Dataset Information

Cytokine and progesterone receptor interplay in the regulation of MUC1 gene expression.

ABSTRACT: Mucin 1 (MUC1), a transmembrane mucin expressed at the apical surface of uterine epithelia, is a barrier to microbial infection and enzymatic attack. MUC1 loss at implantation sites appears to be required to permit embryo attachment and implantation in most species. MUC1 expression is regulated by progesterone (P) and proinflammatory cytokines, including TNF? and interferon ? (IFN?). TNF? and IFN? are highly expressed in uterine tissues under conditions where MUC1 expression is also high and activate MUC1 expression via their downstream transcription factors, nuclear factor (NF) ?B and signal transducers and activators of transcription. P receptor (PR) regulates MUC1 gene expression in a PR isoform-specific fashion. Here we demonstrate that interactions among PR isoforms and cytokine-activated transcription factors cooperatively regulate MUC1 expression in a human uterine epithelial cell line, HES. Low doses of IFN? and TNF? synergistically stimulate MUC1 promoter activity, enhance PRB stimulation of MUC1 promoter activity and cooperate with PRA to stimulate MUC1 promoter activity. Cooperative stimulation of MUC1 promoter activity requires the DNA-binding domain of the PR isoforms. MUC1 mRNA and protein expression is increased by cytokine and P treatment in HES cells stably expressing PRB. Using chromatin immunoprecipitation assays, we demonstrate efficient recruitment of NF?B, p300, SRC3 (steroid receptor coactivator 3), and PR to the MUC1 promoter. Collectively, our studies indicate a dynamic interplay among cytokine-activated transcription factors, PR isoforms and transcriptional coregulators in modulating MUC1 expression. This interplay may have important consequences in both normal and pathological contexts, e.g. implantation failure and recurrent miscarriages.

SUBMITTER: Dharmaraj N

PROVIDER: S-EPMC2999481 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cytokine and progesterone receptor interplay in the regulation of MUC1 gene expression.

Dharmaraj Neeraja N Wang Peng P Carson Daniel D DD

Molecular endocrinology (Baltimore, Md.) 20101020 12

Mucin 1 (MUC1), a transmembrane mucin expressed at the apical surface of uterine epithelia, is a barrier to microbial infection and enzymatic attack. MUC1 loss at implantation sites appears to be required to permit embryo attachment and implantation in most species. MUC1 expression is regulated by progesterone (P) and proinflammatory cytokines, including TNFα and interferon γ (IFNγ). TNFα and IFNγ are highly expressed in uterine tissues under conditions where MUC1 expression is also high and act ...[more]

PMID: 20962044

Similar Datasets

Project description:Preterm birth (PTB) is the leading cause of morbidity and mortality in infants <1 year of age. Intrauterine inflammation is a hallmark of preterm and term parturition; however, this alone cannot fully explain the pathobiology of PTB. For example, the cervix undergoes a prolonged series of biochemical and biomechanical events, including extracellular matrix (ECM) remodeling and mechanochemical changes, culminating in ripening. Vaginal progesterone (P4) prophylaxis demonstrates great promise in preventing PTB in women with a short cervix (<25 mm). We used a primary culture model of human cervical stromal fibroblasts to investigate gene expression signatures in cells treated with interleukin-1β (IL-1β) in the presence or absence of P4 following 17β-estradiol (17β-E2) priming for 7-10 days. Microarrays were used to measure global gene expression in cells treated with cytokine or P4 alone or in combination, followed by validation of select transcripts by semiquantitative polymerase chain reactions (qRT-PCR). Primary/precursor (MIR) and mature microRNAs (miR) were quantified by microarray and NanoString® platforms, respectively, and validated by qRT-PCR. Differential gene expression was computed after data normalization followed by pathway analysis using Kyoto Encyclopedia Genes and Genomes (KEGG), Panther, Gene Ontology (GO), and Ingenuity Pathway Analysis (IPA) upstream regulator algorithm tools. Treatment of fibroblasts with IL-1β alone resulted in the differential expression of 1432 transcripts (protein coding and non-coding), while P4 alone led to the expression of only 43 transcripts compared to untreated controls. Cytokines, chemokines, and their cognate receptors and prostaglandin endoperoxide synthase-2 (PTGS-2) were among the most highly upregulated transcripts following either IL-1β or IL-1β + P4. Other prominent differentially expressed transcripts were those encoding ECM proteins, ECM-degrading enzymes, and enzymes involved in glycosaminoglycan (GAG) biosynthesis. We also detected differential expression of bradykinin receptor-1 and -2 transcripts, suggesting (prominent in tissue injury/remodeling) a role for the kallikrein-kinin system in cervical responses to cytokine and/or P4 challenge. Collectively, this global gene expression study provides a rich database to interrogate stromal fibroblasts in the setting of a proinflammatory and endocrine milieu that is relevant to cervical remodeling/ripening during preparation for parturition.

Project description:BackgroundThe MUC1 gene encodes a mucin glycoprotein(s) which is basally expressed in most epithelial cells. In breast adenocarcinoma and a variety of epithelial tumors its transcription is dramatically upregulated. Of particular relevance to breast cancer, steroid hormones also stimulate the expression of the MUC1 gene. The MUC1 gene directs expression of several protein isoforms, which participate in many crucial cell processes. Although the MUC1 gene plays a critical role in cell physiology and pathology, little is known about its promoter organization and transcriptional regulation. The goal of this study was to provide insight into the structure and transcriptional activity of the MUC1 promoter.ResultsUsing TRANSFAC and TSSG soft-ware programs the transcription factor binding sites of the MUC1 promoter were analyzed and a map of transcription cis-elements was constructed. The effect of different MUC1 promoter regions on MUC1 gene expression was monitored. Different regions of the MUC1 promoter were analyzed for their ability to control expression of specific MUC1 isoforms. Differences in the expression of human MUC1 gene transfected into mouse cells (heterologous artificial system) compared to human cells (homologous natural system) were observed. The role of estrogen on MUC1 isoform expression in human breast cancer cells, MCF-7 and T47D, was also analyzed. It was shown for the first time that synthesis of MUC1/SEC is dependent on estrogen whereas expression of MUC1/TM did not demonstrate such dependence. Moreover, the estrogen receptor alpha, ERalpha, could bind in vitro estrogen responsive cis-elements, EREs, that are present in the MUC1 promoter. The potential roles of different regions of the MUC1 promoter and ER in regulation of MUC1 gene expression are discussed.ConclusionAnalysis of the structure and transcriptional activity of the MUC1 promoter performed in this study helps to better understand the mechanisms controlling transcription of the MUC1 gene. The role of different regions of the MUC1 promoter in expression of the MUC1 isoforms and possible function of ERalpha in this process has been established. The data obtained in this study may help in development of molecular modalities for controlled regulation of the MUC1 gene thus contributing to progress in breast cancer gene therapy.

Dataset Information

Cytokine and progesterone receptor interplay in the regulation of MUC1 gene expression.

Publications

Cytokine and progesterone receptor interplay in the regulation of MUC1 gene expression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets