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At least 325 records · Page 18Linked to original sources
PubMed1999

Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching.

The BCL-6 proto-oncogene encodes a POZ/zinc-finger transcription factor that is expressed in B cells and a subset of CD4(+) T cells within germinal centers. Recent evidence suggests that BCL-6 can act as a sequence-specific repressor of transcription, but the target genes for this activity have not yet been identified. The binding site for BCL-6 shares striking homology to the sites that are the target sequence for the interleukin-4 (IL-4)-induced Stat6 (signal transducers and activators of transcription) signaling molecule. Electrophoretic mobility shift assays demonstrate that BCL-6 can bind, with different affinities, to several DNA elements recognized by Stat6. Expression of BCL-6 can repress the IL-4-dependent induction of immunoglobulin (Ig) germ line epsilon transcripts, but does not repress the IL-4 induction of CD23 transcripts. Consistent with the role of BCL-6 in modulating transcription from the germ line epsilon promoter, BCL-6(-/-) mice display an increased ability to class switch to IgE in response to IL-4 in vitro. These animals also exhibit a multiorgan inflammatory disease characterized by the presence of a large number of IgE(+) B cells. The apparent dysregulation of IgE production is abolished in BCL-6(-/-) Stat6(-/-) mice, indicating that BCL-6 regulation of Ig class switching is dependent upon Stat6 signaling. Thus, BCL-6 can modulate the transcription of selective Stat6-dependent IL-4 responses, including IgE class switching in B cells.

Animals↗
PubMed1988

An RNA polymerase II transcription factor inactivated in poliovirus-infected cells copurifies with transcription factor TFIID.

Inhibition of host cell RNA polymerase II-mediated transcription by poliovirus infection was studied in vitro. Whole-cell extracts prepared from poliovirus-infected HeLa cells at 3 h postinfection were shown to be deficient in a factor required for specific transcription from the adenovirus major late promoter. Three lines of evidence suggest that transcription factor TFIID is deficient in poliovirus-infected cells. First, the activity required to specifically restore transcription in poliovirus-infected cell extracts was shown to copurify with TFIID through three chromatographic steps. Second, transcription reactions reconstituted with phosphocellulose-derived chromatographic fractions revealed a fourfold decrease in the specific activity of the TFIID-containing fraction prepared from poliovirus-infected cells compared with that of the same fraction prepared from mock-infected cells. Finally, TFIID and the activity required to specifically restore transcription in virus-infected cell extracts were shown to have the same kinetics of heat inactivation. Together, these results suggest that inactivation of TFIID is an early event in the inhibition of host cell RNA polymerase II transcription by poliovirus.

Cell Transformation, Viral↗
PubMed1993

Negative transcriptional regulation of human interleukin 2 (IL-2) gene by glucocorticoids through interference with nuclear transcription factors AP-1 and NF-AT.

IL-2 gene transcription is affected by several nuclear proteins. We asked whether dexamethasone (Dex) and cyclosporin A (CsA) inhibit IL-2 gene transcription by interfering with the activity of nuclear proteins that bind to the IL-2 promoter. Nuclear extracts from primary human T lymphocytes were analyzed by electrophoretic DNA mobility shift assays. Both Dex and CsA inhibited the binding of transcription factors AP-1 and NF-AT, but not of NF-kB and OCT-1/OAF, to their corresponding sites on the IL-2 gene promoter. To correlate changes in nuclear factor binding in vitro with transcriptional activity in vivo and define the structural requirements for IL-2 promoter repression, we used transient DNA transfections. Jurkat cells were transfected with plasmids containing either the intact IL-2 promoter or its AP-1, NF-AT, and NF-kB motifs. Dex inhibited the IL-2 promoter and the AP-1, but not the NF-AT and NF-kB plasmids. In contrast, CsA inhibited the IL-2 promoter and the NF-AT, but not the AP-1 and NF-kB plasmids. These results suggest that in human T lymphocytes both Dex and CsA inhibited IL-2 gene transcription through interference with transcription factors AP-1 and NF-AT. We propose that, while maximum inhibition may involve interaction with both transcription factors, AP-1 is the primary target of Dex.

Cyclosporine↗
PubMed2001

Cooperative effects of STAT5 (signal transducer and activator of transcription 5) and C/EBPbeta (CCAAT/enhancer-binding protein-beta) on beta-casein gene transcription are mediated by the glucocorticoid receptor.

