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21세기 첨단과학의 꽃 Life Science
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02-6490-2660~1
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Lab of Tumor Virology and Cellular Senescence
Professor : Eun Seong Hwang
Tel : +82-2-6490-5623
Location : Natural Science Building Room 8-508
List
  • Main Research Area
  • A. Molecular nature of cellular traits of senescence and aging
    • 1) Altered mitochondrial dynamics
      Dysfunctional mitochondria are major source of the high level ROS in aging cells in vivo and in vitro. Cells, as they continue proliferation to approach the end of replicative lifespan, accumulate oxidative damage in cellular constituents including mitochondria1. Defects in electron transport chain complexes cause an increase in ROS and ROS-dependent induction of senescence-like growth arrest2. Mitochondria mass also increases in cells under oxidative stress and those undergoing replicative senescence3. and failure in removing damaged mitochondria along with other organelles has been proposed a mechanism for cellular senescence4. Furthermore, a direct association of the altered mitochondrial density (or defective mitochondrial turnover), ROS generation, and senescence induction has been suggested5. Meanwhile, mitochondria degradation is mediated by autophagy, and recently it was suggested that autophagy along with coordinated mitochondrial fission and fusion selectively removes damaged (depolarized) mitochondria6. Therefore, active mitochondrial autophagy in association with dynamic fission and fusion may be proposed as an important cellular quality maintenance mechanism. Defective or poor maintenance of mitochondrial quality could trigger and accelerate cellular senescence as well as certain aging-associated disorders. We are studying the dynamics of mitochondrial structure and function in cells at various physiological conditions including cellular senescence in a hope that factors that govern the mitochondrial dynamics are determined and molecular pathways that link these factors to the various cellular conditions are uncovered.
    • 2) Altered lysosomal content
      The content and volume of lysosomes are substantially increased in cells undergoing senescence and those isolated from aged individuals7. Most of these increase is known to be attributed to an increase in residual bodies that contain undigestable substrates such as lipofuscin. However, there are reports on the increase in the expression of certain lysosomal enzymes in the senescent and aged cells7. We are currently looking for factors that coordinately induce the genes of the lysosomal proteins in a hope that a molecular mechanism which govern the lysosomal biogenesis in certain cellular physiology including cellular senescence and aging is uncovered.
      1. Sitte N, et al. (2001) Lipofuscin accumulation in proliferating fibroblasts in vitro: an indicator of oxidative
      stress. Exp. Gerontol. 36, 475-486. Merker K, et al. (2000) Hydrogen peroxide-mediated protein oxidation in young and old human MRC-5 fibroblasts. Arch Biochem Biophys. 375, 50-54.
      2. Yoon YS, et al. (2003) Complex II defect via down-regulation of iron-sulfur subunit induces mitochondrial
      dysfunction and cell cycle delay in iron chelation-induced senescence-associated growth arrest. J Biol Chem. 278, 51577-51586. Yoon YS, et al. (2005) TGF beta1 induces prolonged mitochondrial ROS generation through decreased complex IV activity with senescent arrest in Mv1Lu cells. Oncogene 24, 1895-1903.
      3. Lee HC, et al. (2002) Increase in mitochondrial mass in human fibroblasts under oxidative stress and during
      replicative cell senescence. J Biomed Sci. 9, 517-526. Passos JF, et al. (2007) DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res. 35, 7505-7513.
      4. Brunk UT, Terman A. (2002) The mitochondrial-lysosomal axis theory of aging: accumulation of damaged
      mitochondria as a result of imperfect autophagocytosis. Eur J Biochem. 269, 1996-2002.
      5. Lee S, et al. (2007) Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate cellular
      senescence. J Biol Chem. 282, 22977-22983. Yoon YS, et al. (2006) Formation of elongated giant mitochondria in DFO-induced cellular senescence: involvement of enhanced fusion process through modulation of Fis1. J Cell Physiol. 209, 468-480.
      6. Twig G, et al. (2008) Fission and selective fusion govern mitochondrial segregation and elimination by
      autophagy. EMBO J. 27, 433-446.
      7. Hwang ES, Kang HT, & Yoon GS (2009) A comparative analysis of the cell biology of senescence and aging.
      Cellular and Molecular Life Sciences 66, 2503-2525.
  • B. Biological strategies for anti-aging approach
    • We previously have reported that cultivation of human fibroblasts and keratinocytes in media containing 5 mM nicotinamide (NAM) causes a dramatic extension of their cellular life span (a 1.6-fold increase in population doubling capacity in the case of fibroblasts)8. In the NAM-treated cells, ROS accumulation was substantially delayed, and telomere shortening rate and activation of the p53-growth inhibitory pathway were attenuated. In addition, in these cells, mitochondrial membrane potential (ΔΨm) increased while cellular respiration and superoxide generation were substantially decreased. We also found that the treatment selectively removes mitochondria with high level oxidative damage and low ΔΨm through accelerated autophagy9. This autophagy activation was accompanied by active mitochondrial fission and fusion, and dependent on GAPDH as well as SIRT1 and the NAM-conversion to NAD+. Our results suggest that supplying high level NAD+ may help cells lessen the burden of oxidative stress by enhancing autophagy and concomitant mitochondrial turnover through upregulation of the activity of its key regulator molecules. We are currently examining a possibility of utilizing a shift in NAD+ metabolism as an intervention strategy against cellular dysfunction during aging.
      8. Kang HT, Lee HI, Hwang ES (2006) NAM extends replicative lifespan of human cells. Aging Cell 5, 423-436.
      9. Kang HT, Hwang ES (2009) Nicotinamide enhances mitochondria quality through autophagy activation in human
      cells. Aging Cell 8, 426?438
  • Recent Publications
    Status of mTOR activity may phenotypically differentiate senescence and quiescence. Mol Cells. 2012 Jun;33(6):597-604,Sohee Cho, Eun Seong Hwang

