Abstract
CCAAT/enhancer-binding protein beta (C/EBPbeta), also known as nuclear factor-interleukin-6 (NF-IL6), is a transcription factor that plays an important role in the regulation of growth and differentiation of myeloid and lymphoid cells. Mice deficient in C/EBPbeta show impaired generation of B lymphocytes. We show that C/EBPbeta regulates transcription factors critical for proliferation and survival in multiple myeloma. Multiple myeloma cell lines and primary multiple myeloma cells strongly expressed C/EBPbeta, whereas normal B cells and plasma cells had little or no detectable levels of C/EBPbeta. Silencing of C/EBPbeta led to down-regulation of transcription factors such as IRF4, XBP1, and BLIMP1 accompanied by a strong inhibition of proliferation. Further, silencing of C/EBPbeta led to a complete down-regulation of antiapoptotic B-cell lymphoma 2 (BCL2) expression. In chromatin immunoprecipitation assays, C/EBPbeta directly bound to the promoter region of IRF4, BLIMP1, and BCL2. Our data indicate that C/EBPbeta is involved in the regulatory network of transcription factors that are critical for plasma cell differentiation and survival. Targeting C/EBPbeta may provide a novel therapeutic strategy in the treatment of multiple myeloma.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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B-Lymphocytes / metabolism
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CCAAT-Enhancer-Binding Protein-beta / genetics
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CCAAT-Enhancer-Binding Protein-beta / metabolism*
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Cell Line, Tumor
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Cell Proliferation*
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Cell Survival / genetics
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DNA-Binding Proteins / biosynthesis*
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DNA-Binding Proteins / genetics
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Down-Regulation / genetics
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Female
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Gene Expression Regulation, Neoplastic*
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Gene Silencing
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Humans
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Interferon Regulatory Factors / biosynthesis*
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Interferon Regulatory Factors / genetics
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Male
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Mice
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Multiple Myeloma / genetics
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Multiple Myeloma / metabolism*
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Multiple Myeloma / therapy
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Positive Regulatory Domain I-Binding Factor 1
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Regulatory Factor X Transcription Factors
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Repressor Proteins / biosynthesis*
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Repressor Proteins / genetics
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Transcription Factors / biosynthesis*
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Transcription Factors / genetics
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X-Box Binding Protein 1
Substances
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CCAAT-Enhancer-Binding Protein-beta
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DNA-Binding Proteins
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Interferon Regulatory Factors
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Proto-Oncogene Proteins c-bcl-2
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Regulatory Factor X Transcription Factors
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Repressor Proteins
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Transcription Factors
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X-Box Binding Protein 1
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XBP1 protein, human
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Xbp1 protein, mouse
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interferon regulatory factor-4
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PRDM1 protein, human
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Positive Regulatory Domain I-Binding Factor 1