NOVEL MECHANISM OF C EBP-BETA (NF-M) TRANSCRIPTIONAL CONTROL - ACTIVATION THROUGH DEREPRESSION/

Phosphorylation of transcription factors is regarded as a major mechan ism to control their activity in regulation of gene expression. C/EBP beta is a transcription factor that becomes activated after phosphoryl ation to induce genes involved in inflammation, acute-phase response, cytokine expression, cell growth, and differentiation. The chicken hom olog NF-M collaborates with Myb and various kinase oncogenes in normal myeloid differentiation as well as in the leukemic transformation of myelomonocytic cells. Here, we examined the structure of NF-M and its mechanism of activation. We show that NF-M is a repressed transcriptio n factor with concealed activation potential. Derepressed NF-M exhibit s enhanced transcriptional efficacy in reporter assays. More important ly, NF-M activates resident chromatin-embedded, myelomonocyte-specific target genes, even in heterologous cell types such as fibroblasts or erythroblasts. We identified two regions within NF-M that act to repre ss trans-activation. Repression is abolished by deletion of these regi ons, activation of signal transduction kinases including v-erbB, polyo ma middle T, ras and mil/raf, or point mutation of a critical phosphor ylation site for MAP kinases. We provide evidence that phosphorylation plays a unique role to derepress rather than to enhance the trans-act ivation domain as a novel mechanism to regulate gene expression by NF- M/C/EBP beta.