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J Chung

Publications and source records attributed to J Chung.

At least 127 records · Page 7Linked to original sources
PubMed1997

STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation.

Recent studies have indicated that serine phosphorylation regulates the activities of STAT1 and STAT3. However, the kinase(s) responsible and the role of serine phosphorylation in STAT function remain unresolved. In the present studies, we examined the growth factor-dependent serine phosphorylation of STAT1 and STAT3. We provide in vitro and in vivo evidence that the ERK family of mitogen-activated protein (MAP) kinases, but not JNK or p38, specifically phosphorylate STAT3 at serine 727 in response to growth factors. Evidence for additional mitogen-regulated serine phosphorylation is also provided. STAT1 is a relatively poor substrate for all MAP kinases tested both in vitro and in vivo. STAT3 serine phosphorylation, not its tyrosine phosphorylation, results in retarded mobility of the STAT3 protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Importantly, serine 727 phosphorylation negatively modulates STAT3 tyrosine phosphorylation, which is required for dimer formation, nuclear translocation, and the DNA binding activity of this transcriptional regulator. Interestingly, the cytokine interleukin-6 also stimulates STAT3 serine phosphorylation, but in contrast to growth factors, this occurs by an ERK-independent process.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1996

NMR solution structure of Cu(I) rusticyanin from Thiobacillus ferrooxidans: structural basis for the extreme acid stability and redox potential.

The solution structure of the Cu(I) form of the rusticyanin from Thiobacillus ferrooxidans has been calculated from a total of 1979 distance and dihedral angle constraints derived from 1H, 13C and 15N NMR spectra. The structures reveal two beta-sheets, one of six strands and one of seven strands that are tightly packed in a beta-barrel or beta-sandwich arrangement, and a short helix that extends on the outside of one of the sheets to form a second hydrophobic core. The copper coordination sphere is composed of the standard type I ligands (His2CysMet) in a distorted tetrahedral arrangement. The copper-binding site is located within a hydrophobic region at one end of the molecule, surrounded by a number of aromatic rings and hydrophobic residues. This configuration probably contributes to the acid stability of the copper site, since close association of the aromatic rings with the histidine ligands would sterically hinder their dissociation from the copper. An electrostatic analysis based on a comparison of the structures of rusticyanin and French bean plastocyanin shows that factors determining the high redox potential of rusticyanin include contributions from charged side-chains and from the disposition of backbone peptide dipoles, particularly in the 81 to 86 region of the sequence and the ligand cysteine residue. These interactions should also contribute to the acid stability by inhibiting protonation of His143.

Azurin↗
PubMed1996

Interleukin-13 is a potent activator of JAK3 and STAT6 in cells expressing interleukin-2 receptor-gamma and interleukin-4 receptor-alpha.

The lymphocyte growth factors interleukin-2 (IL2), IL4, IL7, IL9 and IL15 use the common IL2 receptor-gamma (IL2R gamma) and activate the IL2R gamma-associated tyrosine kinase JAK3 (Janus kinase 3). IL13 is structurally related to IL4, competes with IL4 for binding to cell surface receptors and exhibits many similar biological effects. The molecular basis for this functional overlap between IL4 and IL13 has been attributed mainly to a shared use of the 140 kDa IL4R alpha, since these cytokines appear to be uniquely different in that, according to several recent reports, IL13 does not recruit the IL2R gamma or JAK3. This notion has been supported by the identification of a novel 70 kDa IL13 receptor in certain IL13-responsive cell lines that lack IL2R gamma. The present study sheds new light on the issue of functional overlap between IL13 and IL4, by demonstrating for the first time that, in cells that express both IL2R gamma and IL4R alpha, IL13 can mimic IL4-induced heterodimerization of IL2R gamma and IL4R alpha, with consequent marked activation of JAK3 and the transcription factor STAT6 (IL4-STAT). Reconstitution experiments in BA/F3 cells showed that both cytokines require the simultaneous presence of IL4R alpha and IL2R gamma to mediate JAK3 and proliferative responses, and analysis of 12 IL4R alpha variants showed that IL4 and IL13 signals were equally affected by mutations of the cytoplasmic domain. We conclude that IL13 activates the IL2R gamma-associated JAK3 tyrosine kinase in appropriate cell types, and propose that IL13 is capable of interacting with multiple receptor subunits in a cell-dependent and combinatorial manner. Consequently, we predict that partial disruption of IL13 signal transduction also contributes to the severe combined immuno-deficiency syndromes associated with inactivation of the IL2R gamma or JAK3 genes.

