Tight DNA binding and oligomerization are dispensable for the ability of p53 to transactivate target genes and suppress transformation.
The p53 tumor suppressor protein can bind tightly to specific sequence elements in the DNA and induce the transactivation of genes harboring such p53 binding sites. Various lines of evidence suggest that p53 binds to its target site as an oligomer. To test whether oligomerization is essential for the biological and biochemical activities of p53, we deleted a major part of the dimerization domain of mouse wild-type p53. The resultant protein, termed p53wt delta SS, was shown to be incapable of forming detectable homo-oligomers in vitro and is, therefore, likely to be predominantly if not exclusively monomeric. In agreement with the accepted model, p53wt delta SS indeed failed to exhibit measurable DNA binding in vitro. Surprisingly, though, it was still capable of suppressing oncogene-mediated transformation and of transactivating in vivo a target gene containing p53 binding sites. These findings indicate that dimerization-defective p53 is biologically active and may engage in productive sequence-specific DNA interactions in vivo. Furthermore, p53 dimerization probably leads to cooperative binding to specific DNA sequences.
Shaulian
E
E
Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Zauberman
A
A
Milner
J
J
Davies
E A
EA
Oren
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001704:Biopolymers; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D001704:Biopolymers; D016159:Tumor Suppressor Protein p53; D004247:DNA