CHROMOSOME CHANGES CAUSED BY ALTERATIONS OF P53 EXPRESSION

It has been proposed that p53 tumor-suppressor plays a key role in mai ntaining genome integrity in mammalian cells. We analyzed karyotype al terations in human and murine cell sublines expressing various exogeno us human mutant (His175, Trp248, His273) or wild-type (wt) p53 cDNAs. In human pseudodiploid LIM 1215 cells that contain two endogenous wt-p 53 gene alleles, p53 mutants caused both an increase in the frequency of chromosome breaks and an emergence of hyperdiploid cells. Murine T- 12 - / - and 10(1) fibroblasts lacking endogenous p53 expression have very unstable karyotypes and show a strong tendency to increase their ploidy levels during growth in culture. Transduction of a wt-p53 const ruct into p53-deficient cells inhibited an accumulation of highly poly ploid cell variants. Transduction of mutant p53 did not show such an e ffect. Modification of endogenous and exogenous p53 expression by caff eine, which interferes with normal induction of p53 in response to DNA damage, showed no correlation between the induction of chromosome bre aks and heteroploidy. We conclude that the caffeine- or mutant p53-ind uced increase in the frequency of chromosomal breaks in dividing LIM12 15 cells is assonated with inactivation of wt-p53 function(s) responsi ble for control of G(1) checkpoint and/or DNA repair, while numerical chromosome changes in these cells may be a result of elimination or mo dification of a separate p53 function, or due to gain-of-function acti vities of p53 mutants. p53 modifications may therefore cause chromosom e instability by different pathways: (1) through changes in the system (s) preventing proliferation of cells with genomic alterations; and (2 ) by increasing the probability of events, such as chromosome non-disj unction and/or endoreduplication that can lead to chromosome gains.