Cloning and functional characterization of PELP1/MNAR promoter (original) (raw)
Related papers
Estrogens Correlate with PELP1 Expression in ER Positive Breast Cancer
PLOS ONE, 2015
The Proline-, glutamic acid-and leucine-rich protein 1 (PELP1) is an estrogen receptor (ER) coactivator and a proto-oncogene known to be deregulated in endocrine cancers. In breast cancer, PELP1 overexpression has been associated with endocrine therapy resistance. Although PELP1 is known to be regulated by estrogens in vitro, its association with estrogen levels within the tissue of breast cancer patients has not previously been assessed. Here, we determined PELP1 mRNA expression levels in paired samples of normal and malignant breast tissue obtained from 32 postmenopausal and 11 premenopausal women. In the total sample set, PELP1 levels were higher in tumors compared to normal breast tissue (P = 0.041). Among postmenopausal women, PELP1 tumor levels correlated positively with estrone (E 1 ) and estradiol (E 2 ) levels in both normal tissue (r = 0.543, P = 0.003 and r = 0.601, P = 0.001, respectively) and plasma (r = 0.392, P = 0.053 and r = 0.403, P = 0.046, respectively). Analyzing all ER+ tumors (n = 26), PELP1 correlated positively with E 1 and E 2 in tumor tissue (r = 0.562, P = 0.003 and r = 0.411, P = 0.037, respectively) and normal tissue (r = 0.461, P = 0.018 and r = 0.427, P = 0.030, respectively) in addition to plasma E 1 , E 2 and estrone sulphate (E 1 S) concentrations (r = 0.576, P = 0.003, r = 0.456, P = 0.025 and r = 0.406, P = 0.049, respectively). Finally, PELP1 correlated positively with ER mRNA (ESR1) (r = 0.553, P = 0.026) in ER+ tumors, whereas a negative association between PELP1 and ESR1 (r = -0.733, P = 0.010) was observed in ER-breast tumors. Taken together, tumor PELP1 mRNA expression is associated with estrogen levels in breast cancer, suggesting a potentially important role of PELP1 in ER+ breast cancer growth in vivo.
Molecular …, 2007
Mol. Endocrinol. published online Dec 13, 2007; , doi: 10.1210/me.2007-0350 ... Darrell W Brann, Shiuan Chen, Rajeshwar Rao Tekmal and Ratna K. Vadlamudi Rajib Rajhans, Hareesh B. Nair, Sujit S. Nair, Valarie Cortez, Kijima Ikuko, Nameer B. Kirma, Dujin Zhou, Alan E. ...
Cancer Research, 2007
Proline-, glutamic acid-, leucine-rich protein 1 (PELP1), a novel nuclear receptor coactivator, and its expression is deregulated in hormone-dependent cancers, including those of the breast, endometrium, and ovary. PELP1 interacts with estrogen receptor and modulates its genomic and nongenomic functions. In this study, we examined whether PELP1 functions as an oncogene. The overexpression of PELP1 in fibroblasts and epithelial model cells resulted in cellular transformation. PELP1 also enhanced the transformation potential of c-Src kinase in focus formation assays, and PELP1 overexpression potentiated estradiol-mediated cell migratory potential and anchorage-independent growth. Using PELP1small interfering RNA, we provided evidence that endogenous PELP1 plays an essential role in E2-mediated anchorageindependent growth, cell migration, and cytoskeletal changes. When compared with control vector transfectants, breast cancer cells stably overexpressing PELP1 showed a rapid tumor growth in xenograft studies. Immunohistochemical analysis of PELP1 expression using a tumor progression array of 252 breast carcinomas and normal breast tissue specimens revealed that PELP1 expression is deregulated to a greater degree in higher grade node-positive invasive tumors than in normal breast tissue or ductal carcinoma in situ. Our data suggest that PELP1 is a potential oncogene, that its expression is deregulated during cancer progression, and that PELP1 may play a role in oncogenesis. [Cancer Res 2007;67(11):5505-12]
Endocrine Related Cancer
The overexpression of estrogen receptor alpha (ERalpha) is frequently observed in the early stage of breast cancer. We previously reported that the specific promoter of the ERalpha gene is responsible for this enhanced transcription of the gene, and identified the cis-acting elements which play an important role in its transcription. Furthermore, methylation of the ERalpha gene promoters also contribute to the regulation of gene transcription. Elucidation of these mechanisms of ERalpha gene expression may provide useful information for the early detection and chemoprevention of breast cancer. On the other hand, the expression of ERbeta has been reported in breast cancer. We have also assessed the significance and function of ERbeta and its variant types in breast cancer, and suggest that ERbeta and ERbetacx specifically suppress the function of ERalpha through different mechanisms. ERbeta isoforms may be important functional modulators of the estrogen-signaling pathway in breast can...
Journal of Molecular Endocrinology, 2008
17β-Estradiol binds to the estrogen receptor (ER) to activate gene expression or repression and this involves both genomic (nuclear) and non-genomic (extranuclear) pathways. Genomic pathways include the classical interactions of ligand-bound ER dimers with estrogen-responsive elements in target gene promoters. ER-dependent activation of gene expression also involves DNA-bound ER that subsequently interacts with other DNA-bound transcriptions factors and direct ER-transcription factor (protein–protein) interactions where ER does not bind promoter DNA. Ligand-induced activation of ER/specificity protein (Sp) and ER/activating protein-1 [(AP-1); consisting of jun/fos] complexes are important pathways for modulating expression of a large number of genes. This review summarizes some of the characteristics of ER/Sp- and ER/AP-1-mediated transactivation, which are dependent on ligand structure, cell context, ER-subtype (ERα and ERβ), and Sp protein (SP1, SP3, and SP4) and demonstrates that...
