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Biomedical subjects

Jaeho Lee

Publications and source records attributed to Jaeho Lee.

15 recordsLinked to original sources
PubMed2006

Metal filament growth in electrically conductive polymers for nonvolatile memory application.

Solution processable polymers that can reproducibly form metal filament by applying voltage are investigated for nonvolatile memory application. Up to present, the understanding of materials enabling to make the metal filament has not been well-documented and the vacuum deposition methods were dominantly used in device fabrication. After screening various polymers, we found that only the polymers having two functionalities, the presence of strongly coordinating heteroatom (S or N) with metal ions and the electrical conductivity, showed the reproducible filament formation behavior. Among the polymers screened, the regiorandom poly(3-hexylthiophene) showed the best switching endurance over 30,000 write-read-erase-read cycles without any switching failure.

Journal Article↗
PubMed2006

In vivo imaging of adenovirus transduction and enhanced therapeutic efficacy of combination therapy with conditionally replicating adenovirus and adenovirus-p27.

Gene therapy is hampered by poor gene transfer to the tumor mass. We previously proposed a combination adenoviral gene therapy containing a conditionally replicating adenovirus (CRAD) expressing mutant E1 (delta24RGD) and a replication-defective E1-deleted adenovirus to enhance the efficiency of gene transfer. Mutant E1 expressed by delta24RGD enables the replication of replication-defective adenoviruses in tumors when cancer cells are co-infected with both viruses. In this study, gene transfer rates in xenografts tumors were monitored by bioluminescence in cells infected with the replication-defective adenovirus-luciferase (ad-luc). Tumor masses treated with CRAD + ad-luc showed dramatically stronger and more prolonged luciferase expression than ad-luc-treated tumors and this expression spread through the entire tumor mass without significant systemic spread. Transduction with CRAD + replication-defective adenovirus-p27 increased the expression of p27 by 24-fold versus transduction with ad-p27 alone. Treatment of a lung cancer cell line and of established lung cancer xenografts with CRAD + adenovirus-p27 also induced stronger growth suppression than treatment with either virus alone. These findings confirm the selective replication of E1-deleted adenovirus containing a therapeutic gene due to the presence of mutant E1 produced by delta24RGD in tumors. Moreover, this replication increased the therapeutic gene transfer rate and enhanced its antitumor effects.

Adenoviridae↗
PubMed2005

The AT-hook of the chromatin architectural transcription factor high mobility group A1a is arginine-methylated by protein arginine methyltransferase 6.

The HMGA1a protein belongs to the high mobility group A (HMGA) family of architectural nuclear factors, a group of proteins that plays an important role in chromatin dynamics. HMGA proteins are multifunctional factors that associate both with DNA and nuclear proteins that have been involved in several nuclear processes, such as transcriptional regulation, viral integration, DNA repair, RNA processing, and chromatin remodeling. The activity of HMGA proteins is finely modulated by a variety of post-translational modifications. Arginine methylation was recently demonstrated to occur on HMGA1a protein, and it correlates with the apoptotic process and neoplastic progression. Methyltransferases responsible for these modifications are unknown. Here we show that the protein arginine methyltransferase PRMT6 specifically methylates HMGA1a protein both in vitro and in vivo. By mass spectrometry, the sites of methylation were unambiguously mapped to Arg(57) and Arg(59), two residues which are embedded in the second AT-hook, a region critical for both protein-DNA and protein-protein interactions and whose modification may cause profound alterations in the HMGA network. The in vivo association of HMGA and PRMT6 place this yet functionally uncharacterized methyltransferase in the well established functional context of the chromatin structure organization.

Apoptosis↗
PubMed2005

Dynamics of human protein arginine methyltransferase 1(PRMT1) in vivo.

