Novel mechanism of C/EBP beta (NF-M) transcriptional control: activation through derepression.

Abstract

Phosphorylation of transcription factors is regarded as a major mechanism to control their activity in regulation of gene expression. C/EBPp is a transcription factor that becomes activated after phosphorylation to induce genes involved in inflammation, acute-phase response, cytokine expression, cell growth, and differentiation. The chicken homolog 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 transcription factor with concealed activation potential. Derepressed NF-M exhibits enhanced transcriptional efficacy in reporter assays. More importantly, 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 repress trans-activation. Repression is abolished by deletion of these regions, activation of signal transduction kinases including v-erbB, polyoma middle T, ras and mil/raf, or point mutation of a critical phosphorylation site for MAP kinases. We provide evidence that phosphorylation plays a unique role to derepress rather than to enhance the trans-activation domain as a novel mechanism to regulate gene expression by NF-M/C/EBPp.

GADD45β Enhances Col10a1 Transcription via the MTK1/MKK3/6/p38 Axis and Activation of C/EBPβ-TAD4 in Terminally Differentiating Chondrocytes

“…Accordingly, DNA binding by C/EBP␤ and/or its homo-or heterodimerization may be required to expose its TAD, allowing for its activation by GADD45␤ and leading to Col10a1 promoter induction. On the other hand, RD2 is also important for C/EBP-mediated promoter responses to a number of signaling pathways, including RAS, ERK, GSK3␤, and p38 (38,39,80), which disrupt RD2 interactions with either the C/EBP DNA-binding or TAD domain, leading to derepression of C/EBP␤ function (62,81). However, although the RD2 threonine 235 is a p38 substrate, mutating that residue did not affect Col10a1 promoter activity, whereas it did disrupt C/EBP-Luc induction (Fig.…”

Signal transduction in the liver: C/EBPβ modulates cell proliferation and survival

“…53 The proposed role of C/EBP␤ (and phosphorylated C/EBP␤) on the modulation of hepatocyte quiescence/ proliferation is supported by the effects of C/EBP␤ on differentiation and cell arrest/proliferation of myelomonocytes, eosinophils, macrophages, B lymphocytes, and adipocytes. 49,[54][55][56] A dual repressive/activation function of unphosphorylated/phosphorylated C/EBP␤ on the hepatocyte cell cycle has been proposed. 9 This hypothesis is supported by the finding that C/EBP␤ is a repressed transcription factor with a concealed activation potential that becomes unmasked by kinase oncogenes.…”

Interaction and Cooperation of the CCAAT-box Enhancer-binding Protein β (C/EBPβ) with the Homeodomain-interacting Protein Kinase 2 (Hipk2)

“…The relative amounts of the different isoforms vary between different cell types and are influenced via a short upstream open reading frame by the status of the cell (11,(13)(14)(15). In addition to differential isoform expression, C/EBP␤, is regulated by posttranslational modifications, such as phosphorylation (16 -18), acetylation (19 -21), and sumoylation (22) as well as by the binding of specific cofactors via protein-protein interactions (23)(24)(25)(26)(27). Besides its function in normal cells, deregulation of C/EBP␤ activity or isoform expression contributes to the development of cancer (28 -31).…”