Functions of Myc and c-Myc-binding proteins

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1).Identification of a novel transrepression pathway of c-Myc and its target geneWe have found that MM-1 bound to TIF13, a transcriptional corepressor, and that MM-1 recruited a corepressor complex, including HDAC1 and mSin3, to c-Myc, thereby leading to repressing c-Myc transcription activity. To identify target genes to this pathway, a MycER cell line harboring a dominant-negative form of TIFiβ, in which the corepressor complex was not recruited to c-Myc, was first established. DNA-microarray method was then applied to identify genes whose expressions were upregulated in this line compared to those in MycER cells. By this system we identified c-fms oncogene as the c-Myc-MM-1 repressed gene. It was then found that third E-box present m c-fins promoter was essential to be repressed by c-Myc.2). Identification of a novel degradation pathway of c-Myc.We have also identified Elongin B, 26Sproteasome subunits Rpt3 and Rpn12 as MM-1-associated proteins. Since these proteins functions for ub … More iquitination and degradation of proteins, we then tested a possibility that MM-1 plays a role in c-Myc degradation. The results indicate that MM-1 stimulated c-Myc degradation through the novel E3 ubiquitin ligase complex, including Spk2, Cullin 1, Elongon BThese findings indicate that MM-1 is a key protein that negatively regulates c-Myc function and that lost of these functions of MM-1 by mutations leads to tumor formation by c-Myc.3) AMY-1 was found to bind to the protein kinase A (P1(A) regulatory subunit type 2 (RII)-binding domains of several PKA-anchoring proteins, AKAPs, including AKAP149, S-AKAP84 and AKAP95, and to be localized in the cytoplasm or nuclei depending on associated AKAPs AMY-1 was also localized in the Golgi apparatus. AMY-1 bound to the first RII-binding domains of the brefeldin A-inhibited guanine nucleotide-exchange proteins BIG2 and BIG1 and colocalized with BIG2 even in the presence of brefeldin A, which inhibits guanine nucleotide-exchange activity of BIG2. AMY-1 was also found to be localized in the trans-Golgi apparatus. These results suggest that AMY-1 as a cofactor plays a role in guanine nucleotide-exchange reaction of BIG2 or BIG1. Less