CCAAT/Enhancer Binding Protein-delta (C/EBP-delta) regulates cell growth, migration and differentiation

C/EBP-delta siRNA transfected MECs exhibited ~90% reduction in C/EBP-delta mRNA and protein levels. C/EBP-delta siRNA treatment resulted in defective growth arrest as demonstrated by persistently elevated BrdU labeling, 3H-thymidine incorporation and cyclin D1 levels in response to growth arrest treatments. C/EBP-delta siRNA treatment also resulted in increased migration/invasion and defective differentiation. C/EBP-delta knockout MEFs exhibited defective growth arrest and increased proliferation/migration. Re-introduction of C/EBP-delta expression restored the growth arrest response of C/EBP-delta knockout MEFs. Finally, deletion of the C/EBP-delta DNA binding domain or the C/EBP-delta bZIP domain resulted in the loss of C/EBP-delta growth inhibition in clonogenic assays.This study demonstrates that C/EBP-delta functions in the regulation of critical cell fate determining programs such as growth arrest, migration, and differentiation. These results support the tumor suppressor function of C/EBP-delta and identify potential mechanisms in which "loss of function" alterations in C/EBP-delta could promote cell transformation and tumorigenesis.CCAAT/enhancer binding proteins (C/EBPs) are a highly conserved family of basic region leucine zipper (bZip) transcription factors [1]. The C/EBP family includes six family members: C/EBPα, C/EBPβ, C/EBPγ, C/EBPδ, C/EBPε, and C/EBPζ [1,2]. C/EBP proteins exhibit significant amino acid homology (>90%) in the bZip (C-terminal) domain, however, the N-terminal regions of C/EBPs are quite divergent exhibiting <20% sequence homology [1]. C/EBPs influence cell fate by forming homo- or heterodimers with other C/EBP family members as well as other bZip-containing proteins such as Fos, Jun and cyclic AMP response element binding protein (CREB) [1-3]. C/EBPs also interact with cell cycle regulators such as Retinoblastoma protein (Rb), E2F, cyclin dependent kinase4 (CDK4) and p21 via the C/EBP N terminal region [1-3]. C/EBP family members, pa