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The Role and Regulation of MCL-1 Proteins in Apoptosis Pathway

  • Bae, Jeehyeon
    • Proceedings of the Korean Society of Applied Pharmacology
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    • 2002.07a
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    • pp.113-113
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    • 2002
  • Phylogenetically conserved Bcl-2 family proteins play a pivotal role in the regulation of apoptosis from virus to human. Members of the Bcl-2 family consist of antiapoptotic proteins such as Bcl-2, Bcl-xL, and Bcl-w, and proapoptotic proteins such as BAD, Bax, BOD, and Bok. It has been proposed that anti- and proapoptotic Bcl-2 proteins regulate cell death by binding to each other and forming heterodimers. A delicate balance between anti- and proapoptotic Bcl-2 family members exists in each cell and the relative concentration of these two groups of proteins determines whether the cell survives or undergoes apoptosis. Mcl-1 (Myeloid cell :leukemia-1) is a member of the Bcl-2 family proteins and was originally cloned as a differentiation-induced early gene that was activated in the human myeloblastic leukemia cell line, ML-1 . Mcl-1 is expressed in a wide variety of tissues and cells including neoplastic ones. We recently identified a short splicing variant of Mcl-1 short (Mcl-IS) and designated the known Mcl-1 as Mcl-1 long (Mcl-lL). Mcl-lL protein exhibits antiapoptotic activity and possesses the BH (Bcl-2 homology) 1, BH2, BH3, and transmembrane (TM) domains found in related Bcl-2 proteins. In contrast, Mcl-1 S is a BH3 domain-only proapoptotic protein that heterodimerizes with Mcl-lL. Although both Mc1-lL and Mcl-lS proteins contain BH domains fecund in other Bcl-2 family proteins, they are distinguished by their unusually long N-terminal sequences containing PEST (proline, glutamic acid, serine, and threonine) motifs, four pairs of arginine residues, and alanine- and glycine-rich regions. In addition, the expression pattern of Mcl-1 protein is different from that of Bcl-2 suggesting a unique role (or Mcl-1 in apoptosis regulation. Tankyrasel (TRF1-interacting, ankyrin-related ADP-related polymerasel) was originally isolated based on its binding to TRF 1 (telomeric repeat binding factor-1) and contains the sterile alpha motif (SAM) module, 24 ankyrin (ANK) repeats, and the catalytic domain of poly(adenosine diphosphate-ribose) polymerase (PARP). Previous studies showed that tankyrasel promotes telomere elongation in human cells presumably by inhibiting TRFI though its poly(ADP-ribosyl)action by tankyrasel . In addition, tankyrasel poly(ADP-ribosyl)ates Insulin-responsive amino peptidase (IRAP), a resident protein of GLUT4 vesicles, and insulin stimulates the PARP activity of tankyrase1 through its phosphorylation by mitogen-activated protein kinase (MAPK). ADP-ribosylation is a posttranslational modification that usually results in a loss of protein activity presumably by enhancing protein turnover. However, little information is available regarding the physiological function(s) of tankyrase1 other than as a PARP enzyme. In the present study, we found tankyrasel as a specific-binding protein of Mcl-1 Overexpression of tankyrasel led to the inhibition of both the apoptotic activity of Mel-lS and the survival action of Mcl-lL in mammalian cells. Unlike other known tankyrasel-interacting proteins, tankyrasel did not poly(ADP-ribosyl)ate either of the Mcl-1 proteins despite its ability to decrease Mcl-1 proteins expression following coexpression. Therefore, this study provides a novel mechanism to regulate Mcl-1-modulated apoptosis in which tankyrasel downregulates the expression of Mcl-1 proteins without the involvement of its ADP-ribosylation activity.

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Low Dose Exposure to Di-2-Ethylhexylphthalate in Juvenile Rats Alters the Expression of Genes Related with Thyroid Hormone Regulation

