A novel transrepression pathway of c-Myc. Recruitment of a transcriptionalcorepressor complex to c-Myc by MM-1, a c-Myc-binding protein.

The protooncogene product c-Myc plays a role in transcription regulation bo th for activation and repression. While transactivation pathways of c-Myc e ither from the N-proximal or the C-proximal region that is linked to the ch romatin remodeling complex have been identified, a transrepression pathway had been identified only from the C-proximal region via Max and Mad that re cruit the histone deacetylase (HDAC) complex. We have reported that a novel c-Myc-binding protein, MM-1, repressed the E-box-dependent transcription a ctivity 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 clari fy the molecular mechanisms of MM-1 toward c-Myc, cDNAs encoding MM-l-bindi ng proteins were screened by the two-hybrid method with MM-1 as a bait usin g a human HeLa cDNA library, and a cDNA encoding TIF1 beta /KAP1, a transcr iptional corepressor, was obtained. MM-1 was found to bind to the central p ortion 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 cel ls 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 inhib itory activity of MM-1 toward c-Myc and greatly stimulated the transcriptio n 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 indic ate that MM-1 is a connecting factor that forms a novel transcription repre ssion pathway of c-Myc.