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Transcription factor C/EBP‐beta is required for the regulation of apoptoic gene, the death‐associated protein kinase‐1 (DAPK1)
Author(s) -
Gade Padmaja,
Li Hui,
Roy Sanjit K
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a251-b
Subject(s) - biology , transcription factor , ccaat enhancer binding proteins , gene , microbiology and biotechnology , regulation of gene expression , promoter , enhancer , gene expression , kinase , protein kinase a , mutant , nuclear protein , genetics
CAAAT/Enhancer binding protein (C/EBP) family of transcription factors plays a major role in regulating energy metabolism, immune response and cell differentiation. They are also suggested to have antitumor functions, although the mechanisms are unclear. Interferons are potent inhibitors of cell growth. A gene expression profiling in a cell line lacking the C/EBP‐β revealed that C/EBP‐β was required for the expression of a number IFN regulated genes, including, DAPK1. DAPK1 is a ca+2/calmodulin regulated serine/threonine kinase and a major tumor suppressor gene. Its expression is lost in multiple tumor types, although the mechanisms are unclear. Therefore, we investigated the regulatory influence of DAPK1 gene. We have isolated the gene promoter of DAPK1 and studied its regulation. ChIP assays showed that C/EBP‐β binds to the promoter of DAPK1. Mutation of a consensus C/EBP binding site (CBS) in the promoter did not decrease the inhibit gene expression. Therefore, we searched for potential sites of C/EBP‐β dependent regulation in this promoter. Mutation of a consensus site for CREB/ATF6 (CABS) still allowed transcription. However, a double mutant lacking both these sites failed to respond to C/EBP‐β. Mutant C/EBP‐β proteins lacking several potential phosphorylation sites also inhibited the DAPK1 gene expression. Thus, C/EBP‐β regulates from at least two sites in the DAPK promoter. Phosphorylation of C/EBP‐β at multiple sites is critical for regulating the gene. Together, these studies show a mechanism by C/EBP‐β exerts its antitumor effects. Supported by NIH Grants CA78282 and CA105005.