Modulation of p53 protein conformation and DNA-binding activity by intracellular chelation of zinc.
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.
Verhaegh
G W
GW
Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
Parat
M O
MO
Richard
M J
MJ
Hainaut
P
P
D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D005029:Ethylenediamines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism*
D002614:Chelating Agents; D004268:DNA-Binding Proteins; D005029:Ethylenediamines; D011500:Protein Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D004247:DNA; D003513:Cycloheximide; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine