role of SRC-1 in peroxisomal proliferator-activated receptor-
(PPAR) function also exhibits certain levels of tissue specificity, which is probably due to relative amounts of PPAR, SRC family members, and other PPAR coactivator such as PPAR coactivator-1 (PGC-1). In the liver, SRC-1 seems not required for expression of PPAR-regulated genes (65). In contrast, in the brown fat, activation of PPAR triggers the recruitment of a coactivator complex containing PGC-1, SRC-1, and CBP/p300 (66). Inactivation of SRC-1 impairs the thermogenic activity of PGC-1 in the brown fat, decreases the energy expenditure, and results in obesity following a high-fat diet (67).
SRC-2
The SRC-2 gene is located in chromosome 8 (q21) in humans and chromosome 1 (A3–5) in mice (53, 68). SRC-2 mRNA has been detected in many tissues including placenta, testis, brain, heart, liver, pancreas, and uterus. The kidney, skeletal muscle, and mammary gland have little SRC-2 mRNA expression (12, 54, 56, 58). SRC-2 protein has also been identified in the testis, lung, brain, liver, and heart by Western blot (13). By immunohistochemistry, different levels of SRC-2 immunoreactivity have been found in epithelial cells of many tissues including gastrointestinal tract, pancreas, kidney, uterus, mammary gland, testis, prostate, lung, and adrenal gland. SRC-2 protein is also expressed in stromal cells of the colon, urinary bladder, uterus, and mammary gland and in smooth muscle cells of the gastrointestinal and urinary tracts, uterus, epididymis, prostate, and blood vessels. SRC-2 protein is undetectable in hepatocytes, thyroid gland, and striated muscle by immunohistochemistry (69). These studies indicate that SRC-2 is widely expressed in many organs and its expression amount varies between cell types and organs.
Similar to SRC-1-/- mice, SRC-2-/- mice exhibit nearly normal somatic growth. However, the fertility is significantly reduced in both male and female SRC-2 null mice. Male hypofertility is due to a decrease in sperm number, defective maturation of the spermatid acrosome, and age-dependent testicular degeneration. The male reproductive defect appears to be of Sertoli cell (SC) origin since SRC-2 is specifically expressed in SCs in the testis. The absence of SRC-2 in SCs results in lipid accumulation in SCs, germ cell apoptosis, and detachment of germ cells from SCs (70). However, it remains unclear what nuclear receptor function is impaired in the SCs without SRC-2. In agreement with the role of SRC-2 in mouse SCs, some men with oligospermic infertility possess an AR mutation from methionine to valine that disrupts the interaction between AR and SRC-2 (71). The hypofertility of female SRC-2 mutant mice is due to a placental hypoplasia caused by the absence of maternal SRC-2 in decidual stromal cells that face the developing placenta (70). In addition, although female SRC-2-/- mice exhibit normal sexual behavior, acute administration of antisense ODNs to either SRC-1 or SRC-2 into the hypothalamus efficiently blocks the sexual behavior of female wild-type rats. Although the mechanism for this discrepancy is unknown, a developmental adaptation such as alteration of other coactivator expression may have occurred in SRC-2-/- mice to support the female sexual behavior (60). These findings indicate that SRC-2 plays a critical role in reproductive behavior and functions.
Recent studies have shown that SRC-2 plays an important role in lipid metabolism and energy balance (67). In the white adipose tissue (WAT), SRC-2 serves as a coactivator for PPAR. In SRC-2-/- mice, WAT expresses higher levels of leptin and lower levels of genes responsible for antilipolysis and fatty acid uptake and trapping, such as the perilipins, fatty acid binding protein aP2, lipoprotein lipase, and PPAR, causing higher levels of lipolysis and a lower potential for fatty acid storage. In the brown adipose tissue (BAT), SRC-1 is a better coactivator than SRC-2 in the stabilization of the PPAR and PGC-1 complex for transcriptional activation. The absence of SRC-2 in BAT facilitates the formation of PPAR/PGC-1/SRC-1 complex for PPAR-dependent transactivation. Thus, BAT lacking SRC-2 expresses higher levels of uncoupling protein 1, PGC-1, and acetyl coenzyme A oxidase, causing higher energy expenditure due to enhanced fatty acid oxidation and uncoupling of respiration. As a result, SRC-2 null mice exhibit higher body temperature under cold conditions, less fat accumulation, lower levels of fasting glycemia and triglyceride, and higher insulin sensitivity. Collectively, these mice are better able to protect themselves against obesity induced by high-fat diet or hyperphagia. Interestingly, a high-fat diet induces SRC-2 expression in both WAT and BAT and increases the ratio of SRC-2 to SRC-1, which may reflect a part of the molecular mechanisms for the enhancement of fat accumulation (67).