Beta-casein gene transcription is controlled primarily by a composite response element (CoRE) that integrates signaling from the lactogenic hormones, PRL, insulin, and hydrocortisone, in mammary epithelial cells. This CoRE contains binding sites for STAT5 (signal transducer and activator of transcription 5) and C/EBPbeta (CCAAT/enhancer-binding protein-beta) and several half-sites for glucocorticoid receptor (GR). To examine how interactions among these three transcription factors might regulate beta-casein gene transcription, a COS cell reconstitution system was employed. Cooperative transactivation was observed when all three factors were expressed, but unexpectedly was not seen between STAT5 and C/EBPbeta in the absence of full-length, transcriptionally active GR. Cooperativity required the amino-terminal transactivation domain of C/EBPbeta, and neither C/EBPalpha nor C/EBPdelta was able to substitute for C/EBPbeta when cotransfected with STAT5 and GR. Different GR determinants were needed for transcriptional cooperation between STAT5 and GR as compared with those required for all three transcription factors. These studies provide some new insights into the mechanisms responsible for high level, tissue-specific expression conferred by the beta-casein CoRE.

Animals↗
PubMed2000

Regulation of tyrosine hydroxylase gene transcription by the cAMP-signaling pathway: involvement of multiple transcription factors.

The conversion of L-tyrosine to 3,4-dihydroxy-L-phenylalanine by tyrosine hydroxylase (TH) is the first and rate-limiting step in biosynthesis of catecholamine neurotransmitters. TH gene expression is regulated in a cell type-specific and cAMP-dependent manner. Evidence from this laboratory and others indicates that the cAMP response element (CRE), residing at -45 to -38 bp upstream of the transcription initiation site, is essential for both basal and cAMP-inducible transcription of the TH gene. To understand the control mechanisms of TH gene transcription in greater detail, we sought to identify and characterize the transcription factors involved in recognition and activation of the CRE of the TH gene. Remarkably, electrophoretic mobility shift assay and antibody supershift experiments indicated that all three major CRE-binding protein factors, i.e. CREB, ATF1, and CREM, may participate in forming specific DNA/protein complexes with the CRE of the TH gene. To address the transcriptional activation function of individual factors, we replaced the TH CRE with a GAL4-binding site and cotransfected this modified TH promoter-reporter gene with an effector plasmid that encodes GAL4-fused transcription factor. Our results indicate that CREB but not ATF1 can support basal promoter activity while both can robustly induce the promoter activity in response to co-expression of the catalytic subunit of cAMP-dependent protein kinase (PKA). We further show that the coactivator CBP up-regulates PKA-mediated activation of the TH promoter and, if tethered to the TH promoter by a GAL4-fusion, can robustly transactivate the TH promoter even in the absence of PKA. Collectively, our results suggest that multiple CRE-binding factors interact with the CRE and regulate, in conjunction with the coactivator CBP, the transcriptional activity of the TH gene.

Activating Transcription Factor 1↗
PubMed1990

Transcriptional and post-transcriptional regulation of c-jun expression during monocytic differentiation of human myeloid leukemic cells.

AP-1, the polypeptide product of c-jun, recognizes and binds to specific DNA sequences and stimulates transcription of genes responsive to certain growth factors and phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA). We studied the effects of TPA on the regulation of c-jun gene expression in HL-60 cells during monocytic differentiation. Low levels of c-jun transcripts were detectable in untreated HL-60 leukemic cells, increased significantly by 6 h, and reached near maximal levels by 24 h of exposure to 32 nM TPA. Similar kinetics of c-jun induction by TPA were observed in human U-937 and THP-1 monocytic leukemia cells. Similar findings were obtained with bryostatin 1 (10 nM), another activator of protein kinase C and inducer of monocytic differentiation. Furthermore, 1,25-dihydroxyvitamin D3 (0.5 microM), a structurally distinct agent which also induces HL-60 monocytic differentiation, increased c-jun expression. TPA treatment of HL-60 cells in the presence of cycloheximide was associated with superinduction of c-jun transcripts. Run-on analysis demonstrated detectable levels of c-jun gene transcription in untreated HL-60 cells, and that exposure to TPA increases this rate 3.3-fold. Treatment of HL-60 cells with both TPA and cycloheximide had no effect on the rates of c-jun transcription. The half-life of c-jun RNA as determined by treating HL-60 cells with TPA and actinomycin D was 30 min. In contrast, the half-life of c-jun RNA in TPA-treated HL-60 cells exposed to cycloheximide and actinomycin D was greater than 2 h. These findings suggested that the increase in c-jun RNA observed during TPA-induced monocytic differentiation is mediated by both transcriptional and post-transcriptional mechanisms.

