.1 Induced By Mnng Surface Receptor Aggregation And Dna Damage, Fret Technology,

The association between chemical exposure and the development of specific human cancers has been recognized for a long time, and such examples include amine dyes and bladder cancer, UV and skin cancer, benzene and leukemia, and cigarette smoking and lung cancer. These agents are called carcinogens, and most of the known human carcinogens are genotoxic, which means they can produce alterations in the DNA of the host. The rest are called epigenetic carcinogens, include those substances that promote cancer in ways other than direct DNA damage.Since society has made human health and safety an important issue, considerable resources are being expended to understand the mechanisms of carcinogenesis. N-methyl-N-nitro-N-nitrosoguanidine (MNNG) is a potent human carcinogen which can be found in cigarette smoke. It is a monofunctional alkylating agent that targets the cellular DNA and induce severe genotoxic stress to the cell, leading to chromosomal aberrations, sister chromatid exchanges and point mutation. Furthermore, We have found that low concentration of MNNG (0.2 uM) treatment does not cause significant cytotoxic effect, but rather induces a phenomenon called untargeted mutation (UTM), in which the mutations occur at undamaged DNA sites. Moreover, this process includes the activation of JNK pathway and changes in gene expression at both transcription and translation levels.Although the mechanism by which the signaling cascades initiated by the DNA damaging agents is not fully understood, accumulating evidences show that parts ofcellular responses are independent of nucleus genomic DNA damaging, one of which is that UV exposure induces rapid tyrosine phosphorylation of EGF receptor (EGFR) and the clustering and activation of TNF receptor (TNFR).Taken the fact that cell membrane receptors are involved in the initiation of lots of transduction pathways, in this study we tried to find out if EGFRs and TNFRs might play a role in the upstream signal of the cellular response induced by MNNG.Our data shows that, similar to the cell response caused by UV, the treatment of low concentration MNNG (0.2 M) induced rapid clustering of cell surface receptors of epidermal growth factor (EGF) and tumor necrosis factor (TNF ). It was further demonstrated that the clustering of the surface receptors is independent of the genomic DNA damage, as this phenomenon was also observed in enucleated cells. These observations indicate that the initiation of signal cascades induced by low concentration of MNNG might be associated with its interaction with cell surface receptors and/or direct activation of related signal proteins but not its DNA damaging property.