BioWave  Vol. 20 No. 10
서울대학교 스트레스 반응 및 노화 연구실 강찬희 교수
연구실 홈페이지
실험실 소개  
Coping with stress is essential for all organisms, and several stress responses have been evolved to maintain homeostasis. Autophagy and cellular senescence are among critical as 1) they respond to many different types of stress and 2) they are closely involved in many human diseases including age-associated diseases, aging itself, and cancer. Our goal is to better understand autophagy and cellular senescence that may provide avenues of therapeutic intervention for the treatment of such devastating human diseases and have important implications for human health.

lab_intro1

Cellular senescence is a terminal program of growth arrest triggered by many stresses, and similar to apoptosis, it acts intrinsically as a tumor suppressive mechanism by limiting further proliferation of damaged cells. Furthermore, in contrast to apoptosis that mainlyacts cell-autonomously, cellular senescence can also function cell-nonautonomously to coordinate homeostasis responses; This occurs through the secretion of pro-inflammatory cytokines, growth factors, and proteases from senescent cells: the Senescence Associated Secretory Phenotype (SASP).

lab_intro2

Despite such pleiotropic effects of the SASP, little is known about how it is regulated until recently, in contrast to well-studied senescence growth arrest where the p53 and p16 tumor suppressor pathways have a crucial role. Our recent study has identified a transcription factor GATA4 as a key switch to activate the SASP, independently from the p53 and p16 pathways. In addition, we have discovered how GATA4 is regulated during cellular senescence by selective autophagy and the DNA damage response (DDR). Thus, our study establishes the GATA4 pathway as a new branch in the senescence regulatory network and opens a new field that connect DDR, autophagy, protein stability, senescence, and inflammation.

lab_intro3

Although we gained new insight into the role of selective autophagy during senescence and SASP regulation through GATA4, our current understanding of the GATA4 pathway is still limited. We are currently employing genetics, molecular biology, biochemistry, genomics and cell biology to elucidate 1) the selective autophagy network and 2) the senescence regulatory network with focus on the SASP in detail. Specifically, we will 1) elucidate the GATA4 pathway in the senescence regulatory network, 2) determine potential in vivo roles of the GATA4-SASP pathway during tumorigenesis and aging, 3) examine the stress-specific regulation of selective autophagy, cellular senescence, and the SASP, and 4) develop the stress-specific reporter system that is suitable for genome-wide genetic screens.

lab_intro4

연구내용  
우리 연구실의 일관된 연구주제는 어떻게 동물과 세포가 다양한 외부 자극에 반응을 하여 항상성을 유지하는 지를 이해하는 것입니다. 특별히 자식작용 (Autophagy)과 세포노화 (Cellular senescence) - 노화와 암을 비롯한 많은 인간 노화관련 질환에 관련되어 있는 두 일반적인 스트레스 반응 - 를 연구하는데 중점을 두고 있습니다. 우리는 현재 유전학, 분자생물학, 생화학, 유전체학, 그리고 세포생물학 등의 다양한 방법들을 이용하여 1) 선택적 자식작용 네트워크 (Selective autophagy network)와 2) 세포노화 조절 네트워크 (Senescence regulatory network)를 자세히 밝히고자 합니다. 이러한 노력이 앞으로 여러 인간 질병들을 치료하는데 도움이 되고, 궁극적으로는 인류의 전반적인 건강 상태를 높이는데 큰 기여를 할 것이라고 생각합니다. 현재 연구하고 있는 주제는 다음과 같습니다.

1. 어떻게 선택적 자식작용이 GATA4-노화연관 분비표현형 (SASP) 경로를 조절하는지, 그 자세한 분자조절 기작에 대한 연구.
2. 세포노화 현상을 조절할 수 있는 GATA4 경로의 표적 검색.
3. GATA4-노화연관 분비표현형 (SASP) 경로가 실제로 동물 개체 수준에서 어떠한 영향을 갖는지를 여러 동물 모델 (종양 모델과 노화모델)들을 통해서 연구.
4. 선택적 자식작용 (Selective autophagy), 세포노화, 그리고 노화연관 분비표현형 (SASP)이 어떻게 특정 스트레스 반응 동안 조절되는지에 대한 연구.
연구성과  
2015년 이후 연구논문들

  • Mazzucco AE, Smogorzewska A, Kang C, Luo J, Schlabach MR, Xu Q, Patel R, Elledge SJ (2017)
    Genetic interrogation of replicative senescence uncovers a dual role for USP28 in coordinating the p53 and GATA4 branches of the senescence program.
    Genes Dev., 31(19):1933-1938

  • Kwon Y, Kim JW, Jeoung JA1, Kim MS1, Kang C (2017)
    Autophagy Is Pro-Senescence When Seen in Close-Up, but Anti-Senescence in Long-Shot.
    Mol Cells, 40(9):607-612

  • Kang C and Elledge SJ (2016)
    How autophagy both activates and inhibits cellular senescence.
    Autophagy, 12(5):898-899

  • Wang Y, Xu Q, Sack L, Kang C, and Elledge SJ (2016)
    A gain-of-function senescence bypass screen identifies the homeobox transcription factor DLX2 as a regulator of ATM-p53 signaling.
    Genes Dev., 30(3):293-306

  • Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Kang C et al (2016)
    Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
    Autophagy, 12(1):1-222

  • Kang C, Xu Q, Martin TD, Li MZ, Demaria M, Aron L, Lu T, Yankner BA, Campisi J, and Elledge SJ (2015)
    The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.
    Science, 349(6255):aaa5612

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      지도교수: 강찬희

     연구교수 : 김미성
     석박통합과정 : 권유진, 이영현, 허예강, 김연주,
                           정조애, 김유현, 노경환, 김재진
     연구원 : 심수경

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    등록 2018.09.19
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