title: PRDM1/Blimp1 downregulates expression of germinal center genes LMO2 and HGAL.
abstract: Human germinal center-associated lymphoma (HGAL) and LIM domain only-2 (LMO2) are proteins highly expressed in germinal center (GC) B lymphocytes. HGAL and LMO2 are also expressed in GC-derived lymphomas and distinguish biologically distinct subgroups of diffuse large B-cell lymphomas (DLBCL) associated with improved survival. However, little is known about their regulation. PRDM1/Blimp1 is a master regulator of terminal B cell differentiation and may also function as a tumor suppressor in the pathogenesis of DLBCL, where it is frequently inactivated by mutations and deletions. We now demonstrate that both HGAL and LMO2 are directly regulated by the transcription repressor PRDM1. In vivo studies demonstrate that PRDM1 directly binds to the recognition sites within the upstream promoters of both HGAL and LMO2. PRDM1 binding suppresses endogenous protein and mRNA levels of HGAL and LMO2. In addition, promoter analysis reveals that site-specific binding of PRDM1 to the promoters is capable of repressing transcriptional activity. This inhibitory effect of PRDM1 suggests that it has a key role in the loss of HGAL and LMO2 expression upon differentiation of GC B cells to plasma cells and may also contribute to absence of HGAL and LMO2 expression in post-GC lymphoid tumors.
authors: Department of Medicine and Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
authors: Elena
authors: E
authors: Cubedo
authors: Michelle
authors: M
authors: Maurin
authors: Xiaoyu
authors: X
authors: Jiang
authors: Izidore S
authors: IS
authors: Lossos
authors: Kenneth L
authors: KL
authors: Wright
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001402:B-Lymphocytes / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D017930:Genes, Reporter; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D016393:Lymphoma, B-Cell / Q000378:metabolism; D008667:Metalloproteins / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C476824:GCSAM protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D008667:Metalloproteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012097:Repressor Proteins; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1