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PubMed2005

Characterization of two candidate genes, NCoA3 and IRF8, potentially involved in the control of HIV-1 latency.

BACKGROUND: The persistence of latent HIV-1 reservoirs is the principal barrier preventing the eradication of HIV-1 infection in patients by current antiretroviral therapy. It is thus crucial to understand the molecular mechanisms involved in the establishment, maintenance and reactivation of HIV-1 latency. Since chromatin remodeling has been implicated in the transcriptional reactivation of the HIV-1 promoter, we assessed the role of the histone deacetylase inhibitor sodium butyrate (NaB) on two HIV-1 latently infected cell lines (U1 and ACH-2) gene expression. RESULTS: Analysis of microarrays data led us to select two candidate genes: NCoA3 (Nuclear Receptor Coactivator 3), a nuclear receptor coactivator and IRF8 (Interferon Regulatory Factor 8), an interferon regulatory factor. NCoA3 gene expression is upregulated following NaB treatment of latently infected cells whereas IRF8 gene expression is strongly downregulated in the promonocytic cell line following NaB treatment. Their differential expressions were confirmed at the transcriptional and translational levels. Moreover, NCoA3 gene expression was also upregulated after treatment of U1 and ACH-2 cells with phorbol myristyl acetate (PMA) but not trichostatin A (TSA) and after treatment with NaB of two others HIV-1 latently infected cell lines (OM10.1 and J1.1). IRF8 gene is only expressed in U1 cells and was also downregulated after treatment with PMA or TSA. Functional analyses confirmed that NCoA3 synergizes with Tat to enhance HIV-1 promoter transcription and that IRF8 represses the IRF1-mediated activation through the HIV-1 promoter Interferon-stimulated response element (ISRE). CONCLUSION: These results led us to postulate that NCoA3 could be involved in the transcriptional reactivation of the HIV-1 promoter from latency and that IRF8 may contribute to the maintenance of the latent state in the promonocytic cell line. Implication of these factors in the maintenance or reactivation of the viral latency may provide potential new targets to control HIV-1 replication in latent viral reservoirs.

Acetyltransferases↗
PubMed2000

Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3.

Steroid and nuclear receptor coactivators (NCoAs) have been implicated in the regulation of nuclear receptor function by enhancing ligand-dependent transcriptional activation of target gene expression. We have previously isolated receptor-associated coactivator 3 (RAC3), which belongs to the steroid receptor coactivator family. In this study, we investigated the differential mechanisms by which RAC3 interacts with and modulates the transcriptional activity of different nuclear receptors. We found that the vitamin D receptor (VDR) and estrogen receptor beta interact with different alpha-helical LXXLL motifs of RAC3. Peptides corresponding to these motifs have diverse affinities for the VDR and estrogen receptor beta, and mutation of specific motifs differentially impairs the ability of RAC3 to interact with these receptors in vitro. Consequently, these mutations inhibit the enhancement of transcriptional activation by these receptors in vivo. Furthermore, we found that the activation function-2 (AF-2) domain of the retinoid X receptor interferes with RAC3 binding to a DNA-bound VDR/retinoid X receptor (RXR) heterodimer, whereas the VDR AF-2 domain is required for this interaction. These results suggest a receptor-specific binding preference for the different LXXLL motifs of RAC3, which may provide flexibility for RAC3 to differentially regulate the function of different nuclear receptors.

Amino Acids↗
PubMed2004

Expression and function of androgen receptor coactivators in prostate cancer.