One study has shown that SRC-2 is expressed in proliferating myoblasts and postmitotic differentiated myotubes and potentiates skeletal muscle differentiation by acting as a critical coactivator for MEF-2- mediated transactivation (27). However, no defect in skeletal muscle development was observed in SRC-2 knockout mice (70), suggesting that SRC-2 is not essential for skeletal muscle differentiation and other SRC members may compensate for the loss of SRC-2 function in skeletal muscle development in vivo.
SRC-3
The SRC-3 gene is located in chromosome 20 (q12) in humans and chromosome 2 (H2–4) in mice (14, 53). Similar to other members of the family, SRC-3 is also widely expressed. Based on Northern blot analysis, SRC-3 mRNA was detected in the placenta, pancreas, lung, kidney, brain, liver, uterus, pituitary, mammary gland, and testis (16, 17, 18, 54, 56). Its protein was also found in the tissue extracts of testis, lung, liver, brain, heart, and mammary gland (13, 72). More notably, a knock-in mouse model harboring a ß-galactosidase reporter downstream of the endogenous SRC-3 promoter revealed that the mouse SRC-3 gene is mainly expressed in mammary gland epithelial cells, oocytes, vaginal epithelial layer, hepatocytes, and in the smooth muscle cells of many tissues such as blood vessels, intestines, and oviducts (72, 73). In the brain, SRC-3 expression in adult mice was mainly detected in the hippocampus and olfactory bulb (72). These results indicate that although widely expressed, SRC-3 is selectively higher in specific cell types.
Unlike SRC-1-/- and SRC-2-/- mice, SRC-3-/- mice displayed growth retardation and reduced adult body size, probably due to lower levels of IGF-I and partial tissue resistance to IGF-I (72, 74). Although the reproductive function of male SRC-3-/- mice was only slightly reduced, the development and function of the female reproductive system was abnormal (72). First, the estrogen levels were significantly lower in female SRC-3-/- mice at all ages examined, which in turn caused a delay in pubertal development evidenced by the postponed onset of vaginal opening and mammary gland growth (72). Second, mammary gland alveolar development in response to a combined stimulation of estrogen and progesterone was significantly decreased in adult SRC-3-/- females, suggesting that SRC-3 is involved in progesterone-stimulated cell proliferation and glandular differentiation during breast alveolar development. Third, the ovulation capacity of female SRC-3-/- mice after receiving pregnant mare’s serum gonadotropin and human chorionic gonadotropin treatments was significantly reduced (72). Because ovulated oocytes were efficiently fertilized when mating with fertile males, the reduction in ovulation capacity may be responsible for the dramatic decrease in total pups produced by the SRC-3-/- females when paired with fertile males for a period of 1 yr (75). The decrease in ovulation could be attributed to poor follicular development because of estrogen inefficiency or to a partial block of oocyte maturation because of the absence of SRC-3 in the oocytes. Collectively, these results indicate that the major physiological functions of SRC-3 are distinct from those of SRC-1 and SRC-2.
SRC-3 is coexpressed with ER and ERß in the endothelial cells and vascular smooth muscle cells and may facilitate the estrogen-mediated vasoprotective effects, through inhibition of neointimal formation after vessel injury (73, 76). For example, the neointimal growth in ovariectomized wild-type mice was almost completely inhibited by estrogen treatment, but only partially inhibited in ovariectomized SRC-3-/- mice due to an insufficient suppression of vascular cell proliferation by estrogen (73).
Recently, SRC-3 was found to be associated with the IB kinase (77). IB kinase could phosphorylate SRC-3 and promote nuclear localization of SRC-3. In addition, SRC-3 was able to augment NF-B-mediated gene expression while the expression of interferon-regulatory factor 1, a well known NF-B target gene, was reduced in SRC-3-/- mice (77). These observations support a former discovery that SRC-3 is a NF-B coactivator (78), suggesting that SRC-3 may play an important role in inflammatory and immune responses as well as cell survival mediated by NF-B.
Functional Redundancy and Specificity Among SRC Family Members
Protein-protein interactions and in vitro or ex vivo transcriptional assays have made it clear that SRC family members possess many common features that permit interaction with and coactivation of NRs when they exist in excess amounts in the assay systems (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 37). The viable phenotypes of knockout mice lacking functional SRC-1, SRC-2, or SRC-3 further support the notion that SRC family members may be able to partially compensate each other’s function in vivo (56, 70, 72).
