Mitomycin C와 세포독성 림프구에 의한 DNA분절현상에 있어서의 ADP-Ribose 중합효소의 역할
Role of Poly(ADP-ribose) Polymerase in DNA Fragmentation by Mitomycin-C and Cytotoxic Lymphocytes
소속 상세정보
민들레/Dullei Min
손정희/이천배/김영상/황대연/백상기/Chung Hee Sonn/Chun Bae Lee/Young Sang Kim/Dae Youn Hwang/Sang-Gi Paik
KMID : 0357119950170040307
Abstract
핵산에 있어서의 상해가 유도되면 세포는 DNA 상해회복 (DNA repair) 또는 세포의 예
정사(programmed cell death)를 맞이하게 된다. 본 연구에서는 alkylating agent인
mitomycin-C (MMC)와 세포독성림프구 (cytotoxic 1ymphocyte)에 의해 유도되는 세포의
예정사의 생화학적 특징인 DNA분절(fragmentation)현상에 ADP-ribose중합효소
(poly(ADP-ribose) polymerase: pADPRp)의 관련성을 알아보기 위하여 pADPRp의 경쟁적
억제제인 3-aminobenzamide(3-AB)의 효과를 조사하였다. p53을 발현하지 않는 인간의
promyelocytic HL-60세포에서 3-AB는 MMC에 의한 DNA분절현상을 효과적으로 억제하였
으나, 생쥐 기원의 P8l5, A20 림프구 세포주에서는 이러한 효과가 나타나지 않았다. 세포독
성 림프구에 의해 유도되는 DNA분절은 세가지 세포주에서 모두 3-AB에 의한 영향을 관찰
할 수 없었다.
이러한 결과는 p53이 결실된 HL-60세포에서 pADPRp가 DNA분절경로에 관련되어 있음
을 의미하며, 세포독성림프구에 의한DNA분절에는 pADPRp가 관련되어 있지 않거나, DNA
분절에 이르는 경로가 중복(redundant)되어 있음을 의미한다.
#초록#
The development of an organism is accompanied by cell proliferation, migration,
differentiation and death. The integrity of an organism is maintained by firmly regulated
cell proliferation and cell death. The genetic molecular studies on cell proliferation have
been studied well, but the cell death by necrosis or programmed cell death recently
draw so much attention. It has been known that the cell death process involves similar
signaling molecule, but sometimes distinct gene products from cell proliferation.
Apoptosis is characterized by cell shrinkage, chromatin condensation, cytoplasm
blebbing, apoptotic body formation and DNA fragmentation in oligonucleosomal sizers.
The apoptosis was recognized during metamorphosis, endocrine-dependent tissue atrophy,
removal of essential growth factors, negative selection of T lymphocytes in thymus and
target cells attacked by cytotoxic T lymphocytess.
In lymphocytes, DNA damage provokes rapid suicide process Apoptosis can be
induced experimentally in tissue cells and cultured cell lines by ionising radiation or
many of the cytotoxic drugs used in cancer treatment.
Critical regulators of the cellular response to DNA damage are the factors encoded by
the p53 tumor suppressor gene and ATM gene. Normal cells express very low levels of
p53, but its level rises rapidly after irradiation or exposure to many other DNA-damage
agents. Forced high level expression of p53 causes either growth arrestls. or apoptosis.
Irradiated p53-/- lymphocytes from mice, in which both p53 alleles had
been inactivated by gene targetin, normally expressing Bcl-2 were subiected to growth
arrest, but resisted apoptosis. The accumulation of the cells in Gl as well as G2 stages
suggests that there is a p53-independent DNA damage Gl check point, that is, Bcl-2.
Recently, Bax and Bcl-Xs were known to play a pivotal role in dotermining the fate of
cells.
When cytotoxic lymphocytes recognize target cells, the specificity of antigen is
determiuated by the antigenic peptide presented on MHC I molecules, but the killing
tools are dependent on the Fas ligand and Fas interaction or the exocytosis of cytotoxic
groanules stored in cytoplasm. The signaling pathway by Fas antigen was not known,
but the pathway through exocytosis was known to be mediated by granzyme B in
effector, then CPP 32/Yama and pADPRp in target cells. The involvement of pADPRp in
DNA fragmentation was controversial yet. Moreover, it is not determined yet if the
signaling pathways by DNA damaging agent and cytotoxic lymphocytes involve the
pADPRp for DNA fragmentation.
We investigated the role of pADPRp in the process of apoptosis induced by MMC or
cytotoxic lymphocytes. When 3-AB was treated to apoptotic cells induced by MMC, the
apoptotic process was inhibited by 3-AB in HL-60 cells, which are deficient in p53. The
DNA fragmentation process induced by cytotoxic lymphocytes in target cells, was not
affected by 3-AB, which suggesting that the signaling pathway inducing DNA
fragmentation was different from that induced by DNA damaging agent.
키워드
Apoptosis; Mitomycin-C; cyotoxic T lymphocyte.;
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