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PubMed1989

[Signals and transcription factors].

The relationship between growth signals and transcriptional activator proteins was studied using polyomavirus enhancer as a probe. Transiently expressed Ha-ras gene and a tumor promoting phorbol ester, TPA, strongly stimulated the activity of polyomavirus enhancer in NIH3T3 cells. In both cases, the target of this stimulation was a 24 base pair long A core. At least two nuclear factors, PEBP1 and 2, bind to this core region. The target of stimulation in both cases was the recognition sequence of PEBP1 which is an AP1 consensus sequence. In nuclear extract of NIH3T3 cells stably transformed by Ha-ras gene, however, binding of neither PEBP1 nor PEBP2 was detected. Instead a new factor, PEBP3, emerged to share the binding site with PEBP2. PEBP3 was purified and found to be composed of 2 subunits, alpha and beta. Each of these subunits binds to the same sequence as that of PEBP3. PEBP3 binds to B core, as well as to A core. Preliminary evidence suggests that PEBP2 has an unidentified subunit in addition to alpha and beta. Proper phosphorylation required for PEBP1 for DNA binding and PEBP2 converts to PEBP3 in under-phosphorylation conditions. A repressor, PEBP4, has been identified which partly shares the recognition sequence with PEBP2. This factor is present in F9 embryonal carcinoma cells as well as in those induced to differentiate. On the other hand, neither PEBP1 nor PEBP2 were detected in F9 cells. Both of them became detectable after differentiation. Based on these results, a hypothesis was proposed for developmental regulation and alteration of such regulation in cancer cells.

Animals↗
PubMed1999

Thermo-labile stability of sigmaH (Spo0H) in temperature-sensitive spo0H mutants of Bacillus subtilis can be suppressed by mutations in RNA polymerase beta subunit.

We isolated novel temperature-sensitive mutants of spo0H, spo0H1 and spo0H5, having E61K and G30E amino-acid substitutions within the sigmaH protein, respectively, and located in the highly conserved region, "2", among prokaryotic sigma factors that participates in binding to core enzyme of RNA polymerase. These mutants showed a sporulation-deficient phenotype at 43 degrees C. Moreover, we successfully isolated suppressor mutants that were spontaneously generated from the spo0H mutants. Our genetic analysis of these suppressor mutations revealed that the suppressor mutations are within the rpoB gene coding for the beta subunit of RNA polymerase. The mutations caused single amino-acid substitutions, E857A and P1055S, in rpoB18 and rpoB532 mutants that were generated from spo0H1 and spo0H5, respectively. Whereas the sigmaH-dependent expression of a spo0A-bgaB fusion was greatly reduced in both spo0H mutants, their expression was partially restored in the suppressor mutants at 43 degrees C. Western blot analysis showed that the level of sigmaH protein in the wild type increased between T0 and T2 and decreased after T3, while the level of sigmaH protein in spo0H mutants was greatly reduced throughout growth, indicating that the mutant sigmaH proteins were rapidly degraded by some unknown proteolytic enzyme(s). The analysis of the half-life of sigmaH protein showed that the short life of sigmaH in spo0H mutants is prolonged in the suppressor mutants. These findings suggest that, at least to some extent, the process of E-sigmaH formation may be involved in stabilization of sigmaH at the onset of sporulation.

Bacillus subtilis↗
PubMed1995

Transactivation of the Moloney murine leukemia virus and T-cell receptor beta-chain enhancers by cbf and ets requires intact binding sites for both proteins.