Human androgen receptor (AR) associates with coactivator or corepressor proteins that modulate its activation in the presence of ligand. Early studies on AR coactivators in carcinoma of the prostate were hampered because of lack of respective antibodies. Investigations at mRNA level revealed that most benign and malignant prostate cells express common coactivators. AR coactivators SRC-1 and TIF-2 are up-regulated in tissue specimens obtained from patients who failed prostate cancer endocrine therapy. Increased expression of these coactivators is associated with enhanced activation of the AR by the adrenal androgen dehydroepiandrosterone. Similar association between AR coactivator expression and high prostate cancer grade and stage was reported for RAC-3 (SRC-3). The transcriptional integrator CBP was detected in clinical specimens representing organ-confined prostate cancer, lymph node metastases and tumour cell lines. Agonistic effect of the nonsteroidal antiandrogen hydroxyflutamide was strongly potentiated in prostate cells transfected with CBP cDNA. A functional homologue of CBP, p300, is implicated in ligand-independent AR activation by interleukin-6. The AR coactivator Tip60, which is up-regulated by androgen ablation, is recruited to the promoter of the prostate-specific antigen gene in the absence of androgen in androgen-independent prostate cancer sublines. It was proposed that the cofactor ARA70 is a specific enhancer of AR action. However, research from other laboratories has demonstrated interaction between ARA70 and other steroid receptors. Although in some cases dominant-negative coactivator mutants inhibited proliferation of prostate cancer cells in vitro, confirmation from in vivo tumour models is missing. In summary, several abnormalities in AR coactivator expression and function are associated with prostate cancer progression.

Acetyltransferases↗
PubMed2006

Androgen and estrogen receptors and co-regulators levels in endometria from patients with polycystic ovarian syndrome with and without endometrial hyperplasia.

OBJECTIVE: To study if the endocrinological status of PCOS women affects the endometrial sensitivity to steroids by evaluating the expression of androgen receptor (AR), estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), co-activators AIB1 and ARA70, and co-repressor NCoR. METHODS: Gene and/or protein expression of steroid receptors and co-regulators was measured in 17 samples of normal endometrium (NE), 23 PCOS endometrium without treatment (PCOSE), 11 endometria from PCOS women and with endometrial hyperplasia (HPCOSE), and 10 endometria from patients with endometrial hyperplasia (HE), using RT-PCR and/or immunohistochemistry and Western blot. RESULTS: Gene and protein expression of AR was relatively elevated in PCOSE and HPCOSE compared with NE. A significant increase in ERalpha protein expression was observed in PCOSE, preferentially in the nucleus of endometrial cells, whereas ERbeta gene and protein expression increased gradually from PCOSE to HPCOSE and HE, mainly in the epithelial compartment. Importantly, we found a gradual increase in the ERbeta/ERalpha gene and protein expression ratio in endometria from the four groups of women. AIB1 showed increased nuclear protein expression in PCOSE compared to NE, in the presence of a high expression of ARA70 in all groups. High expression of ARA70 together with a normal expression level of AIB1 was observed in HPCOSE. The cytoplasmic immunostaining of NCoR was similar between the four groups of patients. CONCLUSION: The PCOS endometrium exhibits a higher sensitivity to steroid action. We can inferred that these alterations could deregulate the transcription of genes involved in the cell cycle, which may lead to the development of endometrial hyperplasia in PCOS women.

Adult↗
PubMed1998

From estrogen to androgen receptor: a new pathway for sex hormones in prostate.

While all three coactivators ARA70, steroid receptor coactivator 1, and RAC3/ACTR can enhance androgen receptor (AR) transcriptional activity at 1 nM dihydrotestosterone, we here demonstrate that only ARA70 can induce AR transcriptional activity >30-fold in the presence of 10 nM 17beta-estradiol (E2), but not diethylstilbestrol. The significance of this newly described E2-induced AR transcriptional activity in DU145 human prostate cancer cells was further strengthened by finding patients with Reifenstein partial-androgen-insensitive syndrome that fail in the E2-AR-ARA70 pathway. Together, our data suggest, for the first time, testosterone/dihydrotestosterone may not be the only ligands for the AR. E2 represents another important natural ligand for AR that may play an essential role for the AR function and the development of the male reproductive system.

Amino Acid Sequence↗
PubMed2003

Loss of coordinated androgen regulation in nonmalignant ovarian epithelial cells with BRCA1/2 mutations and ovarian cancer cells.

