6DMAP inhibition of early cell cycle events and induction of mitotic abnormalities.
N-6 dimethylaminopurine (6DMAP) has been shown to induce aberrant mitosis in different cell types including Chinese hamster fibroblasts (CHEF/18). The mechanism of action and the cellular targets, however, are still not clear. We showed previously that in CHEF/18 cells this compound inhibits DNA synthesis with a kinetic of inhibition suggestive of an effect on early events of the cell cycle. In this paper we investigated which cellular targets were affected by 6DMAP and found that: (i) the compound inhibits phosphorylation of ribosomal protein S6 and activation of the 70 kDa S6 kinase (p70S6k) known to be activated by epidermal growth factor (EGF) in keeping with the notion that it is a protein kinase inhibitor; however the inhibition in vivo appears to be specific as MAP kinase phosphorylation is not inhibited; (ii) 6DMAP drastically affects cytoskeletal components leading to a rapid morphological change in most cells. These data, together with the findings that the dose range and the treatment time effective in inducing the micronuclei containing chromosomes were the same as for DNA synthesis inhibition, suggest that a disturbance in G1 of signal transduction pathways may contribute to abnormal mitosis.
Simili
M
M
G.B.T. Institute of Mutagenesis and Differentiation of CNR, Pisa, Italy.
Pellerano
P
P
Pigullo
S
S
Tavosanis
G
G
Ottaggio
L
L
de Saint-Georges
L
L
Bonatti
S
S
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity; D005347:Fibroblasts; D015162:Micronucleus Tests; D008938:Mitosis; D016296:Mutagenesis; D010766:Phosphorylation; D038601:Ribosomal Protein S6; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors; D012269:Ribosomal Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins; C001020:N(6),N(6)-dimethyladenine; D004247:DNA; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000225:Adenine