Arginine methylation is a posttranslational protein modification catalyzed by a family of protein arginine methyltransferases (PRMT), the predominant member of which is PRMT1. Despite its major role in arginine methylation of nuclear proteins, surprisingly little is known about the subcellular localization and dynamics of PRMT1. We show here that only a fraction of PRMT1 is located in the nucleus, but the protein is predominantly cytoplasmic. Fluorescence recovery after photobleaching experiments reveal that PRMT1 is highly mobile both in the cytoplasm and the nucleus. However, inhibition of methylation leads to a significant nuclear accumulation of PRMT1, concomitant with the appearance of an immobile fraction of the protein in the nucleus, but not the cytoplasm. Both the accumulation and immobility of PRMT1 is reversed when re-methylation is allowed, suggesting a mechanism where PRMT1 is trapped by unmethylated substrates such as core histones and heterogeneous nuclear ribonucleoprotein proteins until it has executed the methylation reaction.

Cell Nucleus↗
PubMed2005

PRMT8, a new membrane-bound tissue-specific member of the protein arginine methyltransferase family.

Protein arginine methylation is a common post-translational modification that has been implicated in signal transduction, RNA processing, transcriptional regulation, and DNA repair. A search of the human genome for additional members of the protein arginine N-methyltransferase (PRMT) family of enzymes has identified a gene on chromosome 12 that we have termed PRMT8. This novel enzyme is most closely related to PRMT1, although it has a distinctive N-terminal region. The unique N-terminal end harbors a myristoylation motif, and we have shown here that PRMT8 is indeed modified by the attachment of a myristate to the glycine residue after the initiator methionine. The myristoylation of PRMT8 results in its association with the plasma membrane. The second singular property of PRMT8 is its tissue-specific expression pattern; it is largely expressed in the brain. A glutathione S-transferase fusion protein of PRMT8 has type I PRMT activity, catalyzing the formation of omega-NG-monomethylated and asymmetrically omega-NG,NG-dimethylated arginine residues on a recombinant glycine- and arginine-rich substrate. PRMT8 is thus an active arginine methyltransferase that is membrane-associated and tissue-specific, two firsts for this family of enzymes.

Amino Acid Motifs↗
PubMed2005

Clinical characteristics of acute pulmonary thromboembolism in Korea.

BACKGROUND: Acute pulmonary thromboembolism (APTE) remains an important cause of morbidity and mortality in Western countries. In Korea, both the incidence and the mortality rate of APTE were thought to be low compared to Western countries. We performed the present study to investigate the current status of APTE in Korea. METHODS: Eight hundred and eight registry patients with APTE were analyzed with respect to clinical symptoms and signs, the presence of underlying diseases or predisposing factors, diagnostic methods, treatment and clinical course. RESULTS: The most common risk factors were prolonged immobilization (22.9%), deep venous thrombosis (22.0%), a recent operation (19.2%), and cancer (15.8%). The most common symptoms were dyspnea (78.6%), and chest pain (26.9%). The most common abnormality on chest radiography was effusion. The overall mortality rate at 3 months was 11.0%. Multivariate logistic regression analysis demonstrated that increased mortality risk was independently associated with the following baseline factors: onset in hospital (OR 1.88; 95% CI 1.03-3.42; p=0.03), lung cancer (OR 9.20; 95% CI 1.96-43.27; p=0.005), tachycardia (OR 3.50; 95% CI 1.86-6.60; p=0.0001), cardiogenic shock (OR 6.74; 95% CI 2.73-16.64; p=0.0001), and cyanosis (OR 3.45; 95% CI 1.27-9.44; p=0.01). CONCLUSIONS: Some differences did exist for the risk factors, symptoms, chest X-ray findings, mortality rate and prognostic factors as compared with those for Western patients. These results can prove especially helpful in the diagnosis as well as for the treatment of patients with APTE.

Acute Disease↗
PubMed2004

Loss of CARM1 results in hypomethylation of thymocyte cyclic AMP-regulated phosphoprotein and deregulated early T cell development.

