title: Activation of protein kinase A and clustering of cell surface receptors by N-methyl-N'-nitro-N-nitrosoguanidine are independent of genomic DNA damage.
abstract: Alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces cellular stress leading to chromosomal aberrations, mutations and cell death. Previous reports from our laboratory have shown that low concentration of MNNG induces untargeted mutation (UTM), which occurs on intact DNA in mammalian cells through changes in gene expression profile. It also causes the activation of cAMP-protein kinase A (PKA) and up-regulation of POL-beta, which is demonstrated to play a role in DNA repair system. In order to find out the possible initial signal involved in UTM, we try to investigate whether the activation of PKA-CREB signal pathway is closely related to DNA damage. Our data shows that the treatment of low concentration MNNG (0.2 microM) activates PKA-CREB pathway in a comparable level both in a nuclear and enucleated cell system. And similar to the cell response caused by UV, the clustering of cell surface receptors of epidermal growth factor (EGF) and tumor necrosis factor alpha (TNFalpha) was also observed in cells exposed to MNNG. 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.
authors.affiliation: Department of Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, 310031 Zhejiang, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Guliang
authors.initials: G
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Yingnian
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000000981:diagnostic imaging; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis*; D004249:DNA Damage; D004789:Enzyme Activation / Q000187:drug effects; D016678:Genome; D008769:Methylnitronitrosoguanidine / Q000633:toxicity*; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D014463:Ultrasonography; D014709:Vero Cells
chemical_list: D011956:Receptors, Cell Surface; D008769:Methylnitronitrosoguanidine; D017868:Cyclic AMP-Dependent Protein Kinases