Abstract
BackgroundCCAAT/enhancer binding protein-delta (C/EBP-delta) is a member of the highly conserved C/EBP family of basic region leucine zipper transcription factors. C/EBP family members regulate cell growth and differentiation and "loss of function" alterations in C/EBPs have been reported in a variety of human cancers. C/EBP-delta gene expression is upregulated by G0 growth arrest, IL-6 family cytokines and endotoxin treatments. C/EBP-delta exhibits properties of a tumor suppressor gene, including reduced expression and promoter methylation-induced silencing in transformed cell lines and primary tumors. In addition, C/EBP-delta gene expression is repressed by c-Myc, an oncogene that is over-expressed in a wide range of human cancers. "ChIP-chip" studies demonstrated that C/EBP-delta functions as a transcriptional activator of target genes that function in intracellular signal transduction, transcription, DNA binding/repair, cell cycle control, cell adhesion, and apoptosis. Despite progress in determining the biochemical functions of C/EBP-delta, the specific cellular defects that are induced by C/EBP-delta "loss of function" alterations are poorly understood. This study investigated the impact of C/EBP-delta "loss of function" alterations on growth arrest, migration/invasion and differentiation in nontransformed mouse mammary epithelial cells (MECs) and primary mouse embryo fibroblasts (MEFs).ResultsC/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.ConclusionsThis 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.
Highlights
CCAAT/enhancer binding protein-delta (C/EBP-delta) is a member of the highly conserved CCAAT/enhancer binding proteins (C/EBPs) family of basic region leucine zipper transcription factors
We reported that CCAAT/Enhancer Binding Proteinδ (C/EBPδ) expression is reduced in 32% (18/ 57) of primary human breast tumors, a finding consistent with Serial Analysis of gene Expression (SAGE) results from Polyak and coworkers [13,14,15]
Silencing of gene expression by epigenetic promoter hypermethylation has been previously reported for a number of tumor suppressor genes including Retinoblastoma protein (Rb), p16, p21, Breast Cancer 1 (BRCA1) and Von Hippel Lindau (VHL) [18]. These results demonstrate that C/EBPδ shares cancer related mechanisms of gene silencing with established tumor suppressor genes
Summary
CCAAT/enhancer binding protein-delta (C/EBP-delta) is a member of the highly conserved C/EBP family of basic region leucine zipper transcription factors. C/EBP family members regulate cell growth and differentiation and “loss of function” alterations in C/EBPs have been reported in a variety of human cancers. C/ EBP-delta gene expression is upregulated by G0 growth arrest, IL-6 family cytokines and endotoxin treatments. This study investigated the impact of C/EBP-delta “loss of function” alterations on growth arrest, migration/invasion and differentiation in nontransformed mouse mammary epithelial cells (MECs) and primary mouse embryo fibroblasts (MEFs). CCAAT/enhancer binding proteins (C/EBPs) are a highly conserved family of basic region leucine zipper (bZip) transcription factors [1]. C/EBP family members, C/EBPa and C/EBPδ, exhibit cell type specific anti-proliferative activities and, as a result, have been termed “molecular stop signs” [2,4]
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