A novel transrepression pathway of c-Myc. Recruitment of a transcriptional corepressor complex to c-Myc by MM-1, a c-Myc-binding protein.
The protooncogene product c-Myc plays a role in transcription regulation both for activation and repression. While transactivation pathways of c-Myc either from the N-proximal or the C-proximal region that is linked to the chromatin remodeling complex have been identified, a transrepression pathway had been identified only from the C-proximal region via Max and Mad that recruit the histone deacetylase (HDAC) complex. We have reported that a novel c-Myc-binding protein, MM-1, repressed the E-box-dependent transcription activity of c-Myc (Mori, K., Maeda, Y., Kitaura, H., Taira, T., Iguchi-Ariga, S. M. M., and Ariga, H. (1998) J. Biol. Chem. 273, 29794-29800). To clarify the molecular mechanisms of MM-1 toward c-Myc, cDNAs encoding MM-1-binding proteins were screened by the two-hybrid method with MM-1 as a bait using a human HeLa cDNA library, and a cDNA encoding TIF1 beta/KAP1, a transcriptional corepressor, was obtained. MM-1 was found to bind to the central portion of TIF1 beta in vitro and in vivo, and these proteins were found to be colocalized in the nucleus. MM-1 and TIF1 beta complex in human HeLa cells was found to also contain c-Myc, mSin3, and HDAC1. Introduction of the C-terminal half of TIF1 beta as a dominant negative form abrogated the inhibitory activity of MM-1 toward c-Myc and greatly stimulated the transcription activity of c-Myc. Moreover, the inhibitory activity of MM-1 toward c-Myc was canceled by trichostatin A, an inhibitor of HDAC1. These results indicate that MM-1 is a connecting factor that forms a novel transcription repression pathway of c-Myc.
Satou
A
A
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060, Japan.
Taira
T
T
Iguchi-Ariga
S M
SM
Ariga
H
H
D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D000076183:Tripartite Motif-Containing Protein 28
D004268:DNA-Binding Proteins; C115636:PFDN5 protein, human; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases