Critical prosurvival roles for C/EBP beta and insulin-like growth factor I in macrophage tumor cells.
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 beta to prevent cell death. In contrast to wild-type cells, C/EBP beta(-/-) 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 beta-deficient cells expressed significantly reduced levels of the prosurvival factor insulin-like growth factor I (IGF-I). Overexpression of C/EBP beta stimulated transcription from the IGF-I promoter, indicating that IGF-I is a direct transcriptional target of C/EBP beta. Serological neutralization of IGF-I in C/EBP beta(+/+) tumor cell cultures induced apoptosis, showing that IGF-I functions as an autocrine survival factor in these cells. Macrophage tumor cells derived from IGF-I(-/-) mice were GF dependent, similar to C/EBP beta-deficient cells. Forced expression of either C/EBP beta or IGF-I in C/EBP beta(-/-) bone marrow cells restored Myc/Raf-induced transformation and permitted neoplastic growth without exogenous GFs. Thus, our findings demonstrate that C/EBP beta is essential for oncogenic transformation of macrophages and functions at least in part by regulating expression of the survival factor IGF-I.
Wessells
Jennifer
J
Eukaryotic Transcriptional Regulation Section, Laboratory of Protein Dynamics and Signaling, National Cancer Institute-Frederick, Frederick, Maryland 21702-1201, USA.
Yakar
Shoshana
S
Johnson
Peter F
PF
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D005260:Female; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007938:Leukemia / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D022782:CCAAT-Enhancer-Binding Protein-beta; D007334:Insulin-Like Growth Factor I; D016173:Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D020929:Mitogen-Activated Protein Kinase Kinases