Steinmann S, Schulte K, Beck K, Chachra S, Bujnicki T, Klempnauer K-H
Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Münster, Germany.
Oncogene. 2009 Jul 2;28(26):2446-55. doi: 10.1038/onc.2009.90. Epub 2009 May 18.
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/EBPbeta. We show that v-Myc is recruited to the aminoterminal domain of C/EBPbeta and interferes with the cooperation of C/EBPbeta and the co-activator p300 by preventing C/EBPbeta-induced phosphorylation of p300. We have identified the protein kinase responsible for C/EBPbeta-induced phosphorylation of p300 as homeo-domain interacting protein kinase 2 (HIPK2) and show that v-Myc displaces the kinase from the C/EBPbeta-p300 complex. Overall, our findings that the modulation of the C/EBPbeta-induced phosphorylation of p300 as a new mechanism of transcriptional suppression by v-Myc.
Myc是细胞增殖、分化和凋亡的关键调节因子，它通过激活或抑制特定靶基因集的转录来发挥其生物学功能。C/EBP转录因子在各种细胞类型的分化过程中发挥重要作用，并且已被确定为v-Myc和c-Myc依赖性抑制髓系和脂肪细胞分化的关键靶点。在此，我们探讨了v-Myc抑制C/EBPβ活性的机制。我们发现v-Myc被招募到C/EBPβ的氨基末端结构域，并通过阻止C/EBPβ诱导的p300磷酸化来干扰C/EBPβ与共激活因子p300的协同作用。我们已确定负责C/EBPβ诱导p300磷酸化的蛋白激酶为同源结构域相互作用蛋白激酶2（HIPK2），并表明v-Myc将该激酶从C/EBPβ-p300复合物中置换出来。总体而言，我们的研究结果表明，C/EBPβ诱导的p300磷酸化的调节是v-Myc转录抑制的一种新机制。
