Modulation of p53 protein conformation and DNA-binding activity by intracellular chelation of zinc

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Abstract
The transcription factor p53 controls the proliferation and survival of 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)ethylenediamine induced wild‐type p53 to accumulate in an immunologically “mutant” form (Pab240+, Pab1620–) with decreased DNA‐binding activity. Removal of N,N,N′,N′‐tetrakis(2‐pyridylmethyl)ethylenediamine from culture medium allowed p53 to refold into the immunologically wild‐type form, followed by a transient increase in DNA binding, expression of the cyclin‐dependent kinase inhibitor p21WAF1, and cell‐cycle delay in the G1 phase. Thus, modulation of intracellular zinc induced conformational changes in p53 that activated wild‐type function, suggesting that metalloregulation may play a role in controlling p53. Mol. Carcinog. 21:205–214, 1998.