The Moloney murine leukemia virus (Mo-MLV) enhancer contains binding sites (LVb and LVc) for the ets gene family of proteins and a core site that binds the polyomavirus enhancer-binding protein 2/core-binding factor (cbf) family of proteins. The LVb and core sites in the Mo-MLV enhancer contribute to its constitutive activity in T cells. All three binding sites (LVb, LVc, and core) are required for phorbol ester inducibility of the Mo-MLV enhancer. Adjacent binding sites for the ets and cbf proteins likewise constitute a phorbol ester response element within the human T-cell receptor beta-chain (TCR beta) enhancer and contribute to constitutive transcriptional activity of the TCR beta enhancer in T cells. Here we show that the CBF alpha subunit encoded by the mouse Cbfa2 gene (the murine homolog of human AML1) and three ets proteins, Ets-1, Ets-2, and GA-binding protein (GABP), transactivate both the Mo-MLV and mouse TCR beta enhancer in transient-expression assays. Moreover, we show that transactivation by Cbf alpha 2 requires both intact ets and cbf binding sites. Transactivation by Ets-1, Ets-2, and GABP likewise requires intact binding sites for ets proteins and CBF. Supportive biochemical analyses demonstrate that both proteins can bind simultaneously to a composite enhancer element. These findings suggest that ets and cbf proteins cooperate in vivo to regulate transcription from the Mo-MLV and TCR beta enhancers.

Animals↗
PubMed1991

Characterization of a factor(s) from partially purified human gonadotrophin preparations which inhibit(s) the binding of radiolabelled human LH and human chorionic gonadotrophin to Candida albicans.

We have shown previously that partially purified human chorionic gonadotrophin (hCG) preparations inhibited the specific binding of 125I-labelled hLH or hCG to Candida albicans membranes at much lower concentrations than did highly purified hLH or hCG preparations. We now describe the characterization and partial purification of a heat-labile glycoprotein from commercially available gonadotrophin preparations. The factor strongly inhibited LH binding to Candida membranes, but not to sheep or pig luteal LH receptors. This material had a molecular weight of 16,000-21,000 daltons, bound strongly to CM-Sepharose at physiological pH, and could be resolved completely from hCG and from epidermal growth factor-like factors present in commercial gonadotrophin preparations. Its activity was not attenuated by a range of inhibitors specific for the four major classes of proteolytic enzymes, nor did it inhibit hormone binding by causing degradation of 125I-labelled hLH or hCG tracers. Factors which inhibited hLH binding to Candida membranes were also present in partially purified human urinary and equine serum gonadotrophin preparations and in placental extracts, but were not detected in highly purified CG of hLH preparations. The properties of this factor were similar to those described for beta-core protein, a cleavage product of the beta subunit of hCG which is a contaminant of commercial gonadotrophin preparations. Highly purified beta-core protein inhibited 125I-labelled hLH binding to Candida membranes, but not to sheep luteal binding sites. Preparations of hCG depleted of inhibitor activity could stimulate adenylate cyclase activity in Candida membranes almost five fold. In contrast, partially purified inhibitor preparations strongly inhibited basal adenylate cyclase activity (to 18% of control levels). These observations suggest that endogenous LH-like factors, perhaps similar to beta-core proteins of hCG, may play a role in the regulation of morphogenesis in Candida species.

Adenylyl Cyclases↗
PubMed2006

Regulation of osteoblast differentiation by transcription factors.

Runx2, osterix, and beta-catenin are essential for osteoblast differentiation. Runx2 directs multipotent mesenchymal cells to an osteoblastic lineage, and inhibits them from differentiating into the adipocytic and chondrocytic lineages. After differentiating to preosteoblasts, beta-catenin, osterix, and Runx2 direct them to immature osteoblasts, which produce bone matrix proteins, blocking their potential to differentiate into the chondrocytic lineage. Runx2 inhibits osteoblast maturation and the transition into osteocytes, keeping osteoblasts in an immature stage. Other transcription factors including Msx1, Msx2, Dlx5, Dlx6, Twist, AP1(Fos/Jun), Knox-20, Sp3, and ATF4 are also involved in osteoblast differentiation. To gain an understanding of bone development, it is important to position these transcription factors to the right places in the processes of osteoblast differentiation.

Animals↗
PubMed1993

Upstream regulatory sequences from two beta-conglycinin genes.