Calcitriol↗
PubMed1994

Roles for both the RAP30 and RAP74 subunits of transcription factor IIF in transcription initiation and elongation by RNA polymerase II.

Mammalian transcription factor IIF (TFIIF) is a heterodimer composed of approximately 30-kDa (RAP30) and approximately 70-kDa (RAP74) subunits. TFIIF has been shown to bind RNA polymerase II and control the activity of the enzyme in both the initiation and elongation stages of transcription. Although previous studies have established a role for RAP30 in assembly of the preinitiation complex and in transcription initiation, information on the function of RAP74 in these processes has been lacking. Using a highly purified transcription system and assays that permit sensitive measurement of the contributions of both RAP30 and RAP74 to TFIIF function, we have investigated the roles of these TFIIF subunits in transcription initiation and elongation. Results of template competition experiments indicate that both RAP30 and RAP74 contribute to the formation of stable preinitiation intermediates containing RNA polymerase II. Investigation of the role of TFIIF in transcription initiation indicates that both RAP30 and RAP74 function in synthesis of the first few phosphodiester bonds of nascent transcripts and in formation of Sarkosyl-resistant pre-initiation intermediates. Finally, kinetic experiments indicate that both RAP30 and RAP74 function in TFIIF-mediated stimulation of the rate of RNA chain elongation by RNA polymerase II.

Animals↗
PubMed1994

Dominant negative mutant of c-Jun inhibits NF-AT transcriptional activity and prevents IL-2 gene transcription.

Expression of the transcription complex AP-1, composed of Jun and Fos family members, can be induced by a variety of stimuli. In lymphocytes, AP-1 transcriptional activity increases after TCR ligation and plays an important role in T cell activation events such as lymphokine secretion. To explore the requirements for AP-1 in IL-2 production, the AP-1 complex was targeted with a dominant negative mutant c-Jun protein, TAM-67, from which the transactivation domain has been deleted. In transient transfections of Jurkat cells, TAM-67 efficiently inhibited endogenous AP-1 transcriptional activity and blocked the activity of a reporter construct containing the 5' regulatory region of the IL-2 gene. TAM-67 also inhibited the transcriptional activity of nuclear factor-AT (NF-AT), whereas the NF-kappa B, NF-IL-2A, and the proximal TRE-like sites were relatively unaffected. The use of this dominant negative transcription factor suggests that: 1) transactivation-defective nuclear factors represent a novel approach to study the functional consequences of nuclear protein interactions on gene transcription; 2) the proximal TRE-like site from the IL-2 promoter is different from the consensus TRE; and 3) AP-1 plays an important role in the transcriptional activation mediated by the NF-AT binding complex.

Base Sequence↗
PubMed1994

Purification and identification of a vaccinia virus-encoded intermediate stage promoter-specific transcription factor that has homology to eukaryotic transcription factor SII (TFIIS) and an additional role as a viral RNA polymerase subunit.

Enzymes and factors, required for in vitro transcription of templates regulated by vaccinia virus intermediate stage promoters, are present in HeLa cells infected with vaccinia virus in the presence of an inhibitor of DNA replication. Previous studies indicated that in vitro transcription could be reconstituted by adding a partially purified transcription factor to the viral RNA polymerase and capping enzyme. By using an independent purification procedure, we isolated two vaccinia virus intermediate were necessary for transcription of several different intermediate stage promoter templates but not for early or late stage promoter templates. VITF-1 was purified to homogeneity, and the sequences of two tryptic peptides were mapped to the fourth open reading frame within the HindIII E fragment (E4L) of the vaccinia virus genome, which had previously been shown to encode an RNA polymerase subunit of 30 kDa (RPO30) with homology to eukaryotic transcription elongation factor SII. Co-chromatography of VITF-1 with the E4L-derived protein was demonstrated using specific antiserum. In addition, transcriptionally active recombinant VITF-1 was made by expressing the E4L open reading frame in Escherichia coli. Thus, E4L encodes a multifunctional protein, serving as a RNA polymerase subunit and a stage-specific transcription factor. The stepwise binding of capping enzyme, VITF-1, and VITF-2 to a DNA/viral RNA polymerase complex was demonstrated.

Amino Acid Sequence↗
PubMed1993

The DNA-dependent ATPase activity of vaccinia virus early gene transcription factor is essential for its transcription activation function.

