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Contribution of HSP90 Cleavage to the Cytotoxic Effect of Suberoylanilide Hydroxamic Acid In Vivo and the Involvement of TXNIP in HSP90 Cleavage

  • Sangkyu Park;Dongbum Kim;Haiyoung Jung;In Pyo Choi;Hyung-Joo Kwon;Younghee Lee
    • Biomolecules & Therapeutics
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    • v.32 no.1
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    • pp.115-122
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    • 2024
  • Heat shock protein (HSP) 90 is expressed in most living organisms, and several client proteins of HSP90 are necessary for cancer cell survival and growth. Previously, we found that HSP90 was cleaved by histone deacetylase (HDAC) inhibitors and proteasome inhibitors, and the cleavage of HSP90 contributes to their cytotoxicity in K562 leukemia cells. In this study, we first established mouse xenograft models with K562 cells expressing the wild-type or cleavage-resistant mutant HSP90β and found that the suppression of tumor growth by the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was interrupted by the mutation inhibiting the HSP90 cleavage in vivo. Next, we investigated the possible function of thioredoxin interacting protein (TXNIP) in the HSP90 cleavage induced by SAHA. TXNIP is a negative regulator for thioredoxin, an antioxidant protein. SAHA transcriptionally induced the expression of TXNIP in K562 cells. HSP90 cleavage was induced by SAHA also in the thymocytes of normal mice and suppressed by an anti-oxidant and pan-caspase inhibitor. When the thymocytes from the TXNIP knockout mice and their wild-type littermate control mice were treated with SAHA, the HSP90 cleavage was detected in the thymocytes of the littermate controls but suppressed in those of the TXNIP knockout mice suggesting the requirement of TXNIP for HSP90 cleavage. We additionally found that HSP90 cleavage was induced by actinomycin D, β-mercaptoethanol, and p38 MAPK inhibitor PD169316 suggesting its prevalence. Taken together, we suggest that HSP90 cleavage occurs also in vivo and contributes to the anti-cancer activity of various drugs in a TXNIP-dependent manner.

Amino Acid Contents and Meat Quality Properties on the Loin from Crossbred Black and Crossbred Black and Crossbred Pigs Reared in Jejudo (제주도에서 사육된 개량 흑돼지와 비육돈 등심의 아미노산 함량 및 육질 특성)

  • Yang Seung-Joo;Kim Young-Kil;Hyon Jae-Suk;Moon Yoon-Hee;Jung In-Chul
    • Food Science of Animal Resources
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    • v.25 no.1
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    • pp.7-12
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    • 2005
  • The amino acid contents, physical and sensory properties for the loins of crossbred pigs (JJ90: live weight of 90∼100 kg; and JJ110: live weight of 110∼120 kg) and crossbred Jeju black pig (JB90: live weight of 90∼100 kg) were evaluated to investigate their quality. The total contents of structural amino acid, which were 18.15∼20.22% for all the samples without showing significant differences, included significant amount of glutamic acid, aspartic acid, lysine and leucine. The free amino acid content was 0.486% for JB90, which was greater than JJ90 and JJ110. Also, significant amount of taurine, serine, glycine, alanine, valine, and leucine could be observed in the free amino acid content of the samples. The redness (a/sup */) and yellowness (b/sup */) of JB90 were significantly higher titan those of JJ90 and JJ110. The water holding capacity, hardness, chewiness, juiciness and palatability of JJ110 and JB90 were higher than those of JJ90, but their difference was not significant.

A Study on $90^{\cire}$ Constant Phase Shifter (전송선형 $90^{\cire}$ 정위상기에 관한 연구)

  • 이충웅
    • Journal of the Korean Institute of Telematics and Electronics
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    • v.13 no.6
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    • pp.12-15
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    • 1976
  • This paper presents the realization method of 90$^{\circ}$ constant phase shifter in the VHF band, constructed by the entirely differens idea from the conventional method of the realization of constant phase shifter in the audio frequency range. The construction of 90$^{\circ}$ constant phase shifter is. simple and can be easily realized by using the distributed constant element, transmission line, and the lumped constant elements, R,C,L.

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Design of miniaturized active 90$^{\circ}$ phase divider on RFIC/MMIC for application to maritime wireless communication components (해상 무선통신소자의 응용을 위한 RFIC/MMIC용 소형화된 능동형 90$^{\circ}$ 위상 분배기의 설계)

  • Park, Young-Bae;Yun, Young
    • Proceedings of the Korean Society of Marine Engineers Conference
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    • 2005.06a
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    • pp.406-411
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    • 2005
  • In this paper, we propose an active 90$^{\circ}$ phase divider for application to MMIC. Because of their very large size, conventional passive 90$^{\circ}$ dividers can't be integrated on MMIC. Therefore, highly miniaturized 90$^{\circ}$ dividers are required for a development of highly integrated MMIC. For this reason, active 90$^{\circ}$ divider is indispensable because active phase divider is much smaller than conventional passive dividers, and it can be integrated on MMIC. In this work, we developed active 90$^{\circ}$ divider with emitter inductor, and it was employed for the operation of the balanced mixer in order to verify the performance of the active 90$^{\circ}$ divider. According to the results, it was found that the active 90$^{\circ}$ divider exhibited good RF performances comparable to conventional passive power dividers.

