P53 Suppresses c-Myb-induced trans-Activation and Transformation by Recruiting the Corepressor mSin3A

Jun Tanikawa,Teruaki Nomura,Elizabeth M Macmillan,Toshie Shinagawa,Wanzhu Jin,Kenji Kokura,Daichi Baba,Masahiro Shirakawa,Thomas J Gonda,Shunsuke Ishii

doi:10.1074/jbc.m411658200

Abstract

p53 is known to repress transcription of a number of genes, but the mechanism of p53 recruitment to these target genes is unknown. The c-myb proto-oncogene product (c-Myb) positively regulates proliferation of immature hematopoietic cells, whereas p53 blocks cell cycle progression. Here, we demonstrate that p53 inhibits c-Myb-induced transcription and transformation by directly binding to c-Myb. The ability of c-Myb to maintain the undifferentiated state of M1 cells was also suppressed by p53. p53 did not affect the ability of c-Myb to bind to DNA but formed a ternary complex with the corepressor mSin3A and c-Myb. Thus, p53 antagonizes c-Myb by recruiting mSin3A to down-regulate specific Myb target genes.

Highlights

P53 is known to repress transcription of a number of genes, but the mechanism of p53 recruitment to these target genes is unknown
During analysis of the interactions between p53, c-myb proto-oncogene product (c-Myb), and heat shock transcription factor 3, we have found that p53 directly binds to c-Myb
The results indicate that the region containing repeats 2 and 3 in the DNA-binding domain (DBD) of c-Myb bind to GST-p53 (Fig. 1A and supplemental Fig. S1)

Summary

Introduction

P53 is known to repress transcription of a number of genes, but the mechanism of p53 recruitment to these target genes is unknown. P53 directly binds to the DBD of c-Myb. To identify the regions of p53 that interact with c-Myb, we used various forms of in vitro translated p53 in pull-down assays with GST-c-Myb. The results indicate that the C-terminal 78-amino acid region, which contains the tetramerization domain, is responsible for the interaction with c-Myb (Fig. 1B and supplemental Fig. S2).

Results

Conclusion