A peptide aptamer to antagonize BCL-6 function.
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.
Mesh Terms:
Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Aptamers, Peptide, Blotting, Western, Bone Neoplasms, Cell Differentiation, Cell Survival, Combinatorial Chemistry Techniques, Cyclin D2, Cyclins, DNA-Binding Proteins, Humans, Immunoprecipitation, Lectins, C-Type, Nuclear Receptor Co-Repressor 2, Osteosarcoma, Peptide Library, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-6, Repressor Proteins, Saccharomyces cerevisiae, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Tumor Cells, Cultured, Two-Hybrid System Techniques
Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Aptamers, Peptide, Blotting, Western, Bone Neoplasms, Cell Differentiation, Cell Survival, Combinatorial Chemistry Techniques, Cyclin D2, Cyclins, DNA-Binding Proteins, Humans, Immunoprecipitation, Lectins, C-Type, Nuclear Receptor Co-Repressor 2, Osteosarcoma, Peptide Library, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-6, Repressor Proteins, Saccharomyces cerevisiae, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Tumor Cells, Cultured, Two-Hybrid System Techniques
Oncogene
Date: Apr. 06, 2006
PubMed ID: 16331266
View in: Pubmed Google Scholar
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