Vaccinia virus early transcription factor (VETF) activates the transcription of early gene templates by the viral RNA polymerase. VETF is a heterodimeric protein that binds to transcription promoters and has an associated DNA-dependent ATPase activity. The small subunit of VETF has sequences resembling two motifs commonly found in ATPases: an A-type ATP binding motif and a DEAH box. To investigate the functional role of the ATPase activity, we have analyzed the effect of mutations in each of the putative ATPase motifs. Recombinant VETF was expressed in HeLa cells using a vaccinia virus/T7 RNA polymerase system. Simultaneous expression of both subunits of VETF was required to obtain soluble protein with promoter binding, DNA-dependent ATPase, and transcription activation functions. The mutants with altered ATPase motifs retained promoter binding activity but had no detectable ATPase activity and no ability to activate transcription. The DEAH box mutant was shown to dominantly repress transcription activation by wildtype VETF. These results indicate that the DNA-dependent ATPase activity of VETF is essential for its transcription activation function.

Adenosine Triphosphatases↗
PubMed1993

Wild-type but not mutant p53 can repress transcription initiation in vitro by interfering with the binding of basal transcription factors to the TATA motif.

It has previously been shown that excess wild type (wt) p53 can repress the transcriptional activity of a variety of promoters in intact cells. To determine whether this transcriptional repression represented a direct effect of p53, wt and mutant p53 were prepared from E. coli-produced p53 and from insect cells infected with a recombinant baculovirus. When added into an in vitro transcription system, wt p53, but not mutant p53 reduced markedly transcription from the c-myc promoter, as well as from an array of other promoters, with the exception of an MHC class I gene promoter. The presence of wt p53 seemed to affect specifically the formation of the transcription preinitiation complex because preformed initiation complexes were completely refractory to wt p53, as was also the process of transcript elongation. Wild-type but not mutant p53 interfered with the stable binding of TBP and TFIIA to the TATA motif, although both wt and mutant p53 could associate in vitro with purified TBP. We propose that upon binding to TBP, wt but not mutant p53 specifically blocks the ability of TBP to engage in interactions required for efficient transcriptional initiation. This may account, at least in part, for the ability of excess wt p53 to inhibit cell proliferation and to interfere with neoplastic processes.

Base Sequence↗
PubMed1995

Multiple transcripts encoding heme oxygenase-2 in rat testis: developmental and cell-specific regulation of transcripts and protein.

We report for the first time that heme oxygenase-2 (HO-2) expression is regulated by developmental and cell type-specific factors in the testis, and we describe the presence of three unique sizes of HO-2 transcripts in the testis. HO-2, together with HO-1 (HSP32), catalyzes oxidative cleavage of the heme molecule to biliverdin, carbon monoxide, and iron; HO-2 is the major isozyme of the testis. Northern blot analysis was used to demonstrate the presence of five transcripts for HO-2 in rat testis mRNA; they range from approximately 1.3 to approximately 2.1 kg in length with a predominant 1.45-kb message; three of the transcripts, approximately 1.45 kb, approximately 1.7 kb, and approximately 2.1 kg, are unique to testis. The two other transcripts of approximately 1.3 and approximately 1.9 kb are common to every tissue examined, including the testis. Analysis of three distinct cDNAs isolated from rat libraries in phage lambda indicates that all are identical from -37, relative to translation initiation through the coding region to the first of two poly(A) signals previously identified in the HO-2 gene (McCoubrey and Maines, 1994). Upstream of -37, the 5' untranslated sequences of the isolates differ in both length and sequence. Comparison with the genomic sequence suggests that the multiple transcripts arise by splicing of alternative first exons as well as use of alternate poly(A) signals. Northern hybridization with probes specific for the unique portion of each cDNA are consistent with this interpretation. Further, unlike HO-1, HO-2 messages are developmentally regulated; only approximately 1.3- and approximately 1.9-kb transcripts were detected, at minute levels, in the testis RNA of 7-day-old rats. A pronounced increase in total message level was observed by Day 28 postpartum, although the level had not reached the marked amplification seen in the adult testis. Further, the transcript patterns differed when Day 28 and adult testis were compared to Day 7 testis. The very predominant approximately 1.45-kb band and the approximately 1.7- and 2.1-kb bands were absent from Day 7 testis. Heme oxygenase activity and HO-2 protein levels, as assessed by Western blot, reflect the increases at the RNA level. Interestingly, although abundant HO-2 mRNA can be detected by in situ hybridization in spermatogonia, spermatocytes, and spermatids, HO-2 protein was detected, by immunocytochemistry, only in spermatids. These observations demonstrate tissue and cell specificity of HO-2 gene expression and suggest that in the testis, HO-2 expression is regulated at the transcriptional and translational levels.

