Title: MAPK mediates RAS-induced chromosome instability.

Authors: Saavedra, H I; Fukasawa, K; Conn, C W; Stambrook, P J

Published In J Biol Chem, (1999 Dec 31)

Abstract: The generation of micronuclei is a reflection of DNA damage, defective mitosis, and loss of genetic material. The involvement of the MAPK pathway in mediating v-ras-induced micronuclei in NIH 3T3 cells was examined by inhibiting MAPK activation. Conversely, the MAPK pathway was constitutively activated by infecting cells with a v-mos retrovirus. Micronucleus formation was inhibited by the MAPK kinase inhibitors PD98059 and U0126, but not by wortmannin, an inhibitor of the Ras/phosphatidylinositol 3-kinase pathway. Transduction of cells with v-mos resulted in an increase in micronucleus formation, also consistent with the involvement of the MAPK pathway. Staining with the anti-centromeric CREST antibody revealed that instability induced by constitutive activation of MAPK is due predominantly to aberrant mitotic segregation, since most of the micronuclei were CREST-positive, reflective of lost chromosomes. A significant fraction of the micronuclei were CREST-negative, reflective of lost acentric chromosome fragments. Some of the instability observed was due to mitotic events, consistent with the increased formation of bi-nucleated cells, which result from perturbations of the mitotic spindle and failure to undergo cytokinesis. This chromosome instability, therefore, is a consequence of mitotic aberrations, mediated by the MAPK pathway, including centrosome amplification and formation of mitotic chromosome bridges.

PubMed ID: 10608877

MeSH Terms: 3T3 Cells; Animals; Cell Transformation, Viral; Chromosome Deletion*; Enzyme Activation; Enzyme Inhibitors/pharmacology; Leukemia Virus, Murine/physiology; MAP Kinase Signaling System; Mice; Micronuclei, Chromosome-Defective; Mitogen-Activated Protein Kinases/antagonists & inhibitors; Mitogen-Activated Protein Kinases/metabolism*; Mitosis/genetics; Oncogene Protein p21(ras)/physiology*; Oncogene Proteins v-mos/genetics; Phosphorylation