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Biomedical subjects

K H Baek

Publications and source records attributed to K H Baek.

At least 19 recordsLinked to original sources
PubMed2004

Relationship between circulating cytokine levels and thyroid function following bone marrow transplantation.

The relation between thyroid hormone changes and cytokines in bone marrow transplantation (BMT) patients has not been studied. This prospective study was designed to determine the relation between thyroid hormones and cytokine levels after BMT and their effects on the mortality. We studied 80 patients undergoing allogeneic BMT. Serum thyroid hormone parameters and cytokine levels were measured before and serially during 6 months after BMT. Serum T(3) decreased to a nadir 3 weeks post-BMT and serum T(4) was lowest at 3 months post-BMT. Serum thyroid stimulating hormone (TSH) sharply decreased to a nadir at 1 week and recovered. Serum interleukin-6 increased for 2 weeks after BMT and declined thereafter. Serum tumor necrosis factor-alpha increased for 3 weeks after BMT and declined thereafter. After 3 weeks post-BMT, both cytokine levels were negatively correlated with serum T(3) and T(4) levels. A total of 29 patients died before 1 year post-BMT and 51 patients survived longer than 1 year. Those patients who died before 1 year post-BMT had significantly lower levels of T(4) at 3 weeks, 3 and 6 months than surviving patients. In conclusion, increased levels of serum IL-6 and TNF-alpha were negatively correlated with thyroid hormone concentrations in BMT recipients suggesting the role of these cytokines in euthyroid sick syndrome.

Adult↗
PubMed2004

Treatment of taste and odor material by oxidation and adsorption.

Massive blooms of blue-green algae in reservoirs produce the musty-earthy taste and odor, which are caused by compounds such as 2-MIB and geosmin. 2-MIB and geosmin are rarely removed by conventional water treatment. Their presence in the drinking water, even at low levels (ng/L), can be detected and it creates consumer complaints. So those concentrations have to be controlled as low as possible in the drinking water. The removals by oxidation (O3, Cl2, ClO2) and adsorption (PAC, filter/adsorber) were studied at laboratory and pilot plant (50 m3/d) to select suitable 2-MIB and geosmin treatment processes. The following conclusions were derived from the study. Both of the threshold odor levels for 2-MIB and geosmin appeared to be 30 ng/L as a consequence of a lab test. For any given PAC dosage in a jar-test, removal efficiencies of 2-MIB and geosmin were increased in proportion to PAC dosage and were independent of their initial concentration in raw water for the tested PAC dosages. In comparison of geosmin with 2-MIB, the adsorption efficiency of geosmin by PAC was superior to that of 2-MIB. The required PAC dosages to control below the threshold odor level were 30 mg/L for geosmin and 50 mg/L for 2-MIB at 100 ng/L of initial concentration. Removal efficiencies of odor materials by Cl2, ClO2, and O3 were very weak under the limited dosage (1.5 mg/L), however increased ozone dosage (3.8 mg O3/L) showed high removal efficiency (84.8% for 2-MIB) at contact time 6.4 minutes. According to the initial concentrations of 2-MIB and geosmin, their removal efficiencies by filter/adsorber differed from 25.7% to 88.4%. For all those, however, remaining concentrations of target materials in finished waters were maintained below 30 ng/L. The longer run-time given for the filter/adsorber, the higher the effluent concentration generated. So it is necessary that the run-time of the filter/adsorber be decreased, when 2-MIB or geosmin occurs in raw water.

Adsorption↗
PubMed2001

A novel function of phosphorothioate oligodeoxynucleotides as chemoattractants for primary macrophages.

Phosphorothioate cytosine-guanine oligodeoxynucleotides (CpG PS-ODNs) has been reported to induce Th1 immune responses against coadministered Ags more efficiently than phosphodiester CpG ODNs (CpG PO-ODNs). Here, we demonstrated that PS-ODNs, but not PO-ODNs, have a chemotactic effect on primary macrophages, which is independent of the CpG motif. In addition, the conjugation of a hexameric dG run (dG(6) run) at the 3' terminus reduced the concentration required for the optimal chemotactic activity of PS-ODNs by approximately 10-fold. Endosomal maturation blockers, such as monensin and chloroquine, inhibited the chemotactic effect of PS-ODNs. The inhibition of the activities of p38 mitogen-activated protein (MAP) kinase, and extracellular signal-related kinases (ERKs) as well as phosphoinositide 3-kinase with their specific inhibitors also resulted in suppressing the chemotaxis of primary macrophages induced by PS-ODNs. These results indicate that the PS-ODN-mediated chemotaxis requires the activation of ERKs, p38 MAP kinase, and phosphoinositide 3-kinase as well as endosomal maturation. In addition, the phosphorylations of the p38 MAP kinase, ERKs, and protein kinase B, Akt, were induced by PS-ODN, which were further enhanced by the presence of both a dG(6) run and CpG motifs. Our findings suggest that the chemotactic activity of PS-ODNs may be one of the mechanisms by which PS-ODNs exhibit stronger immunomodulatory activities than PO-ODNs in vivo.

Animals↗
PubMed2001

DUB-2A, a new member of the DUB subfamily of hematopoietic deubiquitinating enzymes.

Protein ubiquitination is an important regulator of cytokine-activated signal transduction pathways and hematopoietic cell growth. Protein ubiquitination is controlled by the coordinate action of ubiquitin-conjugating enzymes and deubiquitinating enzymes. Recently a novel family of genes encoding growth-regulatory deubiquitinating enzymes (DUB-1 and DUB-2) has been identified. DUBs are immediate-early genes and are induced rapidly and transiently in response to cytokine stimuli. By means of polymerase chain reaction amplification with degenerate primers for the DUB-2 complementary DNA, 3 murine bacterial artificial chromosome (BAC) clones that contain DUB gene sequences were isolated. One BAC contained a novel DUB gene (DUB-2A) with extensive homology to DUB-2. Like DUB-1 and DUB-2, the DUB-2A gene consists of 2 exons. The predicted DUB-2A protein is highly related to other DUBs throughout the primary amino acid sequence, with a hypervariable region at its C-terminus. In vitro, DUB-2A had functional deubiquitinating activity; mutation of its conserved amino acid residues abolished this activity. The 5' flanking sequence of the DUB-2A gene has a hematopoietic-specific functional enhancer sequence. It is proposed that there are at least 3 members of the DUB subfamily (DUB-1, DUB-2, and DUB-2A) and that different hematopoietic cytokines induce specific DUB genes, thereby initiating a cytokine-specific growth response. (Blood. 2001;98:636-642)

Animals↗
PubMed2001

Critical regions for deubiquitinating activity of DUB-2 expressed in T-lymphocytes.

Ubiquitin- and proteasome-mediated protein degradation is involved in many intracellular processes, including cell cycle regulation, transcriptional activation, and signal transduction in all eukaryotes. Novel subfamily members of the ubp superfamily, DUB-1 and DUB-2, are known to be immediate-early genes and are specifically expressed in B-lymphocytes and T-lymphocytes, respectively. With the site-directed mutagenesis in four conserved amino acids (Cys60, Asp133, His298, and His307) and a series of deletion in the carboxy-terminal region, we demonstrate that these conserved amino acids are critical, but not the C-terminus, for the deubiquitinating activity of DUB-2.

Catalytic Domain↗
PubMed2000

Effects of a hexameric deoxyriboguanosine run conjugation into CpG oligodeoxynucleotides on their immunostimulatory potentials.

CpG oligodeoxynucleotides (ODNs) are promising immunomodulatory agents for treating human diseases and vaccine development. Phosphodiester CpG ODNs were demonstrated to have poor immunostimulatory potentials for cytokine production. However, the conjugation of consecutive deoxyriboguanosine residues, called a dG run, at the 3' terminus of phosphodiester CpG ODNs significantly enhanced TNF-alpha and IL-12 production from mouse splenic dendritic cells (DCs). The optimal induction of cytokine production was achieved by the addition of a hexameric dG (dG6) run. In contrast, the existence of a dG6 run either at the 5' terminus of phosphodiester CpG ODNs or at the 3' terminus of phosphorothioate CpG ODNs diminished CpG-mediated cytokine induction, suggesting that the effects of a dG run depend on its location and the chemical property of the ODN backbone, respectively. In addition, we provided the evidence that the conjugation of a dG6 run caused the structural transformation of CpG ODNs, which facilitates their targeting into mouse APCs such as splenic DCs, B cells, and peritoneal macrophages with a scavenger receptor type A ligand specificity. Among primary APCs, DCs were the most potent for CpG ODN-mediated IL-12 production. Furthermore, we demonstrated that the conjugation of a dG6 run into the 3' terminus of phosphodiester CpG ODNs was crucial for their ability to generate Th1 immunity in vivo. Thus, the conjugation of a dG6 run into phosphodiester CpG ODNs would be an alternative way to optimize their immunostimulatory potentials in vitro and in vivo.