Animals↗
PubMed1990

Transcriptional and Post-Transcriptional Regulation of RNA Levels in Maize Mitochondria.

Relatively little is known about the mechanisms that govern the expression of plant mitochondrial genomes. We have addressed this problem by analyzing the transcriptional activity of different regions of the maize mitochondrial genome using both in vivo and isolated mitochondrial pulse-labeling systems. The regions examined included the protein genes atpA, atp6, and coxII, the 26S, 18S, and 5S rRNA genes, and sequences surrounding the rRNA genes. The rRNAs were found to be transcribed at rates fivefold to 10-fold higher than the protein genes. These rate differences are comparable with the differences in abundance of these species in the total or steady-state RNA population. Pulse-labeled RNA unexpectedly detected transcription of all regions examined, including approximately 21 kilobases of presumed noncoding sequences flanking the rRNA genes for which stable transcripts were not detected. The results obtained with RNA labeled for short pulses in vivo and in isolated mitochondria were similar, suggesting that isolated mitochondria provide a faithful run-on transcription assay. Our results indicate that the absence in total RNA of transcripts homologous to a given region of maize mitochondrial DNA does not necessarily exclude transcriptional activity of that region and that both transcriptional and post-transcriptional processes play important roles in maize mitochondrial genome expression.

Journal Article↗
PubMed2002

Analysis of Chlamydia pneumoniae growth in cells by reverse transcription-PCR targeted to bacterial gene transcripts.

Chlamydia pneumoniae is an obligate intracellular bacterium and has a unique development cycle consisting of an elementary body (EB) and reticular body (RB). EBs survive in extracellular environments as well as infect susceptible host cells. However, EBs display no measurable metabolic activity. In contrast, RBs are metabolically active and can replicate in a host cell but are noninfectious. Therefore, analysis of C. pneumoniae growth in infected cells by conventional bacterial culture may not permit sufficient information about growth of the bacteria in cells. In this study, therefore, we examined the usefulness of the reverse transcription (RT)-PCR method for analysis of bacterial transcripts to evaluate C. pneumoniae growth in HEp-2 cells because the levels of bacterial gene transcripts are known to show the metabolic activity of bacteria. The transcripts for the C. pneumoniae hsp60 gene and 16S rRNA in the cells were easily detected just after infection, followed by a marked increase. In contrast, pyk and omcB transcripts slowly increased after a latent period. The hydrocortisone treatment of C. pneumoniae-infected cells induced an increase of all bacterial transcripts tested compared with the control group. The treatment of the infected cells with the antibiotic minocycline showed a selective inhibition of bacterial gene transcripts, even though the complete inhibition of EB production determined by the bacterial culture assay was evident. These results indicate that the determination of bacterial gene transcripts by RT-PCR might be a powerful method to analyze in detail growth of C. pneumoniae in host cells, particularly altered bacterial growth caused by agents such as antimicrobials.

Anti-Bacterial Agents↗
PubMed1994

Pax-3 contains domains for transcription activation and transcription inhibition.

Pax-3 is a member of the Pax family of transcription factors involved in transcriptional control events during embryonic development. Here we report a functional dissection of the Pax-3 protein and describe the protein domains which are responsible for different activities. A transcription inhibition activity is located in the first 90 N-terminal amino acids and includes part of the paired domain. Furthermore, the C terminus of Pax-3 is able to confer transcriptional activation of basal promoters. Pax-3 can utilize both transcription modulating functions and activates transcription over a narrow range of protein concentration in the presence of promoter elements containing functional binding sites.

Amino Acid Sequence↗
PubMed1997

Pancreatic beta-cell-specific repression of insulin gene transcription by CCAAT/enhancer-binding protein beta. Inhibitory interactions with basic helix-loop-helix transcription factor E47.