  • Kim, Minjeong;Jeong, Ji Seong;Kim, Hyunji;Hwang, Seungwoo;Park, Il-Hyun;Lee, Byung-Chul;Yoon, Sung Il;Jee, Sun Ha;Nam, Ki Taek;Lim, Kyung-Min
    • Biomolecules & Therapeutics
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    • v.26 no.5
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    • pp.512-519
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    • 2018
  • Phthalates widely used in the manufacture of plastics have deeply penetrated into our everyday lives. Recently, a concern over the toxicity of phthalates on thyroid, has been raised but in most of cases, the doses employed were unrealistically high. To investigate the effects of phthalates on thyroid, we investigated the effects of the repeated oral exposure to low to high doses (0.3, 3, 30 and 150 mg/kg) di-2-ethylhexylphthalate (DEHP) from weaning to maturity for 90 days in juvenile rats on the thyroid. The histological examination revealed that DEHP significantly induced hyperplasia in the thyroid from the doses of 30 mg/kg, which was confirmed with Ki67 staining. In line with this finding, increased mRNA expression of thyrotropin releasing hormone (Trh) was observed in the thyroid of female at 0.3 mg/kg and 150 mg/kg as determined by RNAseq analysis. Moreover, significantly increased expression of parathyroid hormone (Pth) in the female at 0.3 mg/kg, and thyroglobulin (Tg) and thyroid hormone responsive (Thrsp) in the male at 0.3 mg/kg were noted in the blood, of which changes were substantially attenuated at 150 m/kg, alluding the meaningful effects of low dose DEHP on the thyroid hormone regulation. Urinary excretion of mono-2-ethylhexyl-phthalate (MEHP), a major metabolite of DEHP was determined to be 4.10 and 12.26 ppb in male, 6.65 and 324 ppb in female at 0.3 and 30 mg/kg DEHP, respectively, which fell within reported human urine levels. Collectively, these results suggest a potential adverse effects of low dose phthalates on the thyroid.

Preparation and Characterizations of Complex Composed of ${\beta}$-Cyclodextrin Polymer/Cinnamic Acid (베타-사이클로 덱스트린 중합체/신남산 복합체의 제조 및 특성 연구)

  • Mok, Eun Young;Cha, Hyun Ju;Kim, Jin-Chul
    • Applied Chemistry for Engineering
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    • v.23 no.5
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    • pp.462-466
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    • 2012
  • $\beta$-cyclodextrin ($\beta$-CD) polymers were prepared in a strong alkali condition solution (NaOH solution 30% (w/v)) using epichlorohydrin (EPI) as a cross-linker, and the molar ratio of EPI to $\beta$-CD was 10 : 1. The $\beta$-CD content in $\beta$-CD polymers is about 52%. In order to get the photo-responsible and pH-responsible, cinnamic acid was added to be inserted into the cavities of $\beta$-CD due to the hydrophobic interaction. The complex formation was confirmed using transmission electron microscope. The dimerization degree of complexes increased under UV irradiation at $\lambda$ = 365 nm but decreased under the UV irradiation at $\lambda$ = 254 nm. Dynamic light scattering analysis of particle sizes showed that the sizes of complexes did not change with different UV wavelength. Moreover, the complexes were pH-responsible because of the carboxyl group of cinnamic acid, but the size and zeta potential of the complex did not change in strong acid and alkali conditions.

Molecular and Functional Characterization of Monocot-specific Pex5p Splicing Variants, Using OsPex5pL and OsPex5pS from Rice (Oryza sativa)

  • Lee, Jung Ro;Jung, Ji Hyun;Kang, Jae Sook;Kim, Jong Cheol;Jung, In Jung;Seok, Min Sook;Kim, Ji Hye;Kim, Woe Yeon;Kim, Min Gab;Kim, Jae-Yean;Lim, Chae Oh;Lee, Kyun Oh;Lee, Sang Yeol
    • Molecules and Cells
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    • v.23 no.2
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    • pp.161-169
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    • 2007
  • We identified two alternatively spliced variants of the peroxisomal targeting signal 1 (PTS1) receptor protein Pex5ps in monocot (rice, wheat, and barley) but not in dicot (Arabidopsis and tobacco) plants. We characterized the molecular and functional differences between the rice (Oryza sativa) Pex5 splicing variants OsPex5pL and OsPex5pS. There is only a single-copy of OsPEX5 in the rice genome and RT-PCR analysis points to alternative splicing of the transcripts. Putative light-responsive cis-elements were identified in the 5' region flanking OsPEX5L and Northern blot analysis demonstrated that this region affected light-dependent expression of OsPEX5 transcription. Using the pex5-deficient yeast mutant Scpex5, we showed that OsPex5pL and OsPex5pS are able to restore translocation of a model PTS1 protein (GFP-SKL) into peroxisomes. OsPex5pL and OsPex5pS formed homo-complexes via specific interaction domains, and interacted with each other and OsPex14p to form hetero-complexes. Although overexpression of OsPex5pL in the Arabidopsis pex5 mutant (Atpex5) rescued the mutant phenotype, overexpression of OsPex5pS only resulted in partial recovery.

