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.
Chattopadhyay
A
A
MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge, UK.
Tate
S A
SA
Beswick
R W
RW
Wagner
S D
SD
Ko Ferrigno
P
P
D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D052158:Aptamers, Peptide / Q000494:pharmacology*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002470:Cell Survival; D020650:Combinatorial Chemistry Techniques; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D037181:Lectins, C-Type; D056985:Nuclear Receptor Co-Repressor 2; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D019151:Peptide Library; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D052158:Aptamers, Peptide; D056742:Cyclin D2; D016213:Cyclins; D004268:DNA-Binding Proteins; D037181:Lectins, C-Type; D056985:Nuclear Receptor Co-Repressor 2; D019151:Peptide Library; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; D014157:Transcription Factors; D000099192:CD69 Antigens; C080336:CCND2 protein, human; C539130:NCOR2 protein, human; C087042:PRDM1 protein, human