Critical Prosurvival Roles for C/EBPβ and Insulin-Like Growth Factor I in Macrophage Tumor Cells

Abstract

One of the hallmarks of leukemic cells is their ability to proliferate and survive in the absence of exogenous growth factors (GFs). However, the molecular mechanisms used by myeloid tumor cells to escape apoptosis are not fully understood. Here we report that Myc/Raf-transformed macrophages require the transcription factor C/EBP␤ to prevent cell death. In contrast to wild-type cells, C/EBP␤ ؊/؊ macrophages were completely dependent on macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor for survival and displayed impaired tumorigenicity in vivo. Microarray analysis revealed that C/EBP␤-deficient cells expressed significantly reduced levels of the prosurvival factor insulin-like growth factor I (IGF-I). Overexpression of C/EBP␤ stimulated transcription from the IGF-I promoter, indicating that IGF-I is a direct transcriptional target of C/EBP␤. Serological neutralization of IGF-I in C/EBP␤

Critical Role for Transcription Factor C/EBP-β in Regulating the Expression of Death-Associated Protein Kinase 1

“…To better define the impact of IFN-␥-stimulated C/EBP-␤ on cellular gene expression, we generated BM macrophage cell lines from wild-type (cebpb ϩ/ϩ ) and cebpb Ϫ/Ϫ mice (91). The mice used were a mixture of 129/Sv and C57BL/6 strains maintained by a continuous intercrossing of heterozygous animals.…”

Conditional ablation of C/EBPβ demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis

“…C/EBPb also functions as a prosurvival factor in myc/Ras transformed macrophages in vitro (Wessells et al, 2004) and in Wilms tumor cells (Li et al, 2005). In an attempt to characterize the in vitro role of C/EBPb in keratinocytes survival, we previously treated primary keratinocytes isolated from C/EBPb À/À and wild-type mice with various carcinogens or transfected/infected these primary Figure 1 Targeted conditional mutation of the C/EBPb gene in mice.…”

A Role for Mixed Lineage Kinases in Regulating Transcription Factor CCAAT/Enhancer-binding Protein-β-dependent Gene Expression in Response to Interferon-γ

“…C/EBP-␤ (nuclear factor induced by interleukin-6, liver-activated protein, C/EBP-related protein 2, nuclear factor myeloid) (10,11,13) responds to a number of extracellular stimuli including interleukin-6, interleukin-1, tumor necrosis factor-␣, and lipopolysaccharide (10,11) and is necessary for regulating several processes including carbohydrate metabolism, lipid storage, Th1 immune responses, macrophage-mediated antibacterial and antitumor defenses, and female fertility (11,(13)(14)(15). C/EBP-␤ deficiency causes a lymphoproliferative disorder (16), and C/EBP-␤ is also required for B-lymphopoiesis (17), chemical carcinogen-induced Ras-dependent tumor formation in skin keratinocytes (18), and growth factor-independent survival of Myc/Raf-transformed macrophage tumor cells (19). Phosphorylation of several serine and threonine residues distributed across the backbone of C/EBP-␤ by different protein kinases appears to contribute to its diverse actions.…”