Indeed, several observations clearly demonstrate that members of the SRC family can partially compensate each other’s biological functions, probably due to their similar structural and functional domains as well as their partially overlapping expression patterns in certain tissues. These observations include: expression of SRC-2 is elevated in several regions of the brain and some other tissues in SRC-1-/- mice (56, 58); developmental problems exist in the SRC-1-deficient cerebellar PCs where SRC-1 is expressed at high levels and SRC-2 at low levels in wild-type mice, but no developmental problem presents in the SRC-1-deficient hippocampus and olfactory bulb where all SCRs are expressed in wild type mice (58); high levels of SRC-2, low levels of SRC-1 and undetectable levels of SRC-3 are present in the testicular SCs and only SCs of SRC-2-/- mice are incapable of supporting spermatogenesis, probably due to low, noncompensatory amounts of SRC-1 and SRC-3 (70); the majority of SRC-1/SRC-2 double-knockout mice can not survive after birth, and the few survivors are much more resistant to TH as compared with single-mutant mice (75, 79); and down-regulation of both SRC-1 and SRC-2 is required to block estrogen-induced PR synthesis in the rat hypothalamus (60). These results indicate that some biological functions are dependent on the total amount of SRC family members.
However, several studies have demonstrated the existence of certain levels of specificities between different NRs and SRCs that might allow selective uses of distinct downstream coactivators and, therefore, selective activation of target genes for different NRs. For example, microinjection of expression plasmids for SRC-1 or SRC-2, but not SRC-3, was shown to rescue RAR-dependent transcription in SRC-1-immunodepleted cells, suggesting that SRC-3 can not compensate for the function of SRC-1 and SRC-2 in these assays (13). Another study showed that SRC-3 enhances ER- and PR-dependent gene transcription, but stimulation of ERß-mediated transcription was not observed (18). More interestingly, a recent study demonstrated that PR interacts preferentially with SRC-1 in breast cancer cells, which recruits CBP and enhances acetylation of histone H4. In contrast, GR interacts preferentially with SRC-2, which recruits p/CAF and results in histone H3 acetylation. This study suggests that selective recruitment of SRCs by different NRs may determine the specific assembly of coactivator complexes to mediate specific transcription signals (42). In addition, variable tissue-specific expression patterns of SRC family members may be also responsible for their functional specificities. Although members of the SRC family are widely expressed, their expression levels are tissue and cell type dependent. The differences in temporal and spatial expression patterns of SRC members may explain, at least in part, the discrepancies between in vitro experiments where all SRC members enhance most NR-dependent transcriptions and in vivo experiments where SRC-1, SRC-2, and SRC-3 knockout mice exhibit different phenotypes (refer to the preceding sections).
SRC-3 and Breast Cancer
Since SRC-3 can enhance ER- and PR-dependent transcription, it was reasoned that altered SRC-3 expression might play a critical role in hormone-dependent cancers such as breast cancer (14, 80). Indeed, variable amplification frequencies (4.8–9.5%) of the SRC-3 gene have been reported in human breast tumors (14, 80). SRC-3 mRNA is also overexpressed in 31–64% of breast tumors (14, 81). However, elevated levels of the SRC-3 protein may exist in only about 10% of breast tumors (82). Interestingly, overexpressed SRC-3 was detected in breast tumors positive and negative for ER and PR (80, 81). More importantly, SRC-3 overexpression in invasive breast tumors is correlated with high levels of human epidermal growth factor receptor 2 (HER2)/neu (81, 83). In tamoxifen-treated patients, high levels of SRC-3 expression are associated with tamoxifen resistance and worse survival rate. Patients with high levels of both SRC-3 and HER2 exhibit the worst responses to tamoxifen therapy (83). Since HER2 activates MAPK, which in turn phosphorylates ER and SRC-3 (84), the overexpression of both HER2 and SRC-3 may significantly enhance the agonist activity of tamoxifen and, therefore, reduce the antitumor activity of tamoxifen in patients with breast cancer (85).