Epidemiological studies have implicated androgens in the etiology/progression of epithelial ovarian cancer. Because normal and malignant ovarian epithelial cells are growth inhibited by transforming growth factor (TGF) beta, we tested the ability of 5alpha-dihydrotestosterone (DHT) to modulate this response and the expression of TGF-beta receptor types I and II. Cells derived from the ovarian surface epithelium of women undergoing oophorectomy (n = 7) for nonovarian indications or with a germ-line BRCA1 or 2 mutation (n = 9), and from the ascitic fluid of patients with primary ovarian cancer (n = 8) were cultured with and without DHT. Cell proliferation after TGF-beta1 or vehicle treatment was determined, and transcripts for TGF-beta receptors were measured by quantitative reverse transcription-PCR. As low levels of androgen receptor were observed in the cultures, we also measured transcript levels for steroid receptor coactivators SRC-1, ARA70, and AIB1. TGF-beta1 inhibited growth in 12 of 13 cultures tested, and DHT generally reversed this effect, demonstrating that androgens can block TGF-beta-induced growth inhibition in both malignant and nonmalignant ovarian epithelial cells. Transcripts for TGF-beta receptors, SRC-1, and ARA70 were found to be coordinately regulated by androgen in control cells, but not in either malignant or BRCA1/2-positive cell cultures. These findings raise the possibility that by modulating steroid receptor coactivator expression, androgen might affect other hormonal responses and contribute to the initiation of ovarian cancer.

Activin Receptors, Type I↗
PubMed2000

Expression of estrogen receptor coactivators in the rat uterus.

Nuclear receptor coactivators associate in a ligand-dependent manner with estrogen receptors (ER) and other nuclear receptors, and they enhance ligand-dependent transcriptional activation. This study examined basal coactivator expression in rat uterus to investigate if expression of these genes is regulated by estradiol-17 beta or tamoxifen. Ovariectomized mature and immature rats were injected with estradiol-17 beta, tamoxifen, or vehicle (i.e., sesame oil) alone. Uteri were collected and analyzed for changes in coactivator mRNA expression using Northern blot and in situ hybridization analyses. Constitutive uterine mRNA expression of switch protein for antagonist (SPA), SRC-1, GRIP1, RAC3, RIP140, and p300 mRNAs was observed in control uteri, and treatment with ER ligands did not alter coactivator mRNA levels. The data suggest that expression of these coactivator genes is not sensitive to estradiol or tamoxifen in the rat uterus. No cell type-specific pattern of expression was apparent in uterine sections from mature and immature rats; however, silver grains were more abundant in luminal and glandular epithelial cells compared with the stroma and myometrium, indicating that coactivator mRNA levels vary among the uterine compartments. Thus, to our knowledge, we show for the first time that there is constitutive expression of several uterine nuclear receptor coactivators in a physiological setting that remains insensitive to estrogenic regulation. Furthermore, we speculate that higher constitutive levels of coactivator expression in glandular and luminal epithelial cells may be associated with increased hormonal responsiveness by these uterine compartments.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Functional genomics identifies a mechanism for estrogen activation of the retinoic acid receptor alpha1 gene in breast cancer cells.

The identification of estrogen receptor (ERalpha) target genes is crucial to our understanding of its predominant role in breast cancer. In this study, we used a chromatin immunoprecipitation (ChIP)-cloning strategy to identify ERalpha-regulatory modules and associated target genes in the human breast cancer cell line MCF-7. We isolated 12 transcriptionally active genomic modules that recruit ERalpha and the coactivator steroid receptor coactivator (SRC)-3 to different intensities in vivo. One of the ERalpha-regulatory modules identified is located 3.7 kb downstream of the first transcriptional start site of the RARA locus, which encodes retinoic acid receptor alpha1 (RARalpha1). This module, which includes an estrogen response element (ERE), is conserved between the human and mouse genomes. Direct binding of ERalpha to the ERE was shown using EMSAs, and transient transfections in MCF-7 cells demonstrated that endogenous ERalpha can induce estrogen-dependent transcriptional activation from the module or the ERE linked to a heterologous promoter. Furthermore, ChIP assays showed that the coregulators SRC-1, SRC-3, and receptor-interacting protein 140 are recruited to this intronic module in an estrogen-dependent manner. As expected from previous studies, the transcription factor Sp1 can be detected at the RARA alpha1 promoter by ChIP. However, treatment with estradiol did not influence Sp1 recruitment nor help recruit ERalpha to the promoter. Finally, ablation of the intronic ERE was sufficient to abrogate the up-regulation of RARA alpha1 promoter activity by estradiol. Thus, this study uncovered a mechanism by which ERalpha significantly activates RARalpha1 expression in breast cancer cells and exemplifies the utility of functional genomics strategies in identifying long-distance regulatory modules for nuclear receptors.

