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991.
Yu Mi Ahn Michael Clare Carol L. Ensinger Molly M. Hood John W. Lord Wei-Ping Lu David F. Miller William C. Patt Bryan D. Smith Lakshminarayana Vogeti Michael D. Kaufman Peter A. Petillo Scott C. Wise Jan Abendroth Lawrence Chun Robin Clark Michael Feese Hidong Kim Lance Stewart Daniel L. Flynn 《Bioorganic & medicinal chemistry letters》2010,20(19):5793-5798
Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase. 相似文献
992.
993.
Jung Jin Hwang Ha Na Kim Jean Kim Dong-Hyung Cho Mi Joung Kim Yong-Sook Kim Yunha Kim Sung-Jin Park Jae-Young Koh 《Biometals》2010,23(6):997-1013
Treatment of MCF-7 cells with tamoxifen induced vacuole formation and cell death. Levels of the autophagy marker, microtubule-associated
protein light chain 3 (LC3)-II also increased, and GFP-LC3 accumulated in and around vacuoles in MCF-7 cells exposed to tamoxifen,
indicating that autophagy is involved in tamoxifen-induced changes. Live-cell confocal microscopy with FluoZin-3 staining
and transmission electron microscopy with autometallographic staining revealed that labile zinc(II) ion (Zn2+) accumulated in most acidic LC3(+) autophagic vacuoles (AVs). Chelation of Zn2+ with N,N,N′,N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) blocked the increase in phospho-Erk and LC3-II levels, and attenuated
AV formation and cell death. Conversely, the addition of ZnCl2 markedly potentiated tamoxifen-induced extracellular signal-regulated kinase (Erk) activation, autophagy and cell death,
indicating that Zn2+ has an important role in these events. Tamoxifen-induced death was accompanied by increased oxidative stress and lysosomal
membrane permeabilization (LMP) represented as release of lysosomal cathepsins into cytosol. Treatment with the antioxidant
N-acetyl-l-cysteine (NAC) blunted the increase in Zn2+ levels and reduced LC3-II conversion, cathepsin D release and cell death induced by tamoxifen. And cathepsin inhibitors attenuated
cell death, indicating that LMP contributes to tamoxifen-induced cell death. Moreover, TPEN blocked tamoxifen-induced cathepsin
D release and increase in oxidative stress. The present results indicate that Zn2+ contributes to tamoxifen-induced autophagic cell death via increase in oxidative stress and induction of LMP. 相似文献
994.
Radha Karki Pritam Thapa Mi Jeong Kang Tae Cheon Jeong Jung Min Nam Hye-Lin Kim Younghwa Na Won-Jea Cho Youngjoo Kwon Eung-Seok Lee 《Bioorganic & medicinal chemistry》2010,18(9):3066-3077
A new series of 2,4-diphenyl-6-aryl pyridines containing hydroxyl group(s) at the ortho, meta, or para position of the phenyl ring were synthesized, and evaluated for topoisomerase I and II inhibitory activity and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Structure–activity relationship study revealed that the substitution of hydroxyl group(s) increased topoisomerase I and II inhibitory activity in the order of meta > para > ortho position. Substitution of hydroxyl group on the para position showed better cytotoxicity. 相似文献
995.
Byung Chull An Seung Sik Lee Eun Mi Lee Jae Taek Lee Seung Gon Wi Hyun Suk Jung Woojun Park Byung Yeoup Chung 《Molecules and cells》2010,29(2):145-151
Thiol-based peroxiredoxins (Prxs) are conserved throughout all kingdoms. We have found that a conserved typical 2-Cys Prx-like
protein (PaPrx) from Pseudomonas aeruginosa bacteria displays diversity in its structure and apparent molecular weight (MW), and can act alternatively as a peroxidase
and molecular chaperone. We have also identified a regulatory factor involved in this structural and functional switching.
Exposure of P. aeruginosa to hydrogen peroxide (H2O2) causes PaPrx to convert from a high MW (HMW) complex to a low MW (LMW) form, which triggers a chaperone to peroxidase functional
switch. This structural switching is primarily guided by either the thioredoxin (Trx) or glutathione (GSH) systems. Furthermore,
comparison of our structural data [native and non-reducing polyacrylamide gel electrophoresis (PAGE) analysis, size exclusion
chromatography (SEC) analysis, and electron microscopy (EM) observations] and enzymatic analyses (peroxidase and chaperone
assay) revealed that the formation of oligomeric HMW complex structures increased chaperone activity of PaPrx. These results
suggest that multimerization of PaPrx complexes promotes chaperone activity, and dissociation of the complexes into LMW species
enhances peroxidase activity. Thus, the dual functions of PaPrx are clearly associated with their ability to form distinct
protein structures. 相似文献
996.
In a previous study, we recently claimed that dihydrotestosterone (DHT)-inducible dickkopf-1 (DKK-1) expression is one of the key factors involved in androgen-potentiated balding. We also demonstrated that L-ascorbic acid 2-phosphate (Asc 2-P) represses DHT-induced DKK-1 expression in cultured dermal papilla cells (DPCs). Here, we investigated whether or not L-threonate could attenuate DHT-induced DKK-1 expression. We observed via RT-PCR analysis and enzyme-linked immunosorbent assay that DHT-induced DKK-1 expression was attenuated in the presence of L-threonate. We also found that DHT-induced activation of DKK-1 promoter activity was significantly repressed by L-threonate. Moreover, a co-culture system featuring outer root sheath (ORS) keratinocytes and DPCs showed that DHT inhibited the growth of ORS cells, which was then significantly reversed by L-threonate. Collectively, these results indicate that L-threonate inhibited DKK-1 expression in DPCs and therefore is a good treatment for the prevention of androgen-driven balding. 相似文献
997.
Do Young Kim Mi Kyoung Han Hyun-Woo Oh Doo-Sang Park Su-Jin Kim Seung-Goo Lee Dong-Ha Shin Kwang-Hee Son Kyung Sook Bae Ho-Yong Park 《Journal of Molecular Catalysis .B, Enzymatic》2010,62(1):32-39
A novel GH10 endo-β-1,4-xylanase (XylG) gene from Streptomyces thermocarboxydus HY-15, which was isolated from the gut of Eisenia fetida, was cloned, over-expressed, and characterized. The XylG gene (1182 bp) encoded a polypeptide of 393 amino acids with a deduced molecular mass of 43,962 Da and a calculated pI of 6.74. The primary structure of XylG was 69% similar to that of Thermobifida fusca YX endo-β-1,4-xylanase. It was most active at pH 6.0 and 55 °C. The susceptibilities of xylans to XylG were as follows: oat spelt xylan > birchwood xylan > beechwood xylan. The XylG also showed high activity (474 IU/mg) toward p-nitrophenylcellobioside. Moreover, at pH 6.0 and 50 °C, the Vmax and Km values of the XylG were 127 IU/mg and 2.51 mg/ml, respectively, for oat spelt xylan and 782 IU/mg and 5.26 mM, respectively, for p-nitrophenylcellobioside. A homology model indicated that XylG folded to form a (β/α)8-barrel with two catalytic residues of an acid/base (Glu181) and a nucleophile (Glu289). The formation of a disulfide bond between Cys321 and Cys327 were predicted by homology modeling. 相似文献
998.
999.
The enormous regenerative capacity of the blood system to sustain functionally mature cells are generated from highly proliferative, short‐lived progenitors, which in turn arise from a rare population of pluripotent and self‐renewing hematopoietic stem cells (HSC). In the bone marrow, these stem cells are kept in a low proliferative, relatively quiescent state in close proximity to stromal cells and osteoblasts, forming specialized niches. The interaction in particular to bone is crucial to prevent exhaustion of HSCs from uncontrolled cell‐cycle entry and to excessive proliferation. In addition, the niche and its components protect stem cells from stress, such as accumulation of reactive oxygen species and DNA damage. One of the key issues is to identify conditions to increase the number of HSCs, either in vivo or during ex vivo growth cultures. This task has been very difficult to resolve and most attempts have been unsuccessful. However, the mechanistic insights to HSC self‐renewal and preservation are gradually increasing and there is now hope that future research will enable scientists and clinicians to modulate the process. In this review, we will focus on the molecular mechanisms of self‐renewal and HSC maintenance in the light of novel findings that HSCs reside at the lowest end of an oxygen gradient. Hypoxia appears to regulate hematopoiesis in the bone marrow by maintaining important HSC functions, such as cell cycle control, survival, metabolism, and protection against oxidative stress. To improve the therapeutic expansion of HSCs we need to learn more about the molecular mechanisms of hypoxia‐mediated regulation. J. Cell. Physiol. 222:17–22, 2010. © 2009 Wiley‐Liss, Inc. 相似文献
1000.
Young Sook Lee Seokjoo Yoon Mi Sun Park Jin Hwa Kim Jeung‐Hoon Lee Chang‐Woo Song 《Journal of biochemical and molecular toxicology》2010,24(4):260-269
In this study, we determined whether p53 expression affected the sensitivity of non–small cell lung cancer (NSCLC) and colon cancer cells to bleomycin (BLM). Two human NSCLC cell lines (A549 expressing wild‐type p53 and p53‐null H1299) and two colon cancer cell lines (HCT116 p53+/+ and its p53 deficient subline HCT116 p53?/?) were subjected to treatment with BLM. Cells were treated with various concentrations of BLM, and cellular viability was assessed by formazan assay. To investigate the role of p53 in BLM sensitivity, we transduced cells with adenovirus with wild‐type p53, dominant‐negative p53, and GFP control, and analyzed the effect on cellular viability. Cells expressing wild‐type p53 were more sensitive to BLM than p53‐null cells in both NSCLC and colon cancer cells. Sensitivity to BLM of the cells with wild‐type p53 was reduced by overexpression of dominant‐negative p53, while BLM sensitivity of p53‐null cells was increased by wild‐type p53 in both NSCLC cells and colon cancer cells. In conclusion, our data show that p53 sensitizes all four cancer cells lines tested to BLM toxicity and overexpression of p53 confers sensitivity to the cytotoxic activity of the anticancer agent in p53‐null cells. © 2010 Wiley Periodicals, Inc. J Biochem Mol Toxicol 24:260–269, 2010; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.20334 相似文献