v-Myc inhibits C/EBPβ activity by preventing C/EBPβ-induced phosphorylation of the co-activator p300

Myc, a key regulator of cellular proliferation, differentiation and apoptosis, exerts its biological functions by activating or suppressing the transcription of specific sets of target genes. C/EBP transcription factors play important roles during differentiation of various cell types and have been identified as critical targets for v-Myc- and c-Myc-dependent suppression of myeloid and fat cell differentiation. Here, we have addressed the mechanism by which v-Myc suppresses the activity of C/EBP beta. We show that v-Myc is recruited to the aminoterminal domain of C/EBP beta and interferes with the cooperation of C/EBP beta and the co-activator p300 by preventing C/EBP beta-induced phosphorylation of p300. We have identified the protein kinase responsible for C/EBP beta-induced phosphorylation of p300 as homeo-domain interacting protein kinase 2 (HIPK2) and show that v-Myc displaces the kinase from the C/EBP beta-p300 complex. Overall, our findings that the modulation of the C/EBP beta-induced phosphorylation of p300 as a new mechanism of transcriptional suppression by v-Myc. Oncogene (2009) 28, 2446-2455; doi:10.1038/onc.2009.90;published online 18 May 2009