Overexpression of MYC causes p53 -dependent G 2 arrest of normal fibroblasts
p53
G2 Phase
0303 health sciences
Cultured
Cells
Genes, myc
myc
Fibroblasts
Aneuploidy
Genes, p53
Proto-Oncogene Mas
Mice
03 medical and health sciences
Genes
Genetics
2.1 Biological and endogenous factors
Animals
Humans
Generic health relevance
Aetiology
Cell Division
Cells, Cultured
Non-programmatic
Cancer
DOI:
10.1073/pnas.190327097
Publication Date:
2002-07-26T14:43:20Z
AUTHORS (5)
ABSTRACT
Overexpression of the proto-oncogene
MYC
has been implicated in the genesis of diverse human cancers. One explanation for the role of
MYC
in tumorigenesis has been that this gene might drive cells inappropriately through the division cycle, leading to the relentless proliferation characteristic of the neoplastic phenotype. Herein, we report that the overexpression of
MYC
alone cannot sustain the division cycle of normal cells but instead leads to their arrest in G
2
. We used an inducible form of the
MYC
protein to stimulate normal human and rodent fibroblasts. The stimulated cells passed through G
1
and S but arrested in G
2
and frequently became aneuploid, presumably as a result of inappropriate reinitiation of DNA synthesis. Absence of the tumor suppressor gene
p53
or its downstream effector
p21
reduced the frequency of both G
2
arrest and aneuploidy, apparently by compromising the G
2
checkpoint control. Thus, relaxation of the G
2
checkpoint may be an essential early event in tumorigenesis by
MYC
. The loss of
p53
function seems to be one mechanism by which this relaxation commonly occurs. These findings dramatize how multiple genetic events can collaborate to produce neoplastic cells.
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