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Hyog-Young Kwon,Eun-Hye Kim,Thao Dang Hien Tran,표석능,이동권 한국분자세포생물학회 2009 Molecules and cells Vol.27 No.2
In both gram-positive and several gram-negative bacteria, the transcription of dnaK and groE operons is negatively regulated by HrcA; however, the mechanism modulating HrcA protein activity upon thermal stress remains elusive. Here, we demonstrate that HrcA is modulated via reduction and oligomerization in vitro. Native-PAGE analysis was used to reveal the oligomeric structure of HrcA. The oligomeric HrcA structure became monomeric following treatment with the reducing agent dithothreitol, and this process was reversed by treatment with hydrogen peroxide. Moreover, the mutant HrcA C118S exhibited reduced binding to CIRCE elements and became less oligomerized, suggesting that cysteine residue 118 is important for CIRCE element binding as well as oligomerization. Conversely, HrcA mutant C280S exhibited increased oligomerization. An HrcA double mutant (C118S, C280S) was monomeric and exhibited a level of oligomerization and CIRCE binding similar to wild type HrcA, suggesting that cysteine residues 118 and 280 may function as checks to one another during oligomer formation. Biochemical fractionation of E. coli cells overexpressing HrcA revealed the presence of HrcA in the membrane fraction. Together, these results suggest that the two HrcA cysteine residues at positions 118 and 280 function as reduction sensors in the membrane and mediate oligomerization upon stress.
Kwon, Hyog-Young,Kim, Eun-Hye,Kim, Seung-Whan,Kim, Su-Nam,Park, Jong-Dae,Rhee, Dong-Kwon 대한약학회 2008 Archives of Pharmacal Research Vol.31 No.2
Multidrug resistance (MDR) is a major problem in cancer chemotherapy. It was previously reported that a red ginseng saponin, 20(S)-ginsenoside $Rg_3$ could modulate MDR in vitro and extend the survival of mice implanted with ADR-resistant murine leukemia P388 cells. This study examined the cytotoxicity of $Rg_3$ on normal and transformed cells, along with its effect on the membrane fluidity. The cytotoxicity study revealed that 120 ${\mu}M\;of\;Rg_3$ was cytotoxic against a multidrug-resistant human fibroblast carcinoma cell line, KB V20C, but not against normal WI 38 cells in vitro. Flow cytometric analysis using rhodamine 123 as the artificial substrate showed that $Rg_3$ promoted the accumulation of rhodamine 123 in ADR-resistant murine leukemia P388 cells in vivo. Fluorescence polarization studies using the hydrophilic fluorescent probe, DPH, and hydrophobic probe, TMA-DPH, showed that 20 ${\mu}M\; Rg_3$ induced a significant increase in fluorescence anisotropy in KB V20C cells but not in the parental KB cells. These results clearly show that $Rg_3$ decreases the membrane fluidity thereby blocking drug efflux.
Kwon, Hyog-Young,Kim, Eun-Hye,Tran, Thao Dang Hien,Pyo, Suhk-Neung,Rhee, Dong-Kwon Springer-Verlag 2009 Molecules and cells Vol.27 No.2
<P>In both gram-positive and several gram-negative bacteria, the transcription of dnaK and groE operons is negatively regulated by HrcA; however, the mechanism modulating HrcA protein activity upon thermal stress remains elusive. Here, we demonstrate that HrcA is modulated via reduction and oligomerization in vitro. Native-PAGE analysis was used to reveal the oligomeric structure of HrcA. The oligomeric HrcA structure became monomeric following treatment with the reducing agent dithothreitol, and this process was reversed by treatment with hydrogen peroxide. Moreover, the mutant HrcA C118S exhibited reduced binding to CIRCE elements and became less oligomerized, suggesting that cysteine residue 118 is important for CIRCE element binding as well as oligomerization. Conversely, HrcA mutant C280S exhibited increased oligomerization. An HrcA double mutant (C118S, C280S) was monomeric and exhibited a level of oligomerization and CIRCE binding similar to wild type HrcA, suggesting that cysteine residues 118 and 280 may function as checks to one another during oligomer formation. Biochemical fractionation of E. coli cells overexpressing HrcA revealed the presence of HrcA in the membrane fraction. Together, these results suggest that the two HrcA cysteine residues at positions 118 and 280 function as reduction sensors in the membrane and mediate oligomerization upon stress.</P>
84 - kDa 의 폐렴구균 열충격단백질 CipL 의 Cloning 및 면역특성에 관한 연구
권혁영(Hyog Young Kwon),김용환(Yong Hwan Kim),최혜진(Hye Jin Choi),박연진(Youn Jin Park),표석능(Suhk Neung Pyo),이동권(Dong Kwon Rhee) 한국응용약물학회 2001 Biomolecules & Therapeutics(구 응용약물학회지) Vol.9 No.2
Heat shock proteins serve as chaperone by preventing the aggregation of denatured proteins and promote survival of pathogens in harsh environments. In this study, heat shock gene encoding a 84-kDa (p84) protein, which is one of the three major heat shock proteins in S. pneumoniae, was cloned and characterized. PCR with a forward primer derived from N-terminal amino acid sequence of the p84 and a reverse primer derived from the conserved second ATP-binding region of Clp family was used for amplification of the gene encoding the p84 and subsequently the PCR product was used for sequence determination. Sequence analysis of the p84 gene demonstrated that it is a member of ClpL. The deduced amino acid sequence of pneumococcal C1pL shows homology with other members of the Clp family, and particularly, even in variable leader region, with bovine Clp-like protein and L. lactis ClpL. S. pneumoniae clpL is the smallest clp member (701 amono acids) containing the two conserved ATP-binding regions, and hydrophilic N-terminal variable region of pneumococcal Clp ATPase is much shorter than any known Clp ATPases. Histidine tagged ClpL was overexpressed and purified from E. coli. Immunoblot analysis employing antisera raised against pneumococcus p84 demonstrated no cross-reactivity with Clp analog in Eschericha coli, Staphylococcus aureus and human HeLa cells. Preimmunization of mice with ClpL extended mice life partially but did not protect them from death.