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Design of a Phase Splitter(2.4[GHz]) using Differential Amplifier (자동증폭기를 이용한 위상분상기(Phase Splitter) 설계)

  • Roh, Hee-Jung;Seo, Choon-Weon
    • Journal of the Korean Institute of Illuminating and Electrical Installation Engineers
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    • v.22 no.6
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    • pp.14-17
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    • 2008
  • This paper describes the simulation of a phase splitter for the design of Chireix Outphasing power amplifier. Phase splitter separate the input signal with $0[^{\circ}]$ into the signal with $+90[^{\circ}]$ and $-90[^{\circ}]$ Chireix Outphasing power amplifier get a linearized output from the signal amplifying and combining the separated signal with the phase of $+90[^{\circ}]$ and $-90[^{\circ}]$ of the phase splitter. phase splitter is the core device when designing Chireix Outphasing power amplifier. It is very difficult to design phase splitter with the difference of $90[^{\circ}]$. This phase splitter is used to design the difference of $180[^{\circ}]((90[^{\circ}]+{\alpha}),\;-(90[^{\circ}])+{\alpha}))$ using simulation tool and a differential amplifier.

Uptake and Accumulation of Soil Strontium-90 by Peanut and Sesame (토양 strontium-90의 땅콩과 참깨에 의한 흡수 및 축적)

  • Choi, Yong-Ho;Jo, Jae-Seong
    • Korean Journal of Environmental Agriculture
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    • v.15 no.1
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    • pp.11-18
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    • 1996
  • A greenhouse experiment on the Sr-90 uptake by peanut and sesame was conducted through pot cultures on a sandy loam soil of pH 6.35 treated with Sr-90 in 5.2 and 31.2Bq per gram. The rate of Sr-90 transfer from soil to each plant part, the ratio of Sr-90 concentration in the part to the concentration in soil, and the patterns of their temporal changes were not, on the whole, significantly different between the two treatments. About 0.7 and 0.5 % of Sr-90 in soil transferred to all the mature plants of peanut and sesame, respectively, with the radioactivities in their roots not counted. Only 4% and less than 15% of Sr-90 absorbed by peanut and sesame, respectively, translocated to their seeds. Both crops showed the highest Sr-90 concentration in the leaf and the lowest in the seed. At maturities, the concentration ratio in dry seed was 0.4 in peanut and 3.3 in sesame and that in dry leaf was 12.5 and 10.7, respectively. Sr-90 concentrations in the top 15 cm soil after harvests averaged about 80 % of the concentrations at starting. Sr-90 uptake resulted in neither growth inhibition nor yield decrease.

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Vascular Smooth Muscle Cells Secrete CXCL10 in Response to Heat Shock Protein 90 (혈관평활근세포에서 HSP90에 의한 CXCL10 증가에 관여하는 인자에 대한 연구)

  • Rhim, Byung-Yong;Kim, Do-Hyung;Kim, Koan-Hoi
    • Journal of Life Science
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    • v.21 no.5
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    • pp.664-670
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    • 2011
  • Oxidative stress results in sustained release of heat shock protein 90 (HSP90) from vascular smooth muscle cells (VSMCs). We investigated whether extracellular HSP90 predisposed VSMCs to pro-inflammatory phenotype. Exposure of human aortic smooth muscle cells to HSP90 not only significantly enhanced CXCL10 secretion but also increased CXCL10 transcription. HSP90-mediated CXCL10 secretion was attenuated by OxPAPC, a TLR-2/4 inhibitor, and curcumin, a TLR-4 dimerization inhibitor. Inhibitors of diphenyleneiodium chloride and the Akt pathway also attenuated CXCL10 secretion in response to HSP90. The gene delivery of I${\kappa}$B using recombinant adenoviruses and treatment with resveratrol, which inhibit NF-${\kappa}$B activity, significantly attenuated HSP90-induced CXCL10 secretion from VSMCs. We propose that extracellular HSP90 contributes to an inflammatory reaction in the stressed vasculature by inducing CXCL10 expression of VSMCs, and that TLR-4, Akt, and NF-${\kappa}$B play active roles in the process.