3' Untranslated Regions↗
PubMed1999

Analysis of cis-acting sequences and trans-acting factors regulating the interleukin-3 response element of the DUB-1 gene.

The murine DUB-1 gene is a hematopoietic-specific, immediate-early gene that encodes a growth-regulatory deubiquitinating enzyme. DUB-1 contains an IL-3-inducible enhancer element that is activated in a JAK2-dependent, STAT5-independent manner. In this study, we have further characterized this novel IL-3 response element. Transcriptional reporter assays in Ba/F3 cells revealed that two AP-1 sites, a GATA motif, and an Ets site are required for induction of DUB-1 enhancer activity. Gel shift assays indicated that IL-3 activates the binding of an AP-1 complex containing JunD to the AP-1 sites and the binding of another protein complex to the Ets motif. The latter complex was not detectable in Ba/F3 cells stably transfected with a dominant-negative mutant of JAK2. As previously shown, these cells do not express DUB-1 mRNA or protein. Furthermore, we demonstrated that GATA-1 constitutively binds to the DUB-1 enhancer element. The involvement of GATA-1 may be important for the hematopoietic-restricted expression pattern of DUB-1. This combination of inducible and constitutive elements of the DUB-1 enhancer appears to account for the unique STAT-independent expression characteristics of DUB-1.

Animals↗
PubMed1999

Application of temperature-sensitive mutations to oncogene studies in Drosophila.

Recessive oncogenes are genetic functions important in the regulation of tissue growth and differentiation. These genetic functions are defined on the basis of the phenotype expressed by homozygotes. Defining the role of these genes in normal developmental and physiological processes is important to the development of accurate models of the normal regulation of growth and differentiation. Drosophila can be a good system to investigate the neoplastic mechanism of oncogenes and provide a greater understanding in the developmental progression of both invertebrates and vertebrates. The lethal (2) giant larvae gene is a recessive oncogene of Drosophila and temperature sensitive mutations of this gene have been isolated. Here, the application of temperature-sensitive mutations in Drosophila oncogene studies is discussed.

Animals↗
PubMed1999

The first oncogene in Drosophila melanogaster.

Discovered by Bridges in the 1930s, lethal (2) giant larvae was the first of more than 27 recessive oncogenes identified in Drosophila, which provides an excellent model to study neoplastic mechanisms due to the fact that homologs of human oncogenes and tumor suppressors have been isolated and most of the complexes and associated pathways are conserved. This review explores the potential of neoplastic studies in Drosophila to help understand the genomic mechanisms of neoplastic development in vertebrates and invertebrates. Starting from neoplasms and genetic mutations, the article introduces the reader to one of the possibilities that the studies on neoplastic mechanisms of oncogenes in Drosophila can provide a great understanding of the developmental progression in both vertebrates and invertebrates.

Amino Acid Sequence↗
PubMed1999

Increased intracellular cAMP renders HL-60 cells resistant to cytotoxicity of taxol.

The treatment of advanced cancers with paclitaxel (taxol) is hindered by the development of drug resistance. Resistance to taxol is known to be associated with multidrug resistance (MDR) and a mutation affecting either the alpha- or beta-subunit of tubulin. In this study, we demonstrated that an intracellular cAMP level may also play an important role in resistance to taxol in HL-60, acute promyelocytic leukemia cells. Exposure of HL-60 cells to various doses of taxol for 18 hr resulted in cell death. However, pretreatment of the cells with cAMP analogs such as N6:O2-dibutyl cAMP (Db-cAMP), 8-(4-chlorophenylthio) cAMP (CPT-cAMP) and 8-bromo-cAMP (8-Br-cAMP) or an intracellular cAMP elevating agent such as forskolin apparently rendered HL-60 cells more resistant to taxol, but not with dimethyl sulfoxide (DMSO) or retinoic acid (RA), well known differentiating agents. To investigate whether protein kinase A (PKA) activated by an increase in intracellular cAMP level could be involved in increased taxol resistance of the cells, we examined the effects of PKA inhibitors, including H-89 and KT5720, on taxol resistance induced by Db-cAMP. The PKA inhibitors significantly abolished Db-cAMP-induced taxol resistance. These results suggest that cAMP analogs may render tumor cells more resistant to taxol via PKA activation.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Dual functions of the heartless fibroblast growth factor receptor in development of the Drosophila embryonic mesoderm.