Acetyltransferases↗
PubMed2005

Differential recruitment of p160 coactivators by glucocorticoid receptor between Schwann cells and astrocytes.

In the nervous system, glucocorticoids can exert beneficial or noxious effects, depending on their concentration and the duration of hormonal stimulation. They exert their effects on neuronal and glial cells by means of their cognate receptor, the glucocorticoid receptor (GR), which recruits the p160 coactivator family members SRC-1 (steroid receptor coactivator 1), SRC-2, and SRC-3 after hormone binding. In this study, we investigated the molecular pathways used by the GR in cultured glial cells of the central and the peripheral nervous systems, astrocytes and Schwann cells (MSC80 cells), respectively. We performed functional studies based on transient transfection of a minimal glucocorticoid-sensitive reporter gene into the glial cells to test the influence of overexpression or selective inhibition by short interfering RNA of the three p160 coactivator family members on GR transactivation. We demonstrate that, depending on the glial cell type, GR differentially recruits p160 family members: in Schwann cells, GR recruited SRC-1a, SRC-1e, or SRC-3, whereas in astrocytes, SRC-1e and SRC-2, and to a lesser extent SRC-3, were active toward GR signaling. The C-terminal nuclear receptor-interacting domain of SRC-1a participates in its exclusion from the GR transcriptional complex in astrocytes. Immunolocalization experiments revealed a cell-specific intracellular distribution of the p160s, which was dependent on the duration of the hormonal induction. For example, within astrocytes, SRC-1 and SRC-2 were mainly nuclear, whereas SRC-3 unexpectedly localized to the lumen of the Golgi apparatus. In contrast, in Schwann cells, SRC-1 showed a nucleocytoplasmic shuttling depending on hormonal stimulation, whereas SRC-2 remained strictly nuclear and SRC-3 remained predominantly cytoplasmic. Altogether, these results highlight the cell specificity and the time dependence of p160s recruitment by the activated GR in glial cells, revealing the complexity of GR-p160 assembly in the nervous system.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Association of NCOA3 polymorphisms with breast cancer risk.

The nuclear receptor coactivator 3 (NCOA3, also known as AIB1) is a coactivator of nuclear receptors like the estrogen receptor. NCOA3 is overexpressed in approximately 60% of primary human breast tumors, and high levels of NCOA3 expression are associated with tamoxifen resistance and worse survival rate. In contrast, NCOA3 deficiency suppresses v-Ha-ras-induced breast cancer initiation and progression in mice. Here, we analyzed the influence of NCOA3 coding single nucleotide polymorphisms on breast cancer risk by performing a case-control study using a German and a Polish study population and identified an association between NCOA3 polymorphisms and breast cancer. A joint analysis of the German and the Polish study population revealed a significant protective effect for the 1758G>C (Q586H) and 2880A>G (T960T) variants. In addition, haplotype analysis showed a protective effect of the 1758C-2880A and 1758G-2880G haplotypes (odds ratio 0.79; 95% confidence interval, 0.67-0.93; P = 0.004). Because of the impact of NCOA3 in antiestrogen therapy resistance, these polymorphisms might also influence therapy outcome in breast cancer.

Acetyltransferases↗
PubMed1998

The receptor-associated coactivator 3 activates transcription through CREB-binding protein recruitment and autoregulation.

Transcriptional coactivators are involved in gene activation by nuclear hormone receptors. The receptor-associated coactivator 3 (RAC3) was recently identified to be highly related to the steroid receptor coactivator-1 and transcriptional intermediate factor 2, thereby establishing a novel family of nuclear receptor coactivators. In this study, we identified a RAC3 fragment containing three LXXLL motifs conserved among this family, which is sufficient to mediate nuclear receptor interaction in vivo and in vitro. Point mutations that disrupt ligand-dependent activation function of the receptor inhibited the interaction. We found that a 162-amino acid fragment of RAC3 conferred transcriptional activation and recruited the CREB-binding protein and that three distinct LXXLL motifs mediated the transcriptional activation. A trimeric far Western analysis demonstrated the formation of a ternary complex containing CREB-binding protein, RAC3, and the receptor. In addition, we showed that RAC3, transcriptional intermediate factor 2, and steroid receptor coactivator-1 are expressed in specific tissues and cancer cells and that RAC3 transcript is directly up-regulated by retinoid treatment. These results suggest that RAC3 may contribute to amplified transcriptional responses through both recruitment of additional coactivators and autoregulation by the receptor-coactivator complex.

Animals↗
PubMed2001

Gene amplification and expression of the steroid receptor coactivator SRC3 (AIB1) in sporadic breast and endometrial carcinomas.

Steroid receptor coactivator 3 (SRC3) functions as a coactivator for nuclear receptor mediated transcriptional activation. It binds to nuclear receptors in a ligand-dependent fashion and recruits other factors such as CBP and p300 to the transactivation complex. Due to its function as activator of nuclear receptors, overexpression of SRC3 might enhance their effects. Gene amplification is a common mechanism that causes overexpression, already described for oncogenes like c-erbB2, c-myc and int2. In this study, SRC3 gene amplification and expression levels were analyzed in 127 sporadic breast carcinomas, 30 endometrial carcinomas and different cell lines (MCF7, HeLa, Ishikawa, T47D, BT-20, SK-BR-3, HEC-1a, RL 95-2, OVCAR3 and A-431). To determine gene amplification and mRNA expression levels, quantitative differential PCR and RT-PCR were performed in combination with fluorescent DNA technology. Gene amplification was not found in any of the breast and endometrial carcinomas, but was found in the carcinoma cell lines MCF7 (10-fold) and HeLa (3-fold). SRC3 overexpression was detected in 13% (3/23) of breast carcinomas and 17% (5/30) of endometrial carcinomas, as well as in MCF7 and HeLa cells. Thus, SRC3 overexpression found in breast and endometrial tumors is not caused by SRC3 gene amplification. A carcinogenic potential provided by SRC3 overexpression has to be elucidated in further studies.

Breast Neoplasms↗
PubMed2006

Absence of the steroid receptor coactivator-3 induces B-cell lymphoma.

Steroid receptor coactivator 3 (SRC-3/ACTR/AIB-1/pCIP/RAC3/TRAM-1) is a member of the p160 family of nuclear receptor coactivators that plays an important role in mammary gland growth, development, and tumorigenesis. We show that deletion of SRC-3 gene decreases platelet and increases lymphocytes numbers, leading to the development of malignant B-cell lymphomas upon aging. The expansion of the lymphoid lineage in SRC-3(-/-) mice is cell autonomous, correlates with an induction of proliferative and antiapoptotic genes secondary to constitutive NF-kappaB activation, and can be reversed by restoration of SRC-3 expression. NF-kappaB activation is explained by the degradation of IkappaB, consequent to increases in free IkappaB kinase, which is no longer inhibited by SRC-3. These results demonstrate that SRC-3 regulates lymphopoiesis and in combination with previous studies indicate that SRC-3 has vastly diverging effects on cell proliferation depending on the cellular context, ranging from proliferative and tumorigenic (breast) to antiproliferative (lymphoid cells) effects.

Animals↗
PubMed2003

Role of the steroid receptor coactivator SRC-3 in cell growth.

Steroid receptor coactivator 3 (SRC-3/p/CIP/AIB1/ACTR/RAC3/TRAM-1) is a member of the p160 family of nuclear receptor coactivators, which includes SRC-1 (NCoA-1) and SRC-2 (TIF2/GRIP1/NCoA2). Previous studies indicate that SRC-3 is required for normal animal growth and is often amplified or overexpressed in many cancers, including breast and prostate cancers. However, the mechanisms of SRC-3-mediated growth regulation remain unclear. In this study, we show that overexpression of SRC-3 stimulates cell growth to increase cell size in prostate cancer cell lines. Furthermore, our results indicate that overexpression of SRC-3 can modulate the AKT signaling pathway in a steroid-independent manner, which results in the activation of AKT/mTOR signaling concomitant with an increase in cell size. In contrast, down-regulation of SRC-3 expression in cells by small interfering RNA decreases cell growth, leading to a smaller cell size. Similarly, in SRC-3 null mutant mice, AKT signaling is down-regulated in normally SRC-3-expressing tissues. Taken together, these results suggest that SRC-3 is an important modulator for mammalian cell growth.

