Inhibition of the Transcriptional Activity of p53 Through Hetero-Oligomerization

Abstract

Induced pluripotent stem (iPS) cells can be generated by the expression of pluripotency factors and oncogenes; however, the efficiency of generating iPS cells is extremely low (less than 1 %). Activation of the p53-p21 pathway is responsible for this low efficiency and inactivation of p53 enhances the production of induced iPS cells 10–20 fold. Tetramer formation of p53 is crucial to its activity. The tetramerization domain consists of a β-strand, a tight turn, and an α-helix. Two monomers form a dimer through interaction between the antiparallel β-sheets and α-helices, and the two primary dimers associate to form a tetramer with an unusual four-helix bundle. In this study, to inhibit p53 function, p53 tetramerization domain peptides containing a protein transduction domain (PTD-p53tet) were introduced into cells. The PTD-p53tet peptide was efficiently introduced into nuclei and significantly inhibited the transcriptional activity of p53. A monomeric mutant PTD-p53tet peptide showed no inhibitory activity, indicating that the inhibition by the PTD-p53tet peptide was dependent on its ability to form tetramers. The PTD-p53tet peptide formed hetero-tetramers with wild-type p53TD peptide while the monomeric mutant peptide did not. These results suggest that the PTD-p53tet peptide inhibited transcriptional activity in cells via hetero-oligomerization with endogenous p53 protein.