The Drosophila embryonic mesoderm forms by invagination of the ventral-most blastoderm cells. Subsequent development of this germ layer involves the dorsolateral migration of the internalized cells and expansion by cell division, followed by the specification of particular cell fates through the coordinate actions of both intrinsic and extrinsic regulatory mechanisms. The latter include several intercellular signals that function across germ layers. These processes combine to generate a diversity of mesodermal sub-types, including the cardial and pericardial cells of the heart or dorsal vessel, a complete set of somatic muscle founders each with its unique identity, a population of cells that form the visceral musculature, and other cells that develop into hemocytes and the fat body. Here, we review recent evidence for the involvement of a fibroblast growth factor receptor (FGFR) encoded by the heartless (htl) gene in early directional migration of the Drosophila mesoderm. In addition, we provide new data that 1) demonstrate a second role for Htl in promoting the specification of the precursors to certain cardiac and somatic muscle cells in the Drosophila embryo, independent of its cell migration function, 2) suggest that Ras and at least one other signal transduction pathway act downstream of Htl, and 3) establish a functional relationship between the Ras pathway and Tinman (Tin), a homeodomain factor that is essential for specifying some of the same dorsal mesodermal cells that are dependent on Htl. Finally, parallels between requirements for FGFR signaling in Drosophila and vertebrate mesoderm development are considered.

Animals↗
PubMed1997

The lethal (2) giant larva (l(2)gl), a recessive oncogene, is required during embryonic and post-embryonic development in Drosophila.

Recessive oncogenes have genetic functions important for the regulation of tissue growth and differentiation. Defining the role of these genes in normal developmental and physiological processes is important to the development of the accurate models of the normal regulation of growth and differentiation. We report here a genetic analysis of the requirement for the lethal (2) giant larva function during development. The results demonstrate that the lethal (2) giant larva function is required during embryonic and post-embryonic development to maintain the normal developmental capacity.

Animals↗
PubMed1997

Characterization of maternal and zygotic D-raf proteins: dominant negative effects on Torso signal transduction.

The maternal D-raf serine/threonine kinase acts downstream of Torso (Tor) for specification of cell fates at the embryonic termini. D-raf activity is also required in other signal transduction pathways and consistent with its pleiotropic role, we find accumulation of a 90-kD D-raf protein throughout embryonic development. We also characterize the accumulation of maternal D-raf proteins in 0-2-hr embryos derived from females with germ cells lacking D-raf activity. Accumulation of a 90-kD or truncated mutant D-raf protein is observed for some of these embryos, while others lack the maternal D-raf protein. Then to determine whether rescue of the Tor pathway is influenced by pools of nonfunctional maternal D raf. wild-type D-raf mRNA was injected into embryos that inherit maternal stores of inactive 90-kD of truncated D-raf protein. For embryos lacking the maternal D-raf protein, a high level of terminal rescue is obtained. In contrast, rescue is reduced or not observed for embryos that accumulate mutant maternal D-raf proteins. These findings suggest that mutant forms of D-raf may deplete the embryo of a positive activator and/or form inactive protein complexes that affect rescue of the Tor pathway.

Animals↗
PubMed1996

Remodeling of nuclear architecture during the cell cycle in Drosophila embryos.

Little is known about what determines the nuclear matrix or how its reorganization is regulated during mitosis. In this study we report on a monoclonal antibody, mAb2A, which identifies a novel nuclear structure in Drosophila embryos which forms a diffuse meshwork at interphase but which undergoes a striking reorganization into a spindle-like structure during pro- and metaphase. Double labelings with alpha-tubulin and mAb2A antibodies demonstrate that the microtubules of the mitotic apparatus co-localize with this mAb2A labeled structure during metaphase, suggesting it may serve a role in microtubule spindle assembly and/or function during nuclear division. That the mAb2A-labeled nuclear structure is essential for cell division and/or maintenance of nuclear integrity was directly demonstrated by microinjection of mAb2A into early syncytial embryos which resulted in a disintegration of nuclear morphology and perturbation of mitosis.