권혁영(Hyog Young Kwon),이종호(Jong Ho Lee),이동권(Dong Kwon Rhee) 한국응용약물학회 1997 Biomolecules & Therapeutics(구 응용약물학회지) Vol.5 No.3
Since the advent of chemotherapy, certain types of cancer have been particularly resistant to chemotherapeutic treatment. One of the most well-studied types of resistance is resistance to multiple structurally dissimialr hydrophobic chemotherapeutic agents, or multidrug resistance (MDR). We found that MDR cells (KBV20C, KB7D) being highly resistant to colchicine, etoposide, and vincristine were found to have very low level of putrescine and low level of spermidine than the drug sensitive parental cells (KB) but they had almost same level of spermine as the drug sensitive cells. Although both MDR and drug sensitive cells had almost same rate of polyamine uptake, MDR cells were much more sensitive to an inhibitor of polyamine synthesis, methylglyoxal-bis guanylhydrazone (MGBG), suggesting that MDR cells might be defective in polyamine synthesis. These results also suggest that MGBG can be used for treatment of MDR in vivo.
Ryu, Ho-Cheol,Kwon, Hyog-Young,Choi, Il-Kuen,Rhee, Dong-Kwon The Pharmaceutical Society of Korea 2006 Archives of Pharmacal Research Vol.29 No.12
Single nucleotide polymorph isms (SNPs) in the MDR1 gene that are responsible for drug efflux can cause toxicity. Therefore, this study determined the SNPs of the Korean MDR1 gene, and analyzed the haplotypes and a linkage disequilibrium (LD) of the SNPs determined. The frequency of 9 SNPs from the MDR1 gene was determined by PCR-RFLP analyses of 100 to 500 healthy individuals. The frequcies of the SNPs were C3435T (47.7%), G2677T (37.6%), G2677A (4.4%), T1236C (21.7%), T129C (8%), A2956G (2.5%), T307C (1.5%), A41aG (9.2%), C145G (0%), and G4030C (0%). Analyses of the haplotype structure and an estimation of the LD of the combined polymorph isms demonstrated that the frequency of the 1236T-2677G-3435T haplotype is much higher in Koreans (14.1%) than in Chinese and western black Africans and the C3435T SNP in Koreans appears to have LD with T129C in Koreans for the first time. These results provide insight into the genetic variation of MDR1 in Koreans, and demonstrated the possibility of a new LD in this gene.
Ho-Cheol Ryu,Hyog-Young Kwon,Il-Kuen Choi,Dong-Kwon Rhee 대한약학회 2006 Archives of Pharmacal Research Vol.29 No.12
Single nucleotide polymorphisms (SNPs) in the MDR1 gene that are responsible for drug efflux can cause toxicity. Therefore, this study determined the SNPs of the Korean MDR1 gene, and analyzed the haplotypes and a linkage disequilibrium (LD) of the SNPs determined. The frequency of 9 SNPs from the MDR1 gene was determined by PCR-RFLP analyses of 100 to 500 healthy individuals. The frequcies of the SNPs were C3435T (47.7%), G2677T (37.6%), G2677A (4.4%), T1236C (21.7%), T129C (8%), A2956G (2.5%), T307C (1.5%), A41aG (9.2%), C145G (0%), and G4030C (0 %). Analyses of the haplotype structure and an estimation of the LD of the combined polymorphisms demonstrated that the frequency of the 1236T- 2677G-3435T haplotype is much higher in Koreans (14.1%) than in Chinese and western black Africans and the C3435T SNP in Koreans appears to have LD with T129C in Koreans for the first time. These results provide insight into the genetic variation of MDR1 in Koreans, and demonstrated the possibility of a new LD in this gene.
Isolation of a Multidrug Resistance Inhibitor from Aconitum pseudo-laeve var. erectum
Kim, Dae Keun,Kwon, Hyog Young,Lee, Kang Ro,Rhee, Dong Kwon,Zee, Ok Pyo 성균관대학교 약학연구소 1998 成均藥硏論文集 Vol.10 No.1
To overcome multidrug resistance (MDR) in cancer chemotherapy, we prepared various plant extracts and searched for a component which is effective for inhibition of MDR. MDR inhibition activity was determined by measuring cytotoxicity to MDR cells using multidrug resistant human fibrocarcinoma KB V20C, which is resistant to 20 nM vincristine and expresses high level of mdr1 gene. Of various plant extracts, the MeOH extract of the root of Aconitum pseudo-laeve var. erectum was found to have potent inhibitory activity on MDR. The bioassay-guided fractionation of the MeOH extract of the plant led to the isolation of an alkaloid, lycaconitine, as an active principle. And the IC_50 of lycaconitne for KB V20C cells was 74㎍/㎖.