MODULATION OF P53 PROTEIN CONFORMATION AND DNA-BINDING ACTIVITY BY INTRACELLULAR CHELATION OF ZINC

The transcription factor p53 controls the proliferation and survival o f cells exposed to DNA damage. The specific DNA-binding domain of p53 (residues 102-292) has a complex tertiary structure that is stabilized by zinc. In this study, we showed that exposure of cultured cells to the membrane-permeable chelator N,N,N',N'-tetrakis(2-pyridylmethyl)eth ylenedianine induced wild-type p53 to accumulate in an immunologically ''mutant'' form (PAb240+, PAb1620-) with decreased DNA-binding activi ty. Removal of N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine from culture medium allowed p53 to refold into the immunologically wild-ty pe form, followed by a transient increase in DNA binding, expression o f the cyclin-dependent kinase inhibitor p21(WAF1) and cell-cycle delay in the G(1) phase. Thus, modulation of intracellular zinc induced con formational changes in p53 that activated wild-type function, suggesti ng that metalloregulation may play a role in controlling p53. (C) 1998 Wiley-Liss, Inc.