Animals↗
PubMed1996

The activity of D-raf in torso signal transduction is altered by serine substitution, N-terminal deletion, and membrane targeting.

The Raf family of serine/threonine kinases are essential components in many receptor tyrosine kinase-mediated signal transduction pathways. Here, we analyze the function of D-raf in the Torso (Tor) pathway required to specify cellular fates at the embryonic poles. Using mutant embryos lacking endogenous D-raf protein, we show that D-raf's serine/threonine kinase activity is essential for its role in Tor signal transduction and that human Raf-1 will substitute for D-raf in this pathway. After Tor activation, D-raf becomes hyperphosphorylated. We identified two putative serine phosphorylation sites (S388 and S743) in SF9 cells and demonstrate that S743 or its phosphorylation is essential for D-raf function in embryos. Alanine substitution at S388, N-terminal truncation, or targeted membrane association permits transmission of the Torso signal by D-raf, but these D-raf molecules differ in their rescuing potential and relative biological activity. Membrane-targeted D-raftor4021 showed the highest level of activity, followed by alanine-substituted D-rafS388A and N-terminal-truncated D-raf delta 445. Since the activity profiles for these altered forms of D-raf are distinct, these findings indicate that each structural modification differentially affects the regulation and/or propagation of the Tor signal by these mutant D-raf proteins.

Alanine↗
PubMed1994

Thiophosphorylated substrate analogs are potent active site-directed inhibitors of protein-tyrosine phosphatases.

Thiophosphotyrosyl protein and peptide substrate analogs were found to be potent and specific protein-tyrosine phosphatase inhibitors with IC50s in the range of 0.2-30 microM. The analogs were based on highly reactive substrates and included thiophosphotyrosyl forms of reduced carboxamidomethylated and maleylated lysozyme and peptides based on tyrosine phosphorylation sites of lysozyme, alpha s2-casein, and platelet-derived growth factor receptor. These analogs inhibited protein-tyrosine phosphatases from both the intracellular and transmembrane classes and from a variety of species ranging from a prokaryote (Yersinia enterolitica) to man. The extent of inhibition of phosphatase activity by a given analog varied with the phosphatase species. In contrast, protein kinases and protein-serine/threonine phosphatases were not significantly affected by these analogs. The mechanism of inhibition was investigated using rat brain protein-tyrosine phosphatase-1 as a prototype. These studies indicated that the inhibition was rapid and reversible and was competitive in nature. The Ki for inhibition by various thiophosphotyrosyl analogs was generally proportional to the apparent Km for the corresponding phosphorylated substrates. Unphosphorylated substrate molecules were generally much weaker inhibitors than the corresponding thiophosphotyrosyl substrate analogs. Taken together these results point to an active site-directed mechanism for inhibition. These specific inhibitory probes could be used to study substrate binding mechanisms as well as physiological roles of various protein-tyrosine phosphatases.

Animals↗
PubMed1993

Tumors in hepatobiliary tract and pancreatic islet tissues of transgenic mice harboring gastrin simian virus 40 large tumor antigen fusion gene.

Gastrin is expressed in the gastric antrum and in fetal pancreatic islets but not in adult islets. We have now identified the hepatobiliary tract as another, previously unknown, potential site of gastrin gene expression. Two human gastrin simian virus 40 large tumor antigen (SV40 T antigen) fusion genes containing 1.5 kb of 5' flanking sequence and 10.5 kb that included 5.5 kb upstream, 1.5 kb downstream, and the entire transcribed region were used to generate transgenic mice. Analysis of several transgenic lines, derived from both fusion genes, revealed development of transmissible hepatobiliary tract tumors and pancreatic islet cell tumors. Analysis of each of the tumor cells demonstrates expression of SV40 T antigen but no expression of gastrin. Of the two fusion genes, only the 10.5-kb sequence induces hyperplasia of gastrin-producing cells in the antrum. Analysis of these cells demonstrates expression of SV40 T antigen and gastrin, suggesting that the 10.5-kb sequence is sufficient for gastrin cell hyperplasia in the antrum. These data raise the possibility that gastrin is transiently expressed in the hepatobiliary tract.

Adenoma, Islet Cell↗