Genes encoding the beta-conglycinin seed storage proteins of soybean are expressed only in seeds during specific stages of development. The different subunits of beta-conglycinin, alpha', alpha and beta, are encoded by distinct members of a gene family. Yet there are marked differences in the regulation of the genes encoding the alpha'/alpha and beta subunits. Previous work (Chen et al., EMBO J 7: 297-302, 1988) identified a seed specific transcriptional enhancer upstream of a gene encoding the alpha' subunit. Mutations were made within this region to discern its functional components. Among those identified is a 62 bp region (between -77 and -140) that contains a vicilin box consensus sequence as well as a sequence that binds the soybean nuclear factor SEF4 in vitro. A second region, which contains a sequence homologous to the core of the legumin box consensus (i.e., CATGCAT-like or RY repeat element) at -246, was also shown to affect the activity of this enhancer in transgenic plants. A series of 5' terminal deletions were used to identify regulatory elements upstream of the beta subunit gene. Two regions were identified (from -553 to -442 and from -308 to -72) that, when deleted, led to a marked reduction in gene expression. Both of these elements contain sequences that bind SEF4 in vitro. The distal element also contains an AT-rich segment that recognizes a second nuclear factor, SEF1, in vitro. Neither of these elements contains any homology to the vicilin box consensus.

Antigens, Plant↗
PubMed2004

RUNX3 inhibits cell proliferation and induces apoptosis by reinstating transforming growth factor beta responsiveness in esophageal adenocarcinoma cells.

BACKGROUND: SEG-1, a Barrett's-derived esophageal adenocarcinoma cell line, is not responsive to transforming growth factor beta (TGF-beta) growth effects. We hypothesize that SEG-1 cells lack the tumor-suppressor gene Runt domain transcription factor 3 (RUNX3) and that its reinstatement can restore the antiproliferative and apoptotic effects of TGF-beta. METHODS: RUNX3 expression was assessed by immunoblotting. SEG-1 cells were transfected with RUNX3 and treated with TGF-beta. The effects of RUNX3 transfection on cell proliferation and apoptosis were determined. Smad-mediated TGF-beta transcriptional activity was evaluated with the use of dual-luciferase assay. RESULTS: SEG-1 cells are not responsive to TGF-beta. SEG-1 cells lack RUNX3 protein expression, while RUNX3 is highly expressed in normal human gastric and esophageal epithelium. Although the Smad-2 signaling is activated by TGF-beta, SEG-1 cells lack Smad-mediated TGF-beta transcriptional activity. In cells transfected with RUNX3, TGF-beta acquired an antiproliferative effect and induced apoptosis (P = .001). RUNX3 transfection, in the absence of TGF-beta, had no effect on proliferation and apoptosis of SEG-1 cells. RUNX3 expression dramatically increases SMAD-mediated TGF-beta-induced transcriptional activity when compared with controls (P = .0001). CONCLUSIONS: RUNX3 is not expressed in SEG-1 cells, while it is present in normal esophageal mucosa. RUNX3 is essential for the antiproliferative and apoptotic effects of TGF-beta in SEG-1 cells and for the Smad-mediated transcriptional activity of TGF-beta.

Adenocarcinoma↗
PubMed1991

Structural organization and chromosomal localization of the gene for the E1 beta subunit of human branched chain alpha-keto acid dehydrogenase.

