PHORBOL ESTERS ATTENUATE THE EXPRESSION OF P53 IN CELLS TREATED WITH DOXORUBICIN AND PROTECT TS-P53 K562 FROM APOPTOSIS/

The induction of p53 by doxorubicin in normal human fibroblasts was co mpletely reverted by TPA, a phorbol ester. A ts-p53 mutant protein whi ch is ineffective at 37 degrees C, but behaves in a wild-type fashion at 32 degrees C, was overexpressed in the p53-null human leukemia cell line K562. Wild-type-p53 overexpression induced apoptosis, whereas TP A protected K562 cells from this phenomena, By analogy with the observ ed human fibroblasts, TPA was found to decrease p53 amount. The TPA-de pendent down-regulation of p53 could explain the chromosomal gross alt erations typical of cells subjected to a chronic TPA treatment, altera tions also found in cells defective for p53 function. (C) 1995 Academi c Press, Inc.