title: C/EBPbeta regulates transcription factors critical for proliferation and survival of multiple myeloma cells.
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.
authors.affiliation: Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Pal
authors.forename: Martin
authors.initials: M
authors.lastname: Janz
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Galson
authors.forename: Margarete
authors.initials: M
authors.lastname: Gries
authors.forename: Shirong
authors.initials: S
authors.lastname: Li
authors.forename: Korinna
authors.initials: K
authors.lastname: Jöhrens
authors.forename: Ioannis
authors.initials: I
authors.lastname: Anagnostopoulos
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.forename: Markus Y
authors.initials: MY
authors.lastname: Mapara
authors.forename: Lisa
authors.initials: L
authors.lastname: Borghesi
authors.forename: Lela
authors.initials: L
authors.lastname: Kardava
authors.forename: G David
authors.initials: GD
authors.lastname: Roodman
authors.forename: Christine
authors.initials: C
authors.lastname: Milcarek
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lentzsch
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D050835:Interferon Regulatory Factors / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D000071717:X-Box Binding Protein 1; D000099218:Interferon Regulatory Factor-4
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D019253:Proto-Oncogene Proteins c-bcl-2; D000071701:Regulatory Factor X Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D000099218:Interferon Regulatory Factor-4; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C087042:PRDM1 protein, human