Abstract
BCL-6 is a transcription factor essential for germinal centre B-cell development. The BCL-6 gene is involved in diffuse large-cell lymphoma and overexpressed in other types of non-Hodgkin's lymphoma and in high-grade breast cancer. BCL-6 is a transcriptional repressor whose N-terminal POZ domain mediates protein-protein interactions to exert its effects. Reasoning that disruption of POZ domain-mediated interactions may be an effective route to antagonizing the effects of BCL-6 in lymphoma, we screened a library for peptide aptamers that specifically bind to BCL-6 POZ and not the POZ domains of related proteins and describe here the first of these reagents, Apt48. Apt48 binds BCL-6 POZ in a manner distinct from the transcriptional corepressor SMRT, yet was found to prevent BCL-6-mediated repression of a luciferase reporter gene. Apt48 also reproduced several previously validated effects of BCL-6 inhibition. Notably, expression of the differentiation markers CD69, Blimp-1 and cyclin D2 was increased in B-cell lines when Apt48 was expressed. We also show that expression of Apt48 restores cytokine-mediated growth arrest to BCL-6 overexpressing cells. Thus, we have identified a peptide aptamer that affects a function of BCL-6 that is required to prevent differentiation of proliferating B cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD / metabolism
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Antigens, Differentiation, T-Lymphocyte / metabolism
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Aptamers, Peptide / pharmacology*
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Blotting, Western
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Bone Neoplasms / metabolism
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Bone Neoplasms / pathology
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Cell Differentiation
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Cell Survival
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Combinatorial Chemistry Techniques
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Cyclin D2
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Cyclins / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Humans
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Immunoprecipitation
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Lectins, C-Type
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Nuclear Receptor Co-Repressor 2
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Osteosarcoma / metabolism
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Osteosarcoma / pathology
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Peptide Library
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Positive Regulatory Domain I-Binding Factor 1
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-bcl-6 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-6 / genetics
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Proto-Oncogene Proteins c-bcl-6 / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Saccharomyces cerevisiae
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Transcription Factors / metabolism
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Transcription, Genetic
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Transcriptional Activation
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Tumor Cells, Cultured
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Two-Hybrid System Techniques
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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Aptamers, Peptide
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CCND2 protein, human
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CD69 antigen
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Cyclin D2
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Cyclins
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DNA-Binding Proteins
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Lectins, C-Type
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NCOR2 protein, human
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Nuclear Receptor Co-Repressor 2
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Peptide Library
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Proto-Oncogene Proteins c-bcl-6
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Repressor Proteins
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Transcription Factors
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PRDM1 protein, human
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Positive Regulatory Domain I-Binding Factor 1