アポトーシス誘導経路の分子遺伝学的アプローチ
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There are two distinct types of DNA lesions that induce apoptosis: modified bases that cause base mispairing and bulky DNA lesions that block DNA replication. The former requires mismatch repair (MMR) proteins for induction of apoptosis whereas the latter induces apoptosis even without the function of such proteins. O^6-Methylguanine, produced in DNA by the action of simple alkylating agents, does not prevent the progression of DNA replication forks and apparently represents the former class of DNA lesion. To understand the molecular mechanism of O^6-meG-induced apoptosis, we carried out retrovirus-mediated gene-trap mutagenesis and isolated mutants that acquired resistance to a simple alkylating agent, N-methyl-N-nitrosourea (MNU), from MNU-sensitive Mgmt^<-/-> cells. One of the mutants isolated was unable to induce mitochondrial membrane depolarization and caspase-3 activation after treatment with MNU, although it still retains the ability to undergo cell death triggered by ACNU that produces interstrand-crosslinks in DNA. Furthermore, the mutant exhibits an increased mutant frequency after exposure to MNU, implying the function of the gene, disrupted in the mutant, is for the maintenance of genetic stability. The gene was identified as a new gene and designated Mapo1 (for O^6-methylguanine-induced apoptosis1). The homologous proteins are present in various organisms ranging from nematodes to humans. We therefore propose that MAPO1 may play an important role in the regulation of cell proliferation in multi-cellular organisms.
- 2009-12-30
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関連論文
- アポトーシス誘導経路の分子遺伝学的アプローチ
- A-9 ヒトMapo1タンパク質による細胞死誘導活性(一般口演4,第37回福岡歯科大学学会総会抄録)
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- A-6 アポトーシスを誘導するMAPO1複合体の分子機能(一般口演3,第39回福岡歯科大学学会総会抄録)