Animals↗
PubMed1996

Chromatin structure and gene expression.

It is now well understood that chromatin structure is perturbed in the neighborhood of expressed genes. This is most obvious in the neighborhood of promoters and enhancers, where hypersensitivity to nucleases marks sites that no longer carry canonical nucleosomes, and to which transcription factors bind. To study the relationship between transcription factor binding and the generation of these hypersensitive regions, we mutated individual cis-acting regulatory elements within the enhancer that lies between the chicken beta- and epsilon-globin genes. Constructions carrying the mutant enhancer were introduced by stable transformation into an avian erythroid cell line. We observed that weakening the enhancer resulted in creation of two classes of site: those still completely accessible to nuclease attack and those that were completely blocked. This all-or-none behavior suggests a mechanism by which chromatin structure can act to sharpen the response of developmental systems to changing concentrations of regulatory factors. Another problem raised by chromatin structure concerns the establishment of boundaries between active and inactive chromatin domains. We have identified a DNA element at the 5' end of the chicken beta-globin locus, near such a boundary, that has the properties of an insulator; in test constructions, it blocks the action of an enhancer on a promoter when it is placed between them. We describe the properties and partial dissection of this sequence. A third problem is posed by the continued presence of nucleosomes on transcribed genes, which might prevent the passage of RNA polymerase. We show, however, that a prokaryotic polymerase can transcribe through a histone octamer on a simple chromatin template. The analysis of this process reveals that an octamer is capable of transferring from a position in front of the polymerase to one behind, without ever losing its attachment to the DNA.

Animals↗
PubMed1996

IL-4-dependent proliferation of BA/F3 cells expressing a growth-negative mutant of the human IL-4 receptor is restored by enforced expression of Bcl-2.

We have studied the regulation of growth and apoptosis in murine BA/F3 cells stably expressing cytoplasmic deletion mutants of the human interleukin-4 receptor (hIL-4R). Previously, we showed that BA/F3 cell transfectants expressing a cytoplasmic deletion mutant of the hIL-4R that lacks the region between Thr(462) and Ala(580), referred to as delta R3, fails to proliferate in the presence of hIL-4. Here we report that supertransfection of delta R3-expressing cells with a constitutively active murine bcl-2 gene results in prolonged survival of the delta R3/bel-2 double transfectants in the absence of cytokines. More importantly, however, the constitutive expression of Bcl-2 restored their capacity to grow permanently with hIL-4. This may provide an explanation for the discrepancy with previous reports showing growth mediation by hIL-4R truncated at position 367.

Animals↗
PubMed1996

Expression of enhanced spontaneous and gamma-ray-induced apoptosis by lymphocytes of the wasted mouse.

Mice bearing the autosomal recessive mutation wasted (wst/wst) display a disease pattern including increased sensitivity of lymphocytes to ionizing radiation, neurologic dysfunction, and immunodeficiency. Many of the features of this mouse model have suggested a premature or increased spontaneous frequency of apoptosis in thymocytes. Past work has documented an inability to establish cultured T cell lines, and abnormally high death rate of stimulated T cells in culture, and an increased sensitivity of T cells to the killing effects of ionizing radiations in the wst/wst mouse relative to controls. The experiments reported here were designed to examine splenic and thymic lymphocytes from the wasted and control mouse for signs of early apoptosis. Our results revealed enhanced expression of Rp-8 mRNA (which has been associated with apoptosis) in thymic lymphocytes and to a lesser extent in spinal cord in the wst/wst mouse relative to controls; expression of Rp-2 and Tcl-30 mRNA (also reported to be induced during apoptosis) were not detectable in spleen or thymus. Expression of Rp-2, Rp-8, and Tcl-30 mRNA in other affected tissues of the wasted mouse (brain and liver) were similar in the wasted mouse and controls. Thymus and spleen from the wasted mouse have reduced numbers of viable cells relative to controls. Higher spontaneous DNA fragmentation was observed in lymphocytes from the wasted mouse than in controls; however, gamma-ray-induced DNA fragmentation peaked at a lower dose and occurred to a greater extent in lymphocytes derived from the wasted mouse relative to controls. These results suggest that high spontaneous and gamma-ray-induced apoptosis in T cells of the wasted mouse may contribute to the mechanism underlying the observed lymphocyte and DNA repair abnormalities.