A defect in the E1 beta subunit of the branched chain alpha-keto acid dehydrogenase (BCKDH) complex is one cause of maple syrup urine disease (MSUD). In an attempt to elucidate the molecular basis of MSUD, we isolated and characterized the cDNA of the E1 beta subunit of BCKDH. Using the cDNA as a probe, a chromosomal gene related to E1 beta subunit of human BCKDH was isolated from human gene libraries. The gene of E1 beta subunit is over 100 kilobases long and is split into 10 exons. All of the splice donor and acceptor sites conform to the GT/AG rule. The transcription initiation site was determined by nuclease S1 mapping and primer extension and was located 47 bases upstream from the initiation codon. A "CAAT" box and its reverse complement sequences were present at 39 bases and 75 bases upstream from the cap site, but there was no "TATA" box-like sequence. There were three sets of sequences resembling the transcription factor Sp1-binding sites and two sets of sequences resembling the enhancer core sequence. We also analyzed the chromosomal localization of the gene for the E1 beta subunit of BCKDH. The gene was mapped to chromosome 6. Knowledge of the gene structure of human BCKDH E1 beta subunit will facilitate further studies on the expression and regulation of this gene and provide necessary information for analyses of mutations in patients with MSUD.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed2001

Estrogen modulates estrogen receptor alpha and beta expression, osteogenic activity, and apoptosis in mesenchymal stem cells (MSCs) of osteoporotic mice.

In the mouse, ovariectomy (OVX) leads to significant reductions in cancellous bone volume while estrogen (17beta-estradiol, E2) replacement not only prevents bone loss but can increase bone formation. As the E2-dependent increase in bone formation would require the proliferation and differentiation of osteoblast precursors, we hypothesized that E2 regulates mesenchymal stem cells (MSCs) activity in mouse bone marrow. We therefore investigated proliferation, differentiation, apoptosis, and estrogen receptor (ER) alpha and beta expression of primary culture MSCs isolated from OVX and sham-operated mice. MSCs, treated in vitro with 10(-7) M E2, displayed a significant increase in ERalpha mRNA and protein expression as well as alkaline phosphatase (ALP) activity and proliferation rate. In contrast, E2 treatment resulted in a decrease in ERbeta mRNA and protein expression as well as apoptosis in both OVX and sham mice. E2 up-regulated the mRNA expression of osteogenic genes for ALP, collagen I, TGF-beta1, BMP-2, and cbfa1 in MSCs. In a comparison of the relative mRNA expression and protein levels for two ER isoforms, ERalpha was the predominant form expressed in MSCs obtained from both OVX and sham-operated mice. Cumulatively, these results indicate that estrogen in vitro directly augments the proliferation and differentiation, ERalpha expression, osteogenic gene expression and, inhibits apoptosis and ERbeta expression in MSCs obtained from OVX and sham-operated mice. Co-expression of ERalpha, but not ERbeta, and osteogenic differentiation markers might indicate that ERalpha function as an activator and ERbeta function as a repressor in the osteogenic differentiation in MSCs. These results suggest that mouse MSCs are anabolic targets of estrogen action, via ERalpha activation. J. Cell. Biochem. Suppl. 36: 144-155, 2001.

Alkaline Phosphatase↗
PubMed2003

Uni-axial cyclic stretch induces Cbfa1 expression in spinal ligament cells derived from patients with ossification of the posterior longitudinal ligament.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by ectopic bone formation in the spinal ligaments. Mechanical stress, which acts on the posterior ligaments, is thought to be an important factor in the progression of OPLL. To clarify this mechanism, we investigated the effects of in vitro cyclic stretch (120% peak to peak, at 0.5 Hz) on cultured spinal ligament cells derived from OPLL (OPLL cells) and non-OPLL (non-OPLL cells) patients. The mRNA expressions of Cbfa1 (an osteoblast-specific transcription factor), type I collagen, alkaline phosphatase (ALP), osteocalcin and integrin beta1 (a mechanotransducer) were increased by cyclic stretch in OPLL cells, whereas no change was observed in non-OPLL cells. The effects of cyclic stretch on the spinal ligament tissues derived from OPLL and non-OPLL patients were also analyzed by immunohistochemistry using an antibody against Cbfa1. The expression of Cbfa1 was increased by cyclic stretch at the center of the spinal ligament tissues of OPLL patients, whereas no change was observed in the tissues of non-OPLL patients. Furthermore, U0126, a specific inhibitor of MAPK kinase (MEK), suppressed the stretch-induced mRNA expressions of Cbfa1, ALP and type I collagen in OPLL cells. These results suggest that in OPLL cells, mechanical stress is converted by integrin beta1 into intracellular signaling and that Cbfa1 is activated through the MAP kinase pathway. Therefore, we propose that mechanical stress plays a key role in the progression of OPLL through an increase in Cbfa1 expression.

