| Genetic instability can be divided into two levels, the gene level includes microsatellite instability (MIN), the chromosomal level means chromosomal instability (CIN). The mechanism for genetic instability is complicated, including the decreasing DNA replication fidelity (DNA polymerase family), the damaging of DNA repair system (such as BER, NER, MMR, HR, NHEJ), the dysfunction of cell cycle DNA damae checkpoint (p53, DNA-PK, ATM, etc.), the change of telomere and telomerase, and the epigenetic mechnism such as DNA methylation. Genetic instability not only becomes the hot spot of cancer and clinical research, but also accumulated large papers during genetics and genetic toxicology field. Environmental physical or chemical carcinogens can induce prolonged genetic instability in mammalian cells, besides direct DNA damaging. It includes delayed reproductive death, increased frequency of point mutations and chromosome rearrangements. It means that except targeted mutation (TM ), there exits non targeted mutation (NTM), which is the result of genetic instability induced by DNA damaging agents.Non-targeted mutagenesis refers to the mutagenesis that happens at the undamaged base sites of DNA so as to differ from targeted mutagenesis and is regarded to as an important mechanism to maintain the genome integrity of the organisms, which exposed to genetic toxigens. Previous report from Yu labortary demonstrated that alklating agent, N-methyl-N'-nitro-nitrosoguanidine (MNNG), which is a widely distributed environmental mutagen and carcinogen especially for human gastric cancer, could induce non targeted mutagenesis in Africa green monkey kidney Vero cells. Based on the work supported by continuous National Natural Science Foundation, a model was proposed for genetic instability characterized by non targeted mutation. Chemical carcinogen →DNA damage and /or non DNA damage stress → Triggering signal transduction pathway →Alter expression of some specific genes → Decreasing of DNA replication fidelity → Genesis of genetic istability → Non targeted mutation.My paper forcus on step one and two of the model. We want to know how concentration chemical carcinogen MNNG induce DNA damage and /or non DNA damage stress, and how to trigger signal transduction pathway.Further studies from Yu laboratory has showed that the frequency on nontarged mutation could be affected by transcription and translation inhibitor, and that differential mRNA expression could be induced in Vero cells by MNNG. The differentially expressed phosphoprotein in cells treated with MNNG was also found. These results indicated that cell signal transduction pathways might play a significant role in nontargeted mutagenesis. To explore the potential relationship between nontarged mutagenesis and the cascades of protein phosphorylation of signal transduction pathways in cell, they found there are two differential displayed phosphorylated proteins reacted with antiphosphotyrosine in MNNG treatment cells. Their molecular weight of two proteins and the results of western blot suggested that the two differential displayed phosphorylated proteins may be Ser/Thr phosphoproteins and probably members of the MAPK (Mitogen activated protein kinase) .MAPK are evolutionary conserved enzymes connecting cell surface receptors to critical regulatory targets with cells. MAPK also respond to chemical and physical stresses, thereby controlling cell survial and adaptation. It is becoming clear that MAPKs regulate almost all cellular processes, from gene expression to cell death. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal related kinase (ERK)-l/2, Jun N-terminal kinase (JNK1/2/3), P38 MAPK and ERK5. Among MAPKs, both JNK/SAPK and p38MAPK play important roles in cellular stress signal transduction and there are always cross talks between different pathways in cells. In present study the two kinases were observed with the same experimental system so to accumulate knowledge for clarifying the signal transducton pathways act...
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