Animals↗
PubMed1996

Hybrid cysts showing alternate combination of eruptive vellus hair cyst, steatocystoma multiplex, and epidermoid cyst, and an association among the three conditions.

Eruptive vellus hair cyst (EVHC), steatocystoma multiplex (SM), and epidermoid cyst are characterized by formation of multiple cutaneous cysts and have a resemblance in clinical features but have distinctive histologic features. We present herein two patients, who had EVHC, SM, and EVHC with sebaceous gland, and who also had EVHC, SM, and epidermoid cyst with sebaceous gland and vellus hairs. In addition, the interrelation among the three diseases is discussed. We think that EVHC, SM and epidermoid cyst are within the same spectrum of the disease process.

Adult↗
PubMed1996

Mechanisms of tumor-induced hypoglycemia with intraabdominal hemangiopericytoma.

The association of hypoglycemia with nonislet cell tumors is well recognized and in nearly all instances has been related to the production of hormones with insulin-like activity. To determine the mechanism of such tumor-induced hypoglycemia and the response to pharmacological intervention, we studied a 54-yr-old man with refractory hypoglycemia and a large intraabdominal hemangiopericytoma. During a supervised fast, plasma glucose decreased to 2.2 mmol/L. Circulating insulin (< 7 pmol/L), C peptide (< 0.04 nmol/L), and GH levels (< 0.6 microgram/L) were all undetectable, insulin-like growth factor I (IGF-I; 5 nmol/L) was low, IGF-II was in the normal range (87 nmol/L), and free IGF-II and big IGF-II (E1-21 fragment) were elevated at 18 and 142 nmol/L, respectively. On another day, after maintaining euglycemia overnight with a 20% dextrose infusion, a euglycemic (5.0-5.5 mmol/L) glucose clamp study using [3-3H]glucose tracer infusion combined with arteriovenous leg catheterization was performed in the postabsorptive basal state and during 3 h of crystalline somatostatin infusion (0.08-0.24 pmol/kg min). In the postabsorptive state at euglycemia, free IGF-II and big IGF-II remained elevated at 16 and 162 nmol/L, respectively. Whole body glucose disposal was elevated at 21.1 mumol/kg.min, whereas the rate of glucose infusion was 12.1 mumol/kg.min, and depatic glucose output was 7.8 mumol/kg.min. The leg arterio-venous plasma glucose difference was increased at 0.6 mmol/L, as was leg glucose uptake at 203.9 mumol/min. After 3 h of somatostatin infusion, both free and big IGF-II decreased by 35-40% to 10 and 102 nmol/L, respectively. Whole body glucose disposal also decreased to near normal (12.8 mumol/kg.min), whereas leg arterio-venous plasma glucose difference and leg glucose uptake became negligible. The plasma glucose level remained at 5.0-5.5 mmol/L despite a marked fall in hepatic glucose output to 2.9 mumol/kg.min and a decrease in glucose infusion rate to 8.7 mumol/kg.min. During somatostatin treatment, GH remained suppressed at less than 0.6 microgram/L, and glucagon decreased from 99 to 78 ng/L. In this patient with a hemangiopericytoma, hypoglycemia was associated with increased circulating insulin-like activity from elevated free and big IGF-II, which stimulated glucose uptake primarily into muscle tissue. A continuous infusion of crystalline somatostatin effectively reduced the elevated levels of IGF-II and glucose uptake, but was unable to adequately control hypoglycemia without the simultaneous infusion of exogenous glucose or glucagon.

Abdominal Neoplasms↗
PubMed1996

Duplex sonography of the carotid arteries in patients with isolated aortic stenosis: imaging findings and relation to severity of stenosis.