    Nicotinamide-induced mitophagy: Event mediated by high NAD+/NADH ratio and SIRT1 protein activation. J Biol Chem. 287:19304-14 (2012. 05),So-young Jang, Hyun Tae Kang, Eun Seong Hwang

    GSK3 inactivation is involved in mitochondrial complex IV defect in transforming growth factor (TGF) β1-induced senescence. Exp Cell Res. 318(15): 1808-19,Byun HO, Jung HJ, Seo YH, Lee YK, Hwang SC, Seong Hwang ES, Yoon G.

    Kinetics of the cell biological changes occurring in the progression of DNA damage-induced senescence. 2011. Molecules and Cells 31, 539-546 Sohee Cho, Jihoon Park and Eun Seong Hwang

    Fluorescence-based detection and quantification of features of cellular senescence. 2011. Methods Cell Biol. 103, 149-88 Cho S, Hwang ES.

    Kang MR, Um E, Kang HT, Hwang ES, Kim EJ, Um SJ. (2009) Reciprocal roles of SIRT1 and SKIP in the regulation of RAR activity: implication in the retinoic acid-induced neuronal differentiation of P19 cells. Nucleic Acids Res. Nov 24.

    Hwang ES, Yoon G, Kang HT. (2009) A comparative analysis of the cell biology of senescence and aging. Cell Mol Life Sci. 66, 2503-24.

    Kang HT, Hwang ES. (2009) Nicotinamide enhances mitochondria quality through autophagy activation in human cells. Aging Cell. 8, 426-38.

    Lee HI, Jang SY, Kang HT, Hwang ES. (2008) p53-, SIRT1-, and PARP-1-independent downregulation of p21WAF1 expression in nicotinamide treated Cells. BBRC. 368, 298-304.

    Lee HI, Cho HJ, Han JA, Jang SY, Wang KM, Kang HT, Hwang ES. (2008) Transient downregulation of protein O-N-acetylglucosaminylation by treatment of high-dose nicotinamide in human cells. ExperimentalMolecularMedicine. 40, 246-53.

    Ji Hoon Park, Hye Won Yi, Daniel DiMaio, Eun Seong Hwang (2007) Heterogeneous upregulation of lysosomal genes in human fibroblasts and cancer cells undergoing senescence. Kor J. Genetics. 29, 521-527

    Oh JE, Han JA, Hwang ES. (2007) Downregulation of transcription factor, Sp1, during cellular senescence. BBRC. 353, 86-91.

    Kang HT, Lee HI, Hwang ES. (2006) Nicotinamide extends replicative lifespan of human cells. Aging Cell. 5, 423-36.

    Young Sook Song and Eun Seong Hwang (2006) DNA-damage is critical to induce cellular senescence but not apoptosis. Kor J Gerontol. 16, 171-177

    Lee BY, Han JA, Lm JS, Morrone A, Johung K, Goodwin EC, Kleijer WJ, DiMaio D, Hwang ES. (2006) Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell. 5, 187-95.

    Kang HT, Hwang ES.(2006) 2-Deoxyglucose: an anticancer and antiviral therapeutic, but not any more a low glucose mimetic. Life Sci. 78, 1392-9

    Song YS, Lee BY, Hwang ES. (2005) Dinstinct ROS and biochemical profiles in cells undergoing DNA damage-induced senescence and apoptosis. Mech Ageing Dev. 126, 580-90.

  • Patent
    니코틴아마이드를 유효성분으로 포함하는 면역증강용 약학적조성물 Pharmaceutical composition for enhancing immune response comprising nicotinamide as an actie ingredient. 2012,07.19 (Patent-2012-0078609), Eun Seong Hwang, Jeong Soo Ok, So Young Jang, Ho Jin Choi

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