Identification and Characterization of External Copper Responsive Genes of Deinococcus radiodurans (DNA Microarry를 이용한 Deinococcus radiodurans의 구리이온 특이 반응 유전자 탐색 및 특성 분석)

  • Joe, Min-Ho;Lim, Sang-Yong;Jung, Sun-Wook;Song, Du-Sub;Choi, Young-Ji;Kim, Dong-Ho
    • Korean Journal of Microbiology
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    • v.44 no.3
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    • pp.169-177
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    • 2008
  • Global gene expression of Deinococcus radiodurans, a highly radiation resistant bacterium, in response to excess copper was analyzed by using oligonucleotide microarray chip. Among 3,187 open reading frames of D. radiodurans, seventy genes showed a statistically significant expression ratio of at least 2-fold changes under growth conditions of excess copper; 64 genes were induced and 6 genes were reduced. Especially, two operons ($DRB0014{\sim}DRB0017$ and $DRB0125{\sim}DRB0121$) presumably involved in the iron transport and utilization were the most highly induced genes by excess copper. A quantitative real-time PCR assay revealed that DRB00l4 and DRB0125 are highly transcribed responding to excess copper and 2,2'-dipyridyl, an iron chelator. In addition, the transcription of both genes was not changed by excess iron and bathocuproine disulphonate, a copper chelator. These results suggested that the copper metabolism may be closely connected with the iron transport and utilization in D. radiodurans. However, the disruption of each gene, DRB00l4 and DRB0125, did not affect the copper and radiation resistance, the most well-known character of this organism.

Changes on Photosynthesis and SOD Activity in Platanus orientalis and Liriodendron tulipifera According to Ozone Exposing Period (오존 노출 시간에 따른 버즘나무와 백합나무의 광합성과 SOD 활성 변화)

  • Lee Jae-Cheon;Oh Chang-Young;Han Sim-Hee;Kim Pan-Gi
    • Korean Journal of Agricultural and Forest Meteorology
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    • v.7 no.2
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    • pp.156-163
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    • 2005
  • This study was conducted to compare the physiological and biochemical responses of P. orientalis and L. tulipifera in response to ozone. One-year-old seedlings of P. orientalis and L. tulipifera were exposed to 100 ppb ozone concentration for 2, 4, or 8 hr/day for 1 week. Photosynthesis, stomatal conductance and ozone uptake rate were measured daily, and chlorophyll fluorescence, carboxylation efficiency, chlorophyll content, and SOD activity were measured after 1 week. In P. orientalis, photosynthesis and stomatal conductance were not decreased in the 2h/day ozone treatment, but the L. tulipifera response was more sensitive even in the 2h/day ozone treatment. Increased treatment time decreased photosynthesis and stomatal conductance. Chlorophyll fluorescence was not significantly different among treatment times. However, carboxylation efficiency decreased with increased treatment time, and L. tulipifera was more sensitive than P. orientalis. Chlorophyll content did not differ with species or treatment time. SOD activity response was greater in L. tulipifera than in P. orientalis, increasing to $131\%$ of pretreatment observations. Therefore it was concluded that L. tulipifera was more responsive and had lower ozone tolerance than P. orientalis.

lonizing Radiation Hormesis in Crops (저선량 전리방사선에 의한 작물의 활성증진)

  • Kim, Jae-Sung;Lee, Young-Bok
    • Korean Journal of Environmental Agriculture
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    • v.17 no.1
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    • pp.76-83
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    • 1998
  • The most remarkable aspect in the hormesis law is that dose of harmful agents can produce effect that are diametrically opposite to the effect found with high doses of the same agent. Minute quantities of a harmful agent bring about very small change in the organism and control mechanisms appear to subjugate normal processes to place the organism in a state of albert and repair. The stimulated organism in more responsive to changes in environmental factors than it did before being alerted. Routine functions, including repair and defense, have priority for available energy and matetial. The alerted organism utilizes nutrients more efficiently, grows faster, shows improved defense, and lives longer. Accelerated germination, sprouting, growth, development, blooming and ripening, and increased crop yield and resistance to disease are found in plants. Another concept supported by the data in that low doses of ionizing radiation provide increased resistance to subsequent high doses of radiation. The hormesis varies with subject plant, variety, state of seed, environmental and cultural conditions, physiologic function measured, dose rate and total exposure. The results of hormesis are less consistently found, probably due to the great number of uncontrolled variables in the experiments. The general dosage for radiation homlesis in about 100 (10 to 1,000) times ambient or 100 (10 to 1,000) times less than a definitely harmful dose, but these must be modified to the occasion. Although little is known about most mechanisms of homzesis reaction, overcompensation of repair mechanism is offered as one mechanism.