In breast cancer cells, SRC-3 can be recruited to the estrogen-responsive cyclin D1 promoter to enhance cyclin D1 expression (86). Accordingly, depletion of SRC-3 in MCF-7 breast cancer cells significantly reduced the estrogen-mediated cell proliferation and inhibition of apoptosis. Down-regulation of SRC-3 in MCF-7 cells also reduced estrogen-dependent colony formation in soft agar and tumor growth in nude mice (87). Similar to the effect of SRC-3, depletion of SRC-1 or SRC-2 also inhibited the expression of estrogen-responsive genes and estrogen-dependent cell proliferation (88). More importantly, mammary gland tumorigenesis induced by expression of the mouse mammary tumor virus-v-Ha-ras transgene in the mammary epithelial cells can be significantly suppressed in SRC-3 knockout mice (75). These findings indicate that SRC-3, together with other coactivators, may play a permissive role in breast cancer initiation and progression. Selective inhibition of SRC-3 function in the mammary gland may be a useful approach for prevention and treatment of breast cancer.
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CONCLUDING REMARKS |
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TOPABSTRACTINTRODUCTIONIDENTIFICATION OF THE SRC...STRUCTURAL AND FUNCTIONAL...ROLES FOR SRCs IN...BIOLOGICAL FUNCTIONS OF THE...CONCLUDING REMARKSREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: AD, Activation domain; AR, androgen receptor; ARNT, Ah receptor nuclear translocator; BAT, brown adipose tissue; bHLH, basic helix-loop-helix; CBP, cAMP response element binding protein (CREB)-binding protein; DRIP, vitamin D receptor-interacting protein; ER, estrogen receptor; GR, glucocorticoid receptor; HAT, histone acetyltransferase; HER2, human epidermal growth factor receptor 2; HRE, hormone response element; NcoA, nuclear coactivator; NF-B, nuclear factor-B; NR, nuclear receptor; ODN, antisense oligodeoxynucleotide; PC, Purkinje cell; p/CAF, p300/CBP-associated factor; PGC-1, PPAR coactivator-1; PPAR, peroxisomal proliferator-activated receptor; PR, progesterone receptor; PRMT1, protein arginine methyltransferase 1; RAR, retinoic acid receptor; SC, Sertoli cell; SDN, sexually dimorphic nucleus; SRC, steroid receptor coactivator; SWI/SNF, switch defective/sucrose nonfermenter; TH, thyroid hormone; TIF, transcriptional intermediary factor; TR, thyroid hormone receptor; TRAP, TR-associated protein; WAT, white adipose tissue.
Received for publication April 2, 2003. Accepted for publication June 4, 2003.
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TOPABSTRACTINTRODUCTIONIDENTIFICATION OF THE SRC...STRUCTURAL AND FUNCTIONAL...ROLES FOR SRCs IN...BIOLOGICAL FUNCTIONS OF THE...CONCLUDING REMARKSREFERENCES |
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M. S. Ozers, K. M. Ervin, C. L. Steffen, J. A. Fronczak, C. S. Lebakken, K. A. Carnahan, R. G. Lowery, and T. J. Burke Analysis of Ligand-Dependent Recruitment of Coactivator Peptides to Estrogen Receptor Using Fluorescence Polarization Mol. Endocrinol., January 1, 2005; 19(1): 25 - 34. [Abstract] [Full Text] [PDF]
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J. H. Kim and M. R. Stallcup Role of the Coiled-coil Coactivator (CoCoA) in Aryl Hydrocarbon Receptor-mediated Transcription J. Biol. Chem., November 26, 2004; 279(48): 49842 - 49848. [Abstract] [Full Text] [PDF]
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H. Zhang, S.-Q. Kuang, L. Liao, S. Zhou, and J. Xu Haploid Inactivation of the Amplified-in-Breast Cancer 3 Coactivator Reduces the Inhibitory Effect of Peroxisome Proliferator-Activated Receptor {gamma} and Retinoid X Receptor on Cell Proliferation and Accelerates Polyoma Middle-T Antigen-Induced Mammary Tumorigenesis in Mice Cancer Res., October 1, 2004; 64(19): 7169 - 7177. [Abstract] [Full Text] [PDF]
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D. Masiello, S.-Y. Chen, Y. Xu, M. C. Verhoeven, E. Choi, A. N. Hollenberg, and S. P. Balk Recruitment of {beta}-Catenin by Wild-Type or Mutant Androgen Receptors Correlates with Ligand-Stimulated Growth of Prostate Cancer Cells Mol. Endocrinol., October 1, 2004; 18(10): 2388 - 2401. [Abstract] [Full Text] [PDF]