Estrogen Signaling Multiple Pathways to Impact Gene Transcription
Current Genomics, 2006
Steroid hormones exert profound effects on cell growth, development, differentiation, and homeostasis. Their effects are mediated through specific intracellular steroid receptors that act via multiple mechanisms. Among others, the action mechanism starting upon 17 -estradiol (E2) binds to its receptors (ER) is considered a paradigmatic example of how steroid hormones function. Ligand-activated ER dimerizes and translocates in the nucleus where it recognizes specific hormone response elements located in or near promoter DNA regions of target genes. Behind the classical genomic mechanism shared with other steroid hormones, E2 also modulates gene expression by a second indirect mechanism that involves the interaction of ER with other transcription factors which, in turn, bind their cognate DNA elements. In this case, ER modulates the activities of transcription factors such as the activator protein (AP)-1, nuclear factor-B (NF-B) and stimulating protein-1 (Sp-1), by stabilizing DNA-protein complexes and/or recruiting co-activators. In addition, E2 binding to ER may also exert rapid actions that start with the activation of a variety of signal transduction pathways (e.g. ERK/MAPK, p38/MAPK, PI3K/AKT, PLC/PKC). The debate about the contribution of different ER-mediated signaling pathways to coordinate the expression of specific sets of genes is still open. This review will focus on the recent knowledge about the mechanism by which ERs regulate the expression of target genes and the emerging field of integration of membrane and nuclear receptor signaling, giving examples of the ways by which the genomic and non-genomic actions of ERs on target genes converge.
Journal of Molecular Endocrinology, 2005
The expression of estrogen-related receptor-(ERR ) is stimulated by estrogen in selective tissues. Recently, a correlation between ERR expression and the induction of peroxisome proliferator-activated receptor-coactivator-1 (PGC-1 ) in the liver of fasting animals and in cold-stressed brown-fat tissues and skeletal muscle was shown. To explore the molecular mechanisms of ERR regulation by diverse signals, the promoter of the human ERR gene was cloned and characterized. Mutation and deletion analyses revealed that a 53 bp region containing repeated core element AGGTCA motifs of the ERR gene serves as a multi-hormone response element (MHRE) for several nuclear receptors in transient co-transfection studies of human endometrial carcinoma (HEC-1B) cells. Among the nuclear receptors tested, ERR bound to and robustly stimulated the transcription of reporters containing at least two AGGTCA motifs. Ectopic expression of PGC-1 in HEC-1B cells strongly activated the reporter containing the MHRE, presumably via the endogenous nuclear receptor binding to the element. Reducing the endogenous level of ERR by small interfering RNA, and increasing the ERR level by ectopic expression, substantially decreased and increased respectively the transactivation capability of PGC-1 . The activation function 2 domain of the ERR and the L2 and L3 motifs of PGC-1 were essential to transactivate the MHRE. Additionally, PGC-1 increases the amount of endogenous ERR bound to the MHRE region as determined by a chromatin immunoprecipitation assay. The present study demonstrates that the MHRE of the ERR gene is a target for ERR transactivation, which is enhanced by PGC-1 .
Oncogene, 2003
Estrogen receptor (ER) a plays an important role in the proliferation and progression of breast cancer. In order to explore the function of wild-type ERb (ERb1) and its variant form, ERbcx/b2, stable transformants of ERapositive breast cancer MCF7 cells with ERb1 or ERbcx/ b2 expression vector were established. Constitutive expression of ERb1 or ERbcx/b2 reduced the S phase population of the cell cycle in dish culture and the number of colonies in an anchorage-independent assay. DNAprotein complexes of ERE with nuclear extracts from ERb1 transformants were observed in the electrophoretic mobility shift assay, while no complex was observed for ERbcx/b2 transformants. Reporter gene assay using estrogen-responsive element (ERE)-luciferase showed less responsiveness to estrogen in these transformants compared with parental cells. Endogenous mRNA expression of two known estrogen-responsive genes, cathepsin D and IGFBP4, was weakly induced by estrogen in ERb1 and ERbcx/b2 transformants compared with parental cells. A comprehensive gene expression analysis using our custommade cDNA microarray showed that MCF7 and ERb1 transformants had a similar gene expression profile, whereas ERbcx/b2 showed a distinct profile from others. These results indicate that ERb1 and ERbcx/b2 inhibit ERa function differently in MCF7 cells.
Molecular Endocrinology, 1991
Cell proliferation and phenotype of cells from female reproductive tissues are regulated by estrogens. It is therefore important to understand how estrogen action can be modulated. It recently has been reported that certain nuclear receptors can antagonize the tumor promoter 12-O-tetradeconyIphorbol-13acetate (TPA) by direct interaction with the transcription factor AP-1, and that the AP-1 constituents cJun and cFos can inhibit receptor activity. This mutual antagonism appears to be based on direct proteinprotein interaction. In the human breast cancer cell line MCF-7, TPA leads to growth arrest and altered cell morphology. We have investigated here whether in MCF-7 cells and other cell lines AP-1 and estrogen receptors (ERs) can inhibit each other's activity. We find that TPA or the AP-1 components cJun and cFos can inhibit estradiol-dependent estrogen receptor activity in most cell lines investigated. In addition, ER mRNA is rapidly down-regulated in MCF-7 cells. Gel retardation experiments show that ER DNA binding is inhibited in vitro by cJun protein, while ER also can inhibit cJun DNA binding. However, in vivo we do not observe inhibition of AP-1 activity by ER in the cell lines investigated here. On the contrary, we observed an enhancing effect at low ER concentrations on AP-1. Together our data suggest a new regulatory pathway by which ER activity can be modulated by AP-1. Several mechanisms including ER-AP-1 protein interaction appear to be involved.