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The Oxidative Stress Induction and Response of Antioxidative Enzymes in the Large Patch-Infected Zoysiagrass I. Oxidative stress induction (라지 팻치에 감염된 잔디의 산화적 스트레스 발현과 항산화효소의 활력의 변화 I. 산화적 스트레스 발현)

  • Kim, Dae-Hyun;Lee, Bok-Rye;Li, Ming;Kim, Tae-Hwan
    • Journal of The Korean Society of Grassland and Forage Science
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    • v.27 no.2
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    • pp.129-136
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    • 2007
  • To investigate the effect of large patch infection on oxidative stress induction, growth, $H_2O_2$ concentration and lipid peroxidation were compared between pathogen-infected and healthy (control) zoysiagrass. The sampling for leaves and roots were carried out every 2 days for a period of 6 days. Pathogen-infection increased root mortality by 30% compared to control. Dry mass was not significantly affected by pathogen-infection until day 4, but significant decreases in both leaves (-14%) and roots (-20%) were observed at day 6. The $H_2O_2$ concentration in pathogen-infected leaves rapidly increased within the first 2 days(+28%) and then slightly decreased. The increase of $H_2O_2$ in pathogen-infected roots was distinct, showing 1.7-fold higher level than control at day 6. The extent of lipid peroxidation caused by pathogen-infection continuously increased for the first 4 days. This was then stagnated until day 6. In roots, the significant increase of lipid peroxidation was observed only at day 2. These results indicate that large patch-infection induces oxidative stress, and that the oxidative stress responsive pattern was plant organ specific.

Emergence of Social Networked Journalism Model: A Case Study of Social News Site, "wikitree" (소셜 네트워크 저널리즘 모델의 출현: 소셜 뉴스사이트, "위키트리" 사례연구)

  • Seol, Jinah
    • Journal of Internet Computing and Services
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    • v.16 no.1
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    • pp.83-90
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    • 2015
  • This paper examines the rising value of social networked journalism and analyzes the case of a social news site based on the theory of networked journalism. Social networked journalism allows the public to be involved in every aspect of journalism production through crowd-sourcing and interactivity. The networking effect with the public is driving journalism to transform into a more open, more networked and more responsive venue. "wikitree" is a social networking news service on which anybody can write news and disseminate it via Facebook and Twitter. It is operated as an open sourced program which incorporates "Google Translate" to automatically convert all its content, enabling any global citizen with an Internet access to contribute news production and share either their own creative contents or generated contents from other sources. Since its inception, "wikitree global" site has been expanding its coverage rapidly with access points arising from 160 countries. Analyzing its international coverage by country and by news category as well as by the unique visit numbers via SNS, the results of the case study imply that networking with the global public can enhance news traffic to the social news site as well as to specific news items. The results also suggest that the utilization of Twitter and Facebook in social networked journalism can break the boundary between local and global public by extending news-gathering ability while growing audience's interest in the site, and engender a feasible business model for a local online journalism.

AtERF11 is a positive regulator for disease resistance against a bacterial pathogen, Pseudomonas syringae, in Arabidopsis thaliana (애기장대 AtERF11 유전자에 의한 Pseudomonas syringae에 대한 병 저항성 유도)

  • Kwon, Tack-Min;Jung, Yun-Hui;Jeong, Soon-Jae;Yi, Young-Byung;Nam, Jae-Sung
    • Journal of Life Science
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    • v.17 no.2 s.82
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    • pp.235-240
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    • 2007
  • AvrRpt2 protein triggers hypersensitive response (HR) and strong disease resistance when it is translocated from a bacterial pathogen Pseudomonas sp. to host plant cells containing a cognate RPS2 resistance protein through Type III Secretion System (TTSS). However, AvrRpt2 protein can function as the effector that suppresses a basal defense and enhances the disease symptom when functional RPS2 resistance protein is absent in the infected plant cells. Using Affymetrix Arabidopsis DNA chip, we found that many genes were specifically regulated by AvrRpt2 protein in the rps2 Arabidopsis mutant. Here, we showed that expression of AtERF11 that is known as a member of B1a subcluster of AP2/ERF transcription factor family was down regulated specifically by AvrRpt2. To determine its function in plant resistance, we also generated the Arabidopsis thaliana transgenic plants constitutively overexpressing AtERF11 under CaMV 355 promoter, which conferred an enhanced resistance against a bacterial pathogen, Pseudomonas syringae pv. tomato DC3000. Thus, these results collectively suggest that AtERF11 plays a role as a positive regulator for disease resistance against biotrophic bacterial pathogen in plant.