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N. Khidekel, S. B. Ficarro, E. C. Peters, and L. C. Hsieh-Wilson Exploring the O-GlcNAc proteome: Direct identification of O-GlcNAc-modified proteins from the brain PNAS, September 7, 2004; 101(36): 13132 - 13137. [Abstract] [Full Text] [PDF]
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 A. H. Ludewig, C. Kober-Eisermann, C. Weitzel, A. Bethke, K. Neubert, B. Gerisch, H. Hutter, and A. Antebi A novel nuclear receptor/coregulator complex controls C. elegans lipid metabolism, larval development, and aging Genes & Dev., September 1, 2004; 18(17): 2120 - 2133. [Abstract] [Full Text] [PDF]
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P.-L. Xu, Y.-Q. Liu, S.-F. Shan, Y.-Y. Kong, Q. Zhou, M. Li, J.-P. Ding, Y.-H. Xie, and Y. Wang Molecular Mechanism for the Potentiation of the Transcriptional Activity of Human Liver Receptor Homolog 1 by Steroid Receptor Coactivator-1 Mol. Endocrinol., August 1, 2004; 18(8): 1887 - 1905. [Abstract] [Full Text] [PDF]
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K.-H. Song, Y.-Y. Park, K. C. Park, C. Y. Hong, J. H. Park, M. Shong, K. Lee, and H.-S. Choi The Atypical Orphan Nuclear Receptor DAX-1 Interacts with Orphan Nuclear Receptor Nur77 and Represses Its Transactivation Mol. Endocrinol., August 1, 2004; 18(8): 1929 - 1940. [Abstract] [Full Text] [PDF]
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C. Andrin and M. J. Hendzel F-actin-dependent Insolubility of Chromatin-modifying Components J. Biol. Chem., June 11, 2004; 279(24): 25017 - 25023. [Abstract] [Full Text] [PDF]
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H. J. Lim, I. Moon, and K. Han Transcriptional Cofactors Exhibit Differential Preference toward Peroxisome Proliferator-Activated Receptors {alpha} and {delta} in Uterine Cells Endocrinology, June 1, 2004; 145(6): 2886 - 2895. [Abstract] [Full Text] [PDF]
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A. Goel and R. Janknecht Concerted Activation of ETS Protein ER81 by p160 Coactivators, the Acetyltransferase p300 and the Receptor Tyrosine Kinase HER2/Neu J. Biol. Chem., April 9, 2004; 279(15): 14909 - 14916. [Abstract] [Full Text] [PDF]
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L. Jia, C. S-Y. Choong, C. Ricciardelli, J. Kim, W. D. Tilley, and G. A Coetzee Androgen Receptor Signaling: Mechanism of Interleukin-6 Inhibition Cancer Res., April 1, 2004; 64(7): 2619 - 2626. [Abstract] [Full Text] [PDF]
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J. Huuskonen, P. E. Fielding, and C. J. Fielding Role of p160 Coactivator Complex in the Activation of Liver X Receptor Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 703 - 708. [Abstract] [Full Text] [PDF]
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M. Mark, H. Yoshida-Komiya, M. Gehin, L. Liao, M.-J. Tsai, B. W. O'Malley, P. Chambon, and J. Xu Partially redundant functions of SRC-1 and TIF2 in postnatal survival and male reproduction PNAS, March 30, 2004; 101(13): 4453 - 4458. [Abstract] [Full Text] [PDF]
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S.-Q. Kuang, L. Liao, H. Zhang, A. V. Lee, B. W. O'Malley, and J. Xu AIB1/SRC-3 Deficiency Affects Insulin-Like Growth Factor I Signaling Pathway and Suppresses v-Ha-ras-induced Breast Cancer Initiation and Progression in Mice Cancer Res., March 1, 2004; 64(5): 1875 - 1885. [Abstract] [Full Text] [PDF]
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J.-F. Mouillet, C. Sonnenberg-Hirche, X. Yan, and Y. Sadovsky p300 Regulates the Synergy of Steroidogenic Factor-1 and Early Growth Response-1 in Activating Luteinizing Hormone-{beta} Subunit Gene J. Biol. Chem., February 27, 2004; 279(9): 7832 - 7839. [Abstract] [Full Text] [PDF]
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E. Tzortzakaki, C. Spilianakis, E. Zika, A. Kretsovali, and J. Papamatheakis Steroid Receptor Coactivator 1 Links the Steroid and Interferon {gamma} Response Pathways Mol. Endocrinol., December 1, 2003; 17(12): 2509 - 2518. [Abstract] [Full Text] [PDF]
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