Aged↗
PubMed2006

CCAAT/enhancer-binding protein homologous protein (CHOP) regulates osteoblast differentiation.

Differentiation of committed osteoblasts is controlled by complex activities involving signal transduction and gene expression, and Runx2 and Osterix function as master regulators for this process. Recently, CCAAT/enhancer-binding proteins (C/EBPs) have been reported to regulate osteogenesis in addition to adipogenesis. However, the roles of C/EBP transcription factors in the control of osteoblast differentiation have yet to be fully elucidated. Here we show that C/EBP homologous protein (CHOP; also known as C/EBPzeta) is expressed in bone as well as in mesenchymal progenitors and primary osteoblasts. Overexpression of CHOP reduces alkaline phosphatase activity in primary osteoblasts and suppresses the formation of calcified bone nodules. CHOP-deficient osteoblasts differentiate more strongly than their wild-type counterparts, suggesting that endogenous CHOP plays an important role in the inhibition of osteoblast differentiation. Furthermore, endogenous CHOP induces differentiation of calvarial osteoblasts upon bone morphogenetic protein (BMP) treatment. CHOP forms heterodimers with C/EBPbeta and inhibits the DNA-binding activity as well as Runx2-binding activity of C/EBPbeta, leading to inhibition of osteocalcin gene transcription. These findings indicate that CHOP acts as a dominant-negative inhibitor of C/EBPbeta and prevents osteoblast differentiation but promotes BMP signaling in a cell-type-dependent manner. Thus, endogenous CHOP may have dual roles in regulating osteoblast differentiation and bone formation.

3T3-L1 Cells↗
PubMed2002

Enforced expression of Runx2 perturbs T cell development at a stage coincident with beta-selection.

The development of T cells in the thymus is regulated by a series of stage-specific transcription factors. Deregulated expression of these factors can lead to alterations in thymocyte development with the production of aberrant cell subsets and predispose to tumor formation. The three genes of the Runx family are multilineage regulators of differentiation that have been reported to be expressed in the T cell lineage. However, their roles in thymocyte development and T cell function are largely unknown. While the Runx2/Cbfa1/AML3/Pebp2alphaa gene plays a primary role in osteogenesis and regulates a number of key bone regulatory genes, we show here that Runx2 is also expressed during the earliest phase of thymic development, in the double-negative subset. Furthermore, enforced expression of Runx2 in transgenic mice under the CD2 promoter was found to affect T cell development at a stage coincident with beta-selection, resulting in an expansion of double-negative CD4 and CD8 immature single-positive cells. Unlike wild-type controls this preselection population (CD4-CD8+heat-stable Ag+TCR-) is in a nonproliferative state, but appears to be primed for further transformation events. Overall the data suggest that Runx2 accelerates development to the CD8 immature single-positive stage, but retards subsequent differentiation to the double-positive stage. Thus, Runx2 joins a small group of transcription factors that can interfere with early T cell development, cause an expansion of a specific subset, and predispose to lymphoma.

Animals↗
PubMed2000

Auto-inhibition and partner proteins, core-binding factor beta (CBFbeta) and Ets-1, modulate DNA binding by CBFalpha2 (AML1).

