Negative regulation of the Wnt signal by MM-1 through inhibiting expression of the wnt4 gene.

We have reported that a novel c-Myc-binding protein, MM-1, repressed the E-box-dependent transcription activity of c-Myc through TIF1beta/KAP1, a transcriptional corepressor, and that the c-fms gene was a target gene involved in this pathway. We have also reported that a mutation of A157R in MM-1, which is often observed in patients with leukemia or lymphoma, abrogated all of the repressive activities of MM-1 toward c-Myc, indicating that MM-1 is a novel tumor suppressor. In this study, to further identify target genes of MM-1, DNA microarray analysis was carried out by comparing expression levels of genes in MM-1 knockdown and parental cells, and the wnt4 gene, a member of the Wnt-beta-catenin pathway, was identified as a target gene of MM-1.

Distinct localizations and repression activities of MM-1 isoforms toward c-Myc.

MM-1 was identified as a c-Myc-binding protein and has been reported to repress the E-box-dependent transcription activity of c-Myc by recruiting HDAC1 complex via TIF1 beta/KAP1. In this study, originally isolated MM-1 was found to be a fusion protein comprised of the N-terminal 13 amino acids from the sequence of chromosome 14 and of the rest of the amino acids from that of chromosome 12 and was found to be expressed ubiquitously in all human tissues. Four splicing isoforms of MM-1, MM-1alpha, MM-1beta, MM-1gamma, and MM-1delta, which are derived from the sequence of chromosome 12, were then identified.

Repression of the c-fms gene in fibroblast cells by c-Myc-MM-1-TIF1beta complex.

MM-1 has been reported to repress the E-box-dependent transcription activity of c-Myc by recruiting histone deacetylase 1 complex via TIF1beta/KAP1. In this study, to identify target genes for c-Myc-MM-1-TIF1beta, we established rat-1 cells harboring the dominant-negative form of TIF1beta to abrogate the pathway from TIF1beta to MM-1-c-Myc. This cell line, in which transcription activity of c-Myc was activated, was found to be tumorigenic.