The functionally conserved proteins CBP and p300 act in conjunction with other factors to activate transcription of DNA. A new factor, p/CIP, has been discovered that is present in the cell as a complex with CBP and is required for transcriptional activity of nuclear receptors and other CBP/p300-dependent transcription factors. The highly related nuclear-receptor coactivator protein NCoA-1 is also specifically required for ligand-dependent activation of genes by nuclear receptors. p/CIP, NCoA-1 and CBP all contain related leucine-rich charged helical interaction motifs that are required for receptor-specific mechanisms of gene activation, and allow the selective inhibition of distinct signal-transduction pathways (Torchia, 1997).
Members of the recently recognized SRC-1 family of transcriptional coactivators interact with steroid hormone receptors to enhance ligand-dependent transcription. AIB1, a member of the SRC-1 family, was cloned during a search on the long arm of chromosome 20 for genes whose expression and copy number were elevated in human breast cancers. AIB1 amplification and overexpression were observed in four of five estrogen receptor-positive breast and ovarian cancer cell lines. Subsequent evaluation of 105 unselected specimens of primary breast cancer found AIB1 amplification in approximately 10 percent and high expression in 64 percent of the primary tumors analyzed. AIB1 protein interacts with estrogen receptors in a ligand-dependent fashion, and transfection of AIB1 results in enhancement of estrogen-dependent transcription. These observations identify AIB1 as a nuclear receptor coactivator whose altered expression may contribute to development of steroid-dependent cancers (Anzick, 1997).
Nuclear receptors regulate transcription by binding to specific DNA response elements of target genes. The molecular cloning and characterization of a novel Xenopus cDNA encoding a transcription coactivator xSRC-3 has been carried out by using retinoid X receptor (RXR) as a bait in a yeast two-hybrid screening. It belongs to a growing coactivator family that includes a steroid receptor coactivator amplified in breast cancer (AIB1), p300/ CREB-binding protein (CBP)-interacting protein (p/ CIP), and transcriptional intermediate factor 2 (TIF2). It also interacts with a series of nuclear receptors including retinoic acid receptor (RAR), thyroid hormone receptor (TR), and orphan nuclear receptors [hepatocyte nuclear receptor 4 (HNF4) and constitutive androstane receptor (CAR)]. However, it does not interact with small heterodimer partner (SHP), an orphan nuclear receptor known to antagonize ligand-dependent transactivation of other nuclear receptors. In CV-1 cells, cotransfection of xSRC-3 differentially stimulates ligand-induced transactivation of RXR, TR, and RAR in a dose-dependent manner. Interestingly, xSRC-3 is highly expressed in adult liver and early stages of oocyte development, suggesting that studies of xSRC-3 may lead to better understanding of the roles nuclear receptors play in oocyte development as well as liver-specific gene expression (Kim, 1998).
A family of p160 coactivators was initially identified based on ligand-dependent interactions with nuclear receptors and thought to function, in part, by recruiting CREB-binding protein/p300 to several classes of transcription factors. One of the p160 factors, p/CIP/AIB1, often amplified and overexpressed in breast cancer, also exhibits particularly strong interaction with CREB-binding protein/p300. p/CIP, which exhibits regulated transfer from cytoplasm to nucleus, is required for normal somatic growth from embryonic day 13.5 through maturity. These data suggest that a short stature phenotype of p/CIP gene-deleted mice reflect both altered regulation of insulin-like growth factor-1 (IGF-1) gene expression in specific tissues and a cell-autonomous defect of response to IGF-1, including ineffective transcriptional activities by several classes of regulated transcription factors under specific conditions. The actions of p/CIP are therefore required for full expression of a subset of genes critical for regulating physiological patterns of somatic growth in mammals (Wang, 2000).
Coactivators are believed to mediate estrogen-induced gene responses via interaction with estrogen receptors (ER). Currently, a major challenge is to determine the importance of each coactivator in a specific cell type and promoter context in response to a particular ligand. The potential of ER to interact with a growing list of coactivators has been shown in a variety of in vitro and gene transfer assays, yet very few data have demonstrated the interaction of endogenous coactivators with ER in intact cells. A ligand-specific interaction of endogenous human ER (hER) and the AIB1 coactivator in MCF-7 human breast cancer cells using immunoprecipitation analyses is described. Complexes between endogenously expressed hER and AIB1 are detected in estradiol-treated cells and to a much lesser extent in cells treated with the partial agonist, monohydroxytamoxifen. An hER-SRC-1 complex could not be detected in immunoprecipitations from MCF-7 cells. The in vitro-binding affinity for mouse ER interaction with AIB1 was estimated to be 40-120 nM. It is concluded that AIB1 is a major coactivator for hER in MCF-7 human breast cancer cells (Tikkanen, 2000).
Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. The transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1 (Font de Mora, 2000).
Steroid receptor coactivator-3 (SRC-3) is a coactivator of nuclear receptors in the SRC family as assayed in vitro. Mouse SRC-3 is expressed in a tissue-specific fashion and distributed mainly in the oocytes, mammary glands, hippocampus, olfactory bulb, smooth muscle, hepatocytes, and vaginal epithelium. Genetic disruption of SRC-3 in mice results in a pleiotropic phenotype showing dwarfism, delayed puberty, reduced female reproductive function, and blunted mammary gland development. Hormonal analysis indicates that SRC-3 plays a role in both the growth hormone regulatory pathway and the production of estrogen, which may explain the observed phenotypes. These results suggest that the physiological role of SRC-3 is different from that of SRC-1 and prove the diversity among coactivator family members (Xu, 2000).
The AIB1 gene was isolated upon microdissection of the homogeneously staining regions observed in breast cancer cell lines. It was subsequently shown to map at a region of 20q12 that is frequently amplified in breast tumors. In a screen of breast tumor cell lines, of all the genes mapping to the region, AIB1 appears to be the most consistently amplified and overexpressed. AIB1 shares homology with the SRC-1 family of nuclear receptor coactivators. It interacts in a ligand-dependent manner with the estrogen receptor (ER) and results in increased levels of estrogen-dependent transcription. These properties could be of important biological significance in breast and ovarian cancerigenesis, and it was therefore of interest to determine whether the amplification of the AIB1 gene is associated with a particular phenotype or subgroup in these tumors. A population of 1157 breast and 122 ovarian tumors was tested in which DNA amplification had been determined previously at 15 chromosomal locations. Amplification of the AIB1 gene was observed in 4.8% of breast cancers and 7.4% of ovarian cancers. In breast tumors, AIB1 is correlated positively with both ER and progesterone receptor, as well as with tumor size. A postivie correlation has also been observed with the amplification of MDM2 and FGFR1 genes, but interestingly, no correlation was found with the amplification of CCND1, which is known to be strongly associated with ER. Furthermore, analyzing at 20q12-q13 range, the existence of three amplification cores, represented by AIB3/AIB4, AIB1, and RMC20C001, has been shown. Thus, AIB1 and CCND1 amplifications may represent two different subsets of ER-positive breast tumors (Bautista, 1998).
The gene for the steroid receptor coactivator amplified in breast cancer 1 (AIBI), located on chromosome 20q12, is overexpressed at the mRNA level in up to 60% of primary breast carcinomas; however, only 5% of these tumors show DNA amplification. The transcription factors and signaling pathways relevant to breast cancer, which in the absence of DNA amplification are responsible for and targeted by elevated levels of AIBI mRNA, are unknown. In the present study, in situ hybridization was used to examine AIB1 mRNA expression in 93 breast carcinomas of varying histological grade and immunohistochemical profile. AIB1 mRNA was found to be overexpressed relative to normal breast tissue in 26 of 83 (31%) invasive tumors. This was found to associate with high tumor grade, lack of immunohistochemical staining for the steroid receptors estrogen receptor and progesterone receptor, and strong protein staining for p53. These findings suggest that AIB1 overexpression may impact on breast cancer by a mechanism not wholly dependent on steroid receptor coexpression and which may involve other oncogenic events, such as p53 protein stabilization and HER2/neu overexpression (Bouras, 2001).
Border cell migration is a process that occurs during Drosophila ovarian development in which cells derived from a simple epithelium migrate and invade neighboring tissue. This process resembles the behavior of cancerous cells that derive from the simple epithelium of the human ovary. One important regulator of border cell migration is Taiman, a homolog of steroid receptor coactivator-3 (SRC-3). Because increasing evidence indicates that similarities exist between the molecular control of migration of border cells and of cancer cells, whether SRC-3 controls ovarian cancer cell migration was investigated. Little or no SRC-3 expression was detected in normal ovarian surface epithelium, ovarian cysts and borderline ovarian tumors that lack stromal invasion. In contrast, SRC-3 was abundantly expressed in high-grade ovarian carcinomas. Inhibiting SRC-3 expression in ovarian cancer cells markedly reduced cell spreading and migration, and altered intracellular localization of focal adhesion kinase. This inhibitory effect on cell migration was independent of the estrogen receptor (ER) status of the cells. These studies reveal a novel role for SRC-3 in ovarian cancer progression by promoting cell migration, independently of its role in estrogen receptor signaling (Yoshida, 2005).
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