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. 1994 Mar;69(3):468–472. doi: 10.1038/bjc.1994.85

Wild-type p53 is required for apoptosis induced by growth factor deprivation in factor-dependent leukaemic cells.

Y M Zhu 1, D A Bradbury 1, N H Russell 1
PMCID: PMC1968850  PMID: 8123475

Abstract

The p53 gene is a growth control gene, abnormalities of which have been implicated in a variety of cancers. Recently wild-type p53 has been shown to exist in two interchangeable conformational variants, which can be distinguished by specific p53 monoclonal antibodies. One conformation acts as a suppressor (PAb240-/PAb1620+) and one acts as a promoter (PAb240+/PAb1620-) of cell proliferation; the latter conformation is also that of mutant p53. We have previously shown that acute myeloblastic leukaemia (AML) blasts which proliferate autonomously in vitro express only p53 in the promoter conformation. In contrast, expression of PAb1620 was found only in blasts with non-autocrine growth in vitro and was diminished following stimulation by exogenous growth factors when there was a switch to p53 in the promoter (PAb240+) conformation. As AML blasts with non-autocrine growth undergo apoptosis when deprived of exogenous growth factors, we studied whether this was mediated by wild-type p53. Antisense oligonucleotides to p53 were used to suppress p53 protein expression in blasts with non-autocrine growth and also the factor-dependent human erythroleukaemia cell line TF-1. Following growth factor deprivation for 48 h, 20.6-53.6% of control blasts were apoptotic and demonstrated a typical 'ladder' on DNA electrophoresis characteristic of internucleosomal degradation of DNA. In the presence of p53 antisense, apoptosis was suppressed despite the absence of growth factor, however cell proliferation was not stimulated. We conclude that apoptosis occurring in factor-dependent AML blasts following growth factor deprivation is mediated by wild-type p53 (PAb1620+), and that conformational change of p53 to the PAb240+ conformation occurring either by mutation or by the action of autocrine growth factors would permit leukaemic cell survival by suppressing apoptosis.

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Selected References

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