Expression of HSP90, HSP70 mRNA and Change of Plasma Cortisol and Glucose During Water Temperature Rising in Freshwater Adapted Black Porgy, Acanthopagrus schlegeli (담수 사육 감성돔, Acanthopagrus schlegeli의 수온 상승에 따른 HSP90, HSP70 mRNA의 발현 및 혈장 cortisol과 glucose 변화)

  • Choi, Cheol-Young;Min, Byung-Hwa;Kim, Na-Na;Cho, Sung-Hwoan;Chang, Young-Jin
    • Journal of Aquaculture
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    • v.19 no.4
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    • pp.315-322
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    • 2006
  • The objective of the present study was to investigate the expression of heat shock protein 90 (HSP90) and 70 (HSP70) mRNA as cellular stress responses, the levels of plasma cortisol with glucose as neuro-endocrine stress responses during water temperature rising in freshwater adapted black porgy, Acanthopagrus schlegeli. A cDNA fragment of 891 (HSP90) and 465 (HSP70) bp was cloned from black porgy testis by Reverse transcription-polymerase chain reaction (RT-PCR) with primers designed from the conserved regions of other teleost. The PCR product of HSP90 showed very high homology to red seabream (99%), rainbow trout (95%), Atlantic salmon (94%), zebrafish (94%) HSP90, HSP70 of black porgy was also highly similar to those of rainbow trout (96%), silver seabream (95%), zebrafish (95%) HSP70. Water temperature rising ($20{\sim}30^{\circ}C$) induced elevation of HSP90 mRNA in black porgy gonad, liver, brain, intestine and kidney, whereas it resulted in an induction of the HSP70 mRNA expression in gonad only. Plasma cortisol levels increased significantly at $30^{\circ}C$ in the fish compared to those at $20^{\circ}C$. Glucose levels of the fish showed a tendency of co-increase with cortisol during water temperature rising. These results suggest that increased HSP90 mRNA in liver with plasma cortisol following heat shock may be related to increasing glucose for homeostasis in this species.

Differential Sensitivities of Human Multidrug-resistant Cancer Cells to BIIB021 and Modulation of Hsp90 Inhibitors by NSAIDs and Niclosamide (항암제 다제내성(MDR) 암세포의 Hsp90 저해제 BIIB021에 대한 감수성의 차이 및 NSAIDs 및 Niclosamide에 의한 Hsp90 저해제의 활성 변화)

  • Moon, Hyun-Jung;Lee, Su-Hoon;Kim, Sun-Hee;Kang, Chi-Dug
    • Journal of Life Science
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    • v.28 no.10
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    • pp.1212-1219
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    • 2018
  • The critical role of heat shock protein 90 (Hsp90) in tumorigenesis led to the development of several first- and second-generation Hsp90 inhibitors, which have demonstrated promising responses in cancers. In this study, we found second-generation Hsp90 inhibitor BIIB021-resistant multidrug-resistant (MDR) human cancer cells, although BIIB021 was shown to be active in first-generation Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)-resistant MDR cells. MCF7-MDR and HeyA8- MDR cells were more resistant to BIIB021 than their parental counterparts, indicating that BIIB021 cannot be applicable to all cancer cells expressing MDR proteins. We revealed that dimethyl-celecoxib (DMC), one of the non-steroidal anti-inflammatory drugs (NSAIDs), potentiated cytotoxicity of BIIB021 against both BIIB021-resistant and BIIB021-sensitive MDR cells. The effectiveness of NSAIDs involving celecoxib and DMC in combination with BIIB021 led to the autophagic degradation/down-regulation of mutant p53 (mutp53) that overexpressed MDR cells and the suppression of Hsp70 induction. This resulted in sensitization of MDR cells to BIIB021. Moreover, autophagy induction by sulindac sulfide, another type of NSAID, and niclosamide, an FDA-approved anthelmintic drug, potentiated 17-AAG-mediated autophagic degradation/down-regulation of mutp53 and c-Myc, client proteins of Hsp90. Therefore, our results suggest that NSAIDs and niclosamide positively enhance the anticancer activity of Hsp90 inhibitors through an autophagic pathway. They may also be new candidates for sensitizing MDR cells to Hsp90 inhibitors.

Studies on the Desorption of $Sr^{90}$ from Paddy Soil (답토양(畓土壤)에서 Strontium-90의 탈착(脫着)에 관(關)한 연구(硏究))

  • Kim, Jae-Sung;Lim, Soo-Kil;Lee, Young-Il;Cheong, Kyu-Hoi
    • Korean Journal of Environmental Agriculture
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    • v.6 no.2
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    • pp.31-38
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    • 1987
  • The present study was carried out to determine the effect of the physical, chemical and mineralogical properties of paddy soil on the adsorption and desorption of $Sr^{90}$ from absorbed soils. The results obtained were as follows: 1. Most of the adsorbed $Sr^{90}$ was exchangeable and water soluble. $Sr^{90}$ extracted by ammonium acetate was very high compared to the water soluble fractions, and the ammount decreased with the increase of calcium application, but increased proportionally with the increase of $Sr^{90}$ treatment. 2. The distribution of $Sr^{90}$ in paddy soil depend on the soil type. Average-distribution rates of water soluble, exchangeable and non-exchangeable fractions of $Sr^{90}$ in the soils were 28.6%, 59.3% and 12.1% respectively. 3. The non-exchangeable from of $Sr^{90}$ was high in the soils of high illite and low vermiculite content. 4. The desorption of $Sr^{90}$ from adsorbed soils decreased with the increase of pH and ex-cations of the soils, but increased with the amount of organic matter and clay content in the soil.

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