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Dissection of the genetic programs of p53-mediated G1 growth arrest and
apoptosis: blocking p53-induced apoptosis unmasks G1 arrest
C Guillouf, X Grana, M Selvakumaran, A De Luca, A Giordano, B Hoffman and DA Liebermann
Fels Institute for Cancer Research and Molecular Biology, Temple University
School of Medicine, Philadelphia, PA 19140, USA.
Employing the myeloblastic leukemia M1 cell line, which does not express
endogenous p53, and genetically engineered variants, it was recently shown
that activation of p53, using a p53 temperature- sensitive mutant transgene
(p53ts), resulted in rapid apoptosis that was delayed by high level ectopic
expression of bcl-2. In this report, advantage has been taken of these M1
variants to investigate the relationship between p53-mediated G1 arrest and
apoptosis. Flow cytometric cell cycle analysis has provided evidence that
activation of wild-type (wt) p53 function in M1 cells resulted in the
induction of G1 growth arrest; this was clearly seen in the M1p53/bcl-2
cells because of the delay in apoptosis that unmasked p53-induced G1 growth
arrest. This finding was further corroborated at the molecular level by
analysis of the expression and function of key cell cycle regulatory genes
in M1p53 versus M1p53/bcl-2 cells after the activation of wt p53 function;
events that take place at early times during the p53-induced G1 arrest
occur in both the M1p53 and the M1p53/bcl-2 cells, whereas later events
occur only in the M1p53/bcl-2 cells, which undergo delayed apoptosis,
thereby allowing the cells to complete G1 arrest. Finally, it was observed
that a spectrum of p53 target genes implicated in p53- induced growth
suppression and apoptosis were similarly regulated, either induced (gadd45,
waf1, mdm2, and bax) or suppressed (c-myc and bcl-2), after activation of
wt p53 function in M1p53 and M1p53/bcl-2 cells. Taken together, these
findings show that wt p53 can simultaneously induce the genetic programs of
both G1 growth arrest and apoptosis within the same cell type, in which the
genetic program of cell death can proceed in either G1-arrested
(M1p53/bcl-2) or cycling (M1p53) cells. These findings increase our
understanding of the functions of p53 as a tumor suppressor and how
alterations in these functions could contribute to malignancy.
Volume 85,
Issue 10,
pp. 2691-2698,
05/15/1995
Copyright © 1995 by The American Society of Hematology
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