The coactivator-associated arginine methyltransferase, CARM1, is a positive regulator of transcription. Using high density protein arrays, we have previously identified in vitro substrates for CARM1. One of these substrates, TARPP (thymocyte cyclic AMP-regulated phosphoprotein), is expressed specifically in immature thymocytes. Here, we have demonstrated that TARPP is arginine-methylated at a single residue, Arg(650), both in vitro and in vivo. In addition, recombinant TARPP is not methylated by extracts from Carm1(-/-) cells, indicating that there is no redundancy in this pathway. We show that thymi from Carm1(-/-) embryos (E18.5) have a 5-10-fold reduction in cellularity compared with wild type littermates. Flow cytometric analysis of thymocytes revealed a decrease in the relative proportion of double negative thymocytes in Carm1(-/-) embryos because of a partial developmental arrest in the earliest thymocyte progenitor subset. These results demonstrate that CARM1 plays a significant role in promoting the differentiation of early thymocyte progenitors, possibly through its direct action on TARPP.

Amino Acid Sequence↗
PubMed2004

Techniques in protein methylation.

Proteins can be methylated on the side-chain nitrogens of arginine and lysine residues or on carboxy-termini. Protein methylation is a way of subtly changing the primary sequence of a peptide so that it can encode more information. This common posttranslational modification is implicated in the regulation of a variety of processes including protein trafficking, transcription and protein-protein interactions. In this chapter, we will use the arginine methyltransferases to illustrate different approaches that have been developed to assess protein methylation. Both in vivo and in vitro methylation techniques are described, and the use of small molecule inhibitors of protein methylation will be demonstrated.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Application of p27 gene therapy for human malignant glioma potentiated by using mutant p27.

OBJECT: Malignant glioma could be an ideal candidate for local gene therapy because its invasion is local and it has little metastatic potential. A low expression level and high degradation activity of p27 are known to constitute an independent poor prognostic factor in patients with malignant glioma. In this study, the authors investigated the roles of wild-type p27 and mutant p27 on the treatment of malignant glioma. METHODS: The authors used two adenoviruses: one expressed wild-type p27 (ad-p27wt) and the other, containing a mutation at the major metabolic site, expressed mutant p27 (ad-p27mt). The antitumor effects of the two adenoviruses were compared with respect to cell growth arrest, cell cycle alteration, apoptosis induction, and in vitro tumorigenicity in three glioblastoma mutiforme (GBM) cell lines and in a primary GBM cell line. Transduction with ad-p27wt or ad-p27mt induced the production of p27 and the dephosphorylation of pRB. The protein level of mutant p27 was significantly higher than that of wild-type p27. The ad-p27wt induced cell cycle arrest at the G1-S transition point, whereas the ad-p27mt induced arrest at the G2-M point. Both ad-p27wt and ad-p27mt induced a growth-inhibiting effect, apoptosis, and suppression of in vitro tumorigenicity; however, ad-p27mt displayed a stronger antitumor effect than ad-p27wt in brain tumor cell lines. CONCLUSIONS: Gene therapy involving p27, especially mutant p27, has the potential to become a novel and powerful therapy for malignant glioma.

Adenoviridae↗
PubMed2003

Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice.

Arginine methylation has been implicated in the regulation of gene expression. The coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) binds the p160 family of steroid receptor coactivators (SRCs). This association enhances transcriptional activation by nuclear receptors. Here, we show that embryos with a targeted disruption of CARM1 are small in size and die perinatally. The methylation of two known CARM1 substrates, poly(A)-binding protein (PABP1) and the transcriptional cofactor p300, was abolished in knockout embryos and cells. However, CARM1-dependent methylation of histone H3 was not observed. Furthermore, estrogen-responsive gene expression was aberrant in Carm1-/- fibroblasts and embryos, thus emphasizing the role of arginine methylation as a transcription activation tag. These findings provide genetic evidence for the essential role of CARM1 in estrogen-mediated transcriptional activation.

Amino Acid Sequence↗
PubMed2002

Ventilator-induced cell wounding and repair in the intact lung.