Animals↗
PubMed2004

Role of p160 coactivator complex in the activation of liver X receptor.

OBJECTIVE: Liver X receptor (LXR) is a member of a nuclear receptor family regulating the expression of several key proteins involved in lipid metabolism and inflammation. In contrast to several other nuclear receptors, very little is known about the coactivators needed for the agonist-mediated transactivation by LXR. In this study, we have investigated the role of p160 coactivator complex in the regulation of ATP-binding transporter A1 (ABCA1), a clinically important gene transcriptionally upregulated by LXR/RXR (retinoid X receptor) heterodimer. METHODS AND RESULTS: Overexpression of LXRalpha, SRC-1, and p300, either alone or in combination, increased the luciferase activity driven by the wild-type ABCA1 promoter. The same coactivators bound to the ABCA1 promoter on oxysterol induction in chromatin immunoprecipitation assays. To the contrary, CARM-1 and P/CAF had no effect on ABCA1 transactivation, nor do they bind the promoter. When the DR-4 element was mutated from the ABCA1 promoter, only p300 was able to activate ABCA1 transcription in a ligand-independent manner. CONCLUSIONS: The p160 coactivator complex members SRC-1 and p300, but not CARM-1 and P/CAF, coactivate LXR-mediated transcription of ABCA1 gene. In addition, p300 activates ABCA1 transcription independently of DR-4 element and LXR/RXR.

ATP Binding Cassette Transporter 1↗
PubMed1998

Transcription factor-specific requirements for coactivators and their acetyltransferase functions.

Different classes of mammalian transcription factors-nuclear receptors, cyclic adenosine 3',5'-monophosphate-regulated enhancer binding protein (CREB), and signal transducer and activator of transcription-1 (STAT-1)-functionally require distinct components of the coactivator complex, including CREB-binding protein (CBP/p300), nuclear receptor coactivators (NCoAs), and p300/CBP-associated factor (p/CAF), based on their platform or assembly properties. Retinoic acid receptor, CREB, and STAT-1 also require different histone acetyltransferase (HAT) activities to activate transcription. Thus, transcription factor-specific differences in configuration and content of the coactivator complex dictate requirements for specific acetyltransferase activities, providing an explanation, at least in part, for the presence of multiple HAT components of the complex.

Acetyltransferases↗
PubMed1999

p300/cAMP-responsive element-binding protein interactions with ets-1 and ets-2 in the transcriptional activation of the human stromelysin promoter.

In this paper we show that transcription factors Ets-1 and Ets-2 recruit transcription adapter proteins p300 and CBP (cAMP-responsive element-binding protein) during the transcriptional activation of the human stromelysin promoter, which contains palindromic Ets-binding sites. Ets-2 and p300/CBP exist as a complex in vivo. Two regions of p300/CBP between amino acids (a.a.) 328 and 596 and a. a. 1678 and 2370 independently can interact with Ets-1 and Ets-2 in vitro and in vivo. Both these regions of p300/CBP bind to the transactivation domain of Ets-2, whereas the C-terminal region binds only to the DNA binding domain of Ets-2. The N- and the C-terminal regions of CBP (a.a. 1-1097 and 1678-2442, respectively) which lack histone acetylation activity independently are capable of coactivating Ets-2. Other Ets family transcription factors failed to cooperate with p300/CBP in stimulating the stromelysin promoter. The LXXLL sequence, reported to be important in receptor-coactivator interactions, does not appear to play a role in the interaction of Ets-2 with p300/CBP. Previous studies have shown that the stimulation of transcriptional activation activity of Ets-2 requires phosphorylation of threonine 72 by the Ras/mitogen-activated protein kinase signaling pathway. We show that mutation of this site does not affect its capacity to bind to and to cooperate with p300/CBP.

Binding Sites↗