Chronic exposure of beta-cells to supraphysiologic glucose concentrations results in decreased insulin gene transcription. Here we identify the basic leucine zipper transcription factor, CCAAT/enhancer-binding protein beta (C/EBPbeta), as a repressor of insulin gene transcription in conditions of supraphysiological glucose levels. C/EBPbeta is expressed in primary rat islets. Moreover, after exposure to high glucose concentrations the beta-cell lines HIT-T15 and INS-1 express increased levels of C/EBPbeta. The rat insulin I gene promoter contains a consensus binding motif for C/EBPbeta (CEB box) that binds C/EBPbeta. In non-beta-cells C/EBPbeta stimulates the activity of the rat insulin I gene promoter through the CEB box. Paradoxically, in beta-cells C/EBPbeta inhibits transcription, directed by the promoter of the rat insulin I gene by direct protein-protein interaction with a heptad leucine repeat sequence within activation domain 2 of the basic helix-loop-helix transcription factor E47. This interaction leads to the inhibition of both dimerization and DNA binding of E47 to the E-elements of the insulin promoter, thereby reducing functionally the transactivation potential of E47 on insulin gene transcription. We suggest that the induction of C/EBPbeta in pancreatic beta-cells by chronically elevated glucose levels may contribute to the impaired insulin secretion in severe type II diabetes mellitus.

Animals↗
PubMed1999

Selective binding of steroid hormone receptors to octamer transcription factors determines transcriptional synergism at the mouse mammary tumor virus promoter.

Transcriptional synergism between glucocorticoid receptor (GR) and octamer transcription factors 1 and 2 (Oct-1 and Oct-2) in the induction of mouse mammary tumor virus (MMTV) transcription has been proposed to be mediated through directed recruitment of the octamer factors to their binding sites in the viral long terminal repeat. This recruitment correlates with direct binding between the GR DNA binding domain and the POU domain of the octamer factors. In present study, in vitro experiments identified several nuclear hormone receptors to have the potential to bind to the POU domains of Oct-1 and Oct-2 through their DNA binding domains, suggesting that POU domain binding may be a property shared by many nuclear hormone receptors. However, physiologically relevant binding to the POU domain appeared to be a property restricted to only a few nuclear receptors as only GR, progesterone receptor (PR), and androgen receptor (AR), were found to interact physically and functionally with Oct-1 and Oct-2 in transfected cells. Thus GR, PR, and AR efficiently promoted the recruitment of Oct-2 to adjacent octamer motifs in the cell, whereas mineralocorticoid receptor (MR), estrogen receptor alpha, and retinoid X receptor failed to facilitate octamer factor DNA binding. For MMTV, although GR and MR both induced transcription efficiently, mutation of the promoter proximal octamer motifs strongly decreased GR-induced transcription without affecting the total level of reporter gene activity in response to MR. These results suggest that the configuration of the hormone response element within the MMTV long terminal repeat may promote a dependence for the glucocorticoid response upon the recruitment of octamer transcription factors to their response elements within the viral promoter.

Animals↗
PubMed2003

Selective interactions of Kruppel-like factor 9/basic transcription element-binding protein with progesterone receptor isoforms A and B determine transcriptional activity of progesterone-responsive genes in endometrial epithelial cells.

The Sp/KLF transcription factor basic transcription element-binding protein (BTEB1) regulates gene transcription by binding to GC-rich sequence motifs present in the promoters of numerous tissue-specific as well as housekeeping genes. Similar to other members of this family, BTEB1 can act as a transactivator or transrepressor depending on cell and promoter context, although the molecular mechanism underlying these distinct activities remains unclear. Here we report that BTEB1 can mediate signaling pathways involving the nuclear receptor for the steroid hormone progesterone in endometrial epithelial cells by its selective interaction with the progesterone receptor (PR) isoforms, PR-A and PR-B. Functional interaction with ligand-activated PR-B resulted in superactivation of PR-B transactivity, facilitated the recruitment of the transcriptional integrator CREB-binding protein within the PR-dimer, and was dependent on the structure of the ligand bound by PR-B. By contrast, BTEB1 did not influence agonist-bound PR-A transactivity, although it augmented PR-A inhibition of PR-B-mediated transactivation as well as potentiated ligand-independent PR-A transcriptional activity in the presence of CREB-binding protein. We also demonstrate similar positive modulatory actions of BTEB1-related family members Krüppel-like family (KLF) 13/FKLF2/BTEB3 and Sp1 on PR-B transactivity. Further, we provide support for the potential significance of the selective functional interactions of PR isoforms with BTEB1 in the peri-implantation uterus using mouse and pig models and in the breast cancer cell lines MCF-7 and T47D. Our results suggest a novel mechanism for the divergent physiological consequences of PR-A and PR-B on progesterone-dependent gene transcription in the uterus involving select KLF members.

Animals↗