Functional analysis of p53 and LKB1 in drosophila초파리 모델동물을 이용한 발암 억제 유전자의 기능 연구

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Tumor suppressors are genes that appear to prevent formation of a cancer. Among more than 10 tumor suppressors identified to date, I have focused upon two representative tumor suppressors - p53 and LKB1, whose mutations are responsible for cancer development in the Li-Fraumeni syndrome and the Peutz-Jeghers syndrome, respectively. First, p53 is a representative tumor suppressor protein, which is most frequently altered in human cancers. In order to analyze the physiological function of p53, Dmp53 mutant flies, the first model animal with no p53-family protein, has been generated. Surprisingly, Dmp53-null mutants well developed into adults, only displaying mild defects in longevity and fertility. However, genomic stability and viability of Dmp53 mutants dramatically decreased upon ionizing irradiation. Moreover, the absence of Dmp53 abolished irradiation-induced apoptosis and reaper induction. These results indicate that Dmp53 is a critical component of DNA damage-dependent apoptotic signaling. Second, LKB1 is a recently discovered tumor suppressor, whose down-regulation is generally implicated in the cancer progression. Drosophila LKB1 has been shown to negatively regulate organ growth by caspase-dependent apoptosis, without affecting cell size and cell cycle progression. Through genetic screening for LKB1 modifiers, the c-Jun N-terminal kinase (JNK) pathway was identified as a novel component of LKB1 signaling; the JNK pathway was activated by LKB1 and mediated the LKB1-dependent apoptosis. Furthermore, inhibition of LKB1 resulted in morphogenetic defects associated with a decrease in JNK activity. These results suggest that LKB1 is a cellular gatekeeper which induces developmental and stress-induced apoptosis via the JNK pathway. Finally, to further characterize the biological functions mediated by LKB1, genetic studies of AMP-activated kinase (AMPK), a recently discovered downstream target of LKB1, has been performed. Surprisingly, null-mutant of AMPK is let...
Chung, Jong-Kyeongresearcher정종경researcher
한국과학기술원 : 생명과학과,
Issue Date
254185/325007  / 020025239

학위논문(박사) - 한국과학기술원 : 생명과학과, 2006.2, [ xii, 147 p. ]


p53 LKB1 Drosophila; 암 억제 유전자 초파리 기능 모델동물

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