OBJECTIVE: The purposes of this study were to identify carotid artery duplex waveform abnormalities in patients with isolated aortic stenosis and to determine whether waveform abnormalities correlate with the severity of valvular disease. MATERIALS AND METHODS: Twenty-four patients with various degrees of aortic stenosis diagnosed by echocardiography and/or cardiac catheterization had preoperative carotid artery duplex sonograms that were retrospectively reviewed for acceleration time, peak velocity, waveform contour, upstroke delay, and presence of a dicrotic notch and a second systolic peak. Data were collected for the right and left internal, external, and common carotid arteries separately. These findings were correlated with aortic valve area and compared with data for a control group of 11 age-matched patients with normal echocardiographic findings. Two additional patients with isolated aortic stenosis diagnosed by echocardiography and/or cardiac catheterization were prospectively evaluated in a similar fashion, with acceleration time being calculated directly from the sonography unit. RESULTS: Unlike the patients with mild or moderate stenosis, the patients with critical or severe stenosis had a mean acceleration time that was significantly longer than that in the control subjects (p = .008-.0001). Peak velocities were decreased in all cases of aortic stenosis regardless of severity only in the common carotid arteries. All 13 patients with critical aortic stenosis had delayed upstrokes and rounded waveforms in the common, internal, and external carotid arteries. Twenty percent (one of five) of the patients with severe stenosis and 17% (one of six) of the patients with moderate or mild stenosis also had these characteristics. The two prospectively evaluated patients, who had critical and severe aortic stenoses, had similar findings. None of the control subjects showed these abnormalities. The presence or absence of a second systolic peak or a dicrotic notch was not different between patients with aortic stenosis and control subjects. CONCLUSION: Increased acceleration time, decreased peak velocity, delayed upstroke, and rounded waveform are characteristic abnormalities found in duplex sonographic studies of the carotid arteries in patients with aortic stenosis. The degree of each of these abnormalities correlates with the valve area. Patients with critical or severe aortic stenosis had findings significantly different from those in the control group. Patients with mild or moderate disease showed few or no sonographic abnormalities.

Aged↗
PubMed1996

Transforming growth factor beta 1 supports autonomous growth of human papillomavirus-immortalized cervical keratinocytes under conditions promoting squamous differentiation.

Transforming growth factor beta (TGF-beta) inhibits proliferation of keratinocytes cultured from normal anogenital epithelia; however, human papillomavirus (HPV)-immortalized cell lines often exhibit increased resistance. Present results demonstrate that TGF-beta 1 (1-10 pM) stimulates growth of multiple HPV-immortalized cell lines when cultures are maintained under conditions promoting squamous differentiation (MCDB153-LB medium with 1.0 mM calcium and without epidermal growth factor and bovine pituitary extract). Growth stimulation by TGF-beta 1 was not due to altered expression of type I or II receptors, but was increased after extended passage of cells in culture. Differentiation of immortal keratinocytes resulted in induction of RNAs encoding two markers of squamous differentiation, involucrin and keratin 1, and decreased expression of RNAs for the epidermal growth factor (EGF) receptor and two ligands, amphiregulin and TGF-alpha. Growth stimulation by TGF-beta 1 occurred indirectly via establishment of an autocrine loop. TGF-beta 1 increased expression of RNAs encoding the EGF-R and amphiregulin, and also increased numbers of cell-surface EGF-Rs without altering their affinity. In contrast, TGF-beta 1 inhibited autonomous growth and transcription of amphiregulin RNA in normal keratinocytes. Growth stimulation by TGF-beta 1 could be blocked by a monoclonal antibody that competes for binding to the EGF-R or by a mixture of monoclonal antibodies that neutralize amphiregulin activity, confirming the importance of this autocrine pathway. Thus, partial abrogation of the growth inhibitory response to TGF-beta 1 sensitizes HPV-immortalized keratinocytes to a growth stimulatory signal mediated by an EGF-R-dependent pathway involving autocrine stimulation by amphiregulin.

Animals↗
PubMed1996

Congenital cartilaginous rests of the neck.

We describe a case of congenital cartilaginous rests of the neck arising on the suprasternal midline area of the neck in a Korean infant. The lesion was characterized by discrete nodules of mature elastic cartilage in the lower dermis or superficial subcutaneous soft tissue and multiple vellus hair follicles in the overlying skin.

Biopsy, Needle↗