The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells

• Published in: Nature 2004-12, Vol.432 (7017), p.635-639
• Main Authors: Dalla-Favera, Riccardo, Phan, Ryan T
• Format: Article
• Language: English
• Subjects: Apoptosis; B-Lymphocytes - metabolism; Biological and medical sciences; Cell Line; Deoxyribonucleic acid; DNA; DNA Damage; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation; Gene expression; Gene Silencing; Genes; Genes, Reporter - genetics; Germinal Center - cytology; Germinal Center - immunology; Hematologic and hematopoietic diseases; Humanities and Social Sciences; Humans; Inactivation; letter; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma; Medical sciences; multidisciplinary; Oncology; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-6; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - genetics; Tumor Suppressor Protein p53 - biosynthesis; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature03147

The human proto-oncogene BCL6 encodes a BTB/POZ-zinc-finger transcriptional repressor that is necessary for germinal-centre formation and is implicated in the pathogenesis of B-