We tested the hypothesis that cells of ventilator-injured lungs are subject to reversible plasma membrane stress failure. Rat lungs were perfused with the membrane impermeable fluorescent marker propidium iodide and randomized to one of four ventilation strategies. Subpleural lung regions were imaged with confocal microscopy, and cell injury was quantified as the number of propidium iodide-positive cells per alveolus. The number of injured cells was significantly greater in lungs ventilated with large tidal volumes and zero end-expiratory pressure than in lungs ventilated with small tidal volumes and positive end-expiratory pressure (p < 0.01). Cell injury correlated with lung weight gain, change in dynamic compliance, and histologic injury scores. In a second set of experiments, lungs were mechanically ventilated for 30 minutes at high tidal volume settings, whereas propidium iodide was perfused either during or after injurious ventilation. Labeling after removal of injurious stress revealed significantly fewer injured cells (0.25 +/- 0.09 to 0.08 +/- 0.08, p < 0.01). We conclude that cells of ventilator-injured lungs are subject to reversible plasma membrane stress failure.

Animals↗
PubMed2002

Deuterium structural effects in inorganic and bioinorganic aggregates.

Deuterium kinetic isotope effects are widely used in chemical and biological research. Deuterium thermodynamic effects on the aqueous synthesis of inorganic materials, however, seem not to have been recognized. Here we report that the simple replacement of H(2)O with D(2)O in the synthesis of a solid-state manganese complex results in a new structurally and magnetically distinct phase. When iron oxides are synthesized, the relative amount of the mineral phases obtained in H(2)O vs D(2)O is different. The morphology and magnetic properties of the iron core of the iron storage protein ferritin are likewise different when mineralization is carried out in heavy water. The formation of extra inorganic solids, change in the ratio of two phases or alteration of a single phase morphology in D(2)O suggest that new inorganic and bioinorganic metal complexes might be obtained by using the thermodynamic isotope effect.

Deuterium↗
PubMed2002

PABP1 identified as an arginine methyltransferase substrate using high-density protein arrays.

The arginine methyltransferases CARM1 and PRMT1 associate with the p160 family of nuclear hormone receptor coactivators. This association enhances transcriptional activation by nuclear receptors. We describe a method for identifying arginine N-methyltransferase substrates using arrayed high-density protein membranes to perform solid-phase supported enzyme reactions in the presence of the methyl donor S-adenosyl-l-methionine. Using this screen, we identified distinct substrates for CARM1 and PRMT1. All PRMT1 substrates harbor the expected GGRGG methylation motif, whereas the peptide sequence comparisons of the CARM1 substrates revealed no such motif. The predominant CARM1 substrate identified in this screen was PABP1. We mapped the methylated region of this RNA binding molecule in vitro and demonstrate that PABP1 is indeed methylated in vivo. Prior to these findings, the only known substrate for CARM1 was histone H3. We broaden the number of CARM1 targets and suggest a role for CARM1 in regulating transcription/translation.

Amino Acid Sequence↗
PubMed2001

The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity.

Protein arginine methylation is a prevalent posttranslational modification in eukaryotic cells that has been implicated in signal transduction, the metabolism of nascent pre-RNA, and the transcriptional activation processes. In searching the human genome for protein arginine N-methyltransferase (PRMT) family members, a novel gene has been found on chromosome 1 that encodes for an apparent methyltransferase, PRMT6. The polypeptide chain of PRMT6 is 41.9 kDa consisting of a catalytic core sequence common to other PRMT enzymes. Expressed as a glutathione S-transferase fusion protein, PRMT6 demonstrates type I PRMT activity, capable of forming both omega-N(G)-monomethylarginine and asymmetric omega-N(G),N(G)-dimethylarginine derivatives on the recombinant glycine- and arginine-rich substrate in a processive manner with a specific activity of 144 pmol methyl groups transferred min(-1) mg(-1) enzyme. A comparison of substrate specificity reveals that PRMT6 is functionally distinct from two previously characterized type I enzymes, PRMT1 and PRMT4. In addition, PRMT6 displays automethylation activity; it is the first PRMT to do so. This novel human PRMT, which resides solely in the nucleus when fused to the green fluorescent protein, joins a family of enzymes with diverse functions within cells.

Amino Acid Sequence↗