Selective elimination of human lymphoid cells with unstable chromosome aberrations by p53-dependent apoptosis |
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Authors: | Schwartz JL; Jordan R |
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Institution: | Department of Radiation Oncology, University of Washington, Seattle 98195, USA. |
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Abstract: | Alterations in p53 expression are associated with genomic instability,
presumably because loss of p53 leads to an inability to eliminate damaged
and therefore potentially unstable cells by apoptosis or by induced cell
cycle block. We tested this hypothesis by examining the influence of
apoptosis on X-ray-induced chromosome aberration frequency in two isogenic
human B-lymphoblastoid cell lines; TK6, which is sensitive to the induction
of apoptosis, and WI-L2-NS, a p53 mutant resistant to apoptosis induction.
While TK6 was more sensitive than WI- L2-NS cells to the cytotoxic effects
of X-rays, it showed fewer induced chromosome aberrations. Inhibition of
apoptosis in TK6 cells with phorbol 12-myristate 13-acetate (PMA) resulted
in X-ray-induced aberration frequencies similar in magnitude to WI-L2-NS.
The results support the hypothesis that apoptosis acts to selectively
remove damaged cells. The reduction in aberration frequency associated with
apoptosis was seen primarily for unstable types of aberrations; acentric
chromosome fragments and dicentric chromosomes. There was no effect on the
induced frequency of balanced translocations, the stable counterpart to
dicentrics. The failure to remove cells with unstable types of aberrations
is consistent with the genomic instability that accompanies loss of p53
activity.
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