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J Biol Chem, Vol. 274, Issue 53, 38083-38090, December 31, 1999
From the § Department of Cell Biology, Neurobiology and
Anatomy, University of Cincinnati College of Medicine,
Cincinnati, Ohio 45267-0521
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.
MAPK Mediates RAS-induced Chromosome Instability*
,
*
This work was supported by National Institutes of Health
Grant CA65769.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported in part by NIEHS National Institutes of Health Training
Grant ES07250. Current address: Div. of Cancer Genetics, The Ohio State
University, Rm. 690, Medical Research Facility, 420 W. 12th Ave.,
Columbus, OH 43210. Tel.: 614-292-2459; Fax: 614-688-4245.
¶
To whom correspondence should be addressed. Tel.:
513-558-5685; Fax: 513-558-4454.
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