Core-binding factor alpha2 (CBFalpha2; otherwise known as AML1 or PEBP2alphaB) is a DNA-binding subunit in the family of core-binding factors (CBFs), heterodimeric transcription factors that play pivotal roles in multiple developmental processes in mammals, including hematopoiesis and bone development. The Runt domain in CBFalpha2 (amino acids 51 to 178) mediates DNA binding and heterodimerization with the non-DNA-binding CBFbeta subunit. Both the CBFbeta subunit and the DNA-binding protein Ets-1 stimulate DNA binding by the CBFalpha2 protein. Here we quantify and compare the extent of cooperativity between CBFalpha2, CBFbeta, and Ets-1. We also identify auto-inhibitory sequences within CBFalpha2 and sequences that modulate its interactions with CBFbeta and Ets-1. We show that sequences in the CBFalpha2 Runt domain and sequences C terminal to amino acid 214 inhibit DNA binding. Sequences C terminal to amino acid 214 also inhibit heterodimerization with the non-DNA-binding CBFbeta subunit, particularly heterodimerization off DNA. CBFbeta rescinds the intramolecular inhibition of CBFalpha2, stimulating DNA binding approximately 40-fold. In comparison, Ets-1 stimulates CBFalpha2 DNA binding 7- to 10-fold. Although the Runt domain alone is sufficient for heterodimerization with CBFbeta, sequences N terminal to amino acid 41 and between amino acids 190 and 214 are required for cooperative DNA binding with Ets-1. Cooperative DNA binding with Ets-1 is less pronounced with the CBFalpha2-CBFbeta heterodimer than with CBFalpha2 alone. These analyses demonstrate that CBFalpha2 is subject to both negative regulation by intramolecular interactions, and positive regulation by two alternative partnerships.

Animals↗
PubMed2003

The core-binding factor leukemias: lessons learned from murine models.

The recent development of murine models of core-binding factor leukemias has provided important insights into the underlying molecular pathology of this common subtype of acute myeloid leukemia. Evidence from these models supports the idea that acute myeloid leukemia 1/core-binding factor beta-subunit (AML1/CBFbeta) has a critical role in the control of the self-renewal capacity of hematopoietic stem cells and their progeny. Moreover, the accumulated data demonstrate that the expression of translocation-encoded AML1 or CBFbeta fusion proteins are insufficient by themselves to induce a full leukemic phenotype. The models that have been developed should prove to be of value for defining the range of mutations that can cooperate with AML1/CBFbeta fusion proteins, and for assessing novel therapies targeted toward the pathways that are altered by the expression of these fusion proteins.

Animals↗
PubMed1988

The high molecular weight receptor to transforming growth factor-beta contains glycosaminoglycan chains.

Proteoglycans are constituents of the cell surface that may play important roles in the regulation of cell behavior. Here we report that the 250-kDa receptor subunit that binds the multifunctional protein, transforming growth factor-beta 1 (TGF-beta 1), contains chains of heparan sulfate and chondroitin sulfate and thus is a proteoglycan. Digestion of TGF-beta 1-receptor complexes with glycosaminoglycan (GAG)-specific degradative enzymes yield core proteins of 115-140 kDa. Cell monolayers that had been predigested with GAG-specific degradative enzymes were capable of binding high levels of TGF-beta 1, but the size of the binding components was shifted from the high molecular weight species to the lower molecular weight core proteins, indicating that GAG chains are not necessary for TGF-beta 1 binding to the cell. The presence of GAG chains on the receptor subunit indicates that it has the potential for interaction with the extracellular matrix.

Animals↗
PubMed2001

How sigma docks to RNA polymerase and what sigma does.

It is clear that multiple sites of interaction exist between sigmas and core subunits, likely reflecting the changing pattern of interactions that occur sequentially during the complex process of holoenzyme formation, open promoter formation, and initiation of transcription. Recent studies have revealed that a major site of interaction of Escherichia coli sigma factors is the amino acid 260-309 coiled-coil region of the beta' subunit of core RNA polymerase. This region of beta' interacts with region 2.1-2.2 of sigma(70). Binding of this region of beta' to sigma(70) triggers a conformational change in sigma that allows it to bind to a -10 nontemplate promoter DNA strand oligonucleotide.

Amino Acid Sequence↗