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2016 ; 291
(19
): 10131-47
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Modeling the Etiology of p53-mutated Cancer Cells
#MMPMID27022024
Perez RE
; Shen H
; Duan L
; Kim RH
; Kim T
; Park NH
; Maki CG
J Biol Chem
2016[May]; 291
(19
): 10131-47
PMID27022024
show ga
p53 gene mutations are among the most common alterations in cancer. In most
cases, missense mutations in one TP53 allele are followed by
loss-of-heterozygosity (LOH), so tumors express only mutant p53. TP53 mutations
and LOH have been linked, in many cases, with poor therapy response and worse
outcome. Despite this, remarkably little is known about how TP53 point mutations
are acquired, how LOH occurs, or the cells involved. Nutlin-3a occupies the
p53-binding site in MDM2 and blocks p53-MDM2 interaction, resulting in the
stabilization and activation of p53 and subsequent growth arrest or apoptosis. We
leveraged the powerful growth inhibitory activity of Nutlin-3a to select
p53-mutated cells and examined how TP53 mutations arise and how the remaining
wild-type allele is lost or inactivated. Mismatch repair (MMR)-deficient
colorectal cancer cells formed heterozygote (p53 wild-type/mutant) colonies when
cultured in low doses of Nutlin-3a, whereas MMR-corrected counterparts did not.
Placing these heterozygotes in higher Nutlin-3a doses selected clones in which
the remaining wild-type TP53 was silenced. Our data suggest silencing occurred
through a novel mechanism that does not involve DNA methylation, histone
methylation, or histone deacetylation. These data indicate MMR deficiency in
colorectal cancer can give rise to initiating TP53 mutations and that TP53
silencing occurs via a copy-neutral mechanism. Moreover, the data highlight the
use of MDM2 antagonists as tools to study mechanisms of TP53 mutation acquisition
and wild-type allele loss or silencing in cells with defined genetic backgrounds.
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