C/EBPbeta regulates transcription factors critical for proliferation and survival of multiple myeloma cells.
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.
Pal
Rekha
R
Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
Janz
Martin
M
Galson
Deborah L
DL
Gries
Margarete
M
Li
Shirong
S
Jöhrens
Korinna
K
Anagnostopoulos
Ioannis
I
Dörken
Bernd
B
Mapara
Markus Y
MY
Borghesi
Lisa
L
Kardava
Lela
L
Roodman
G David
GD
Milcarek
Christine
C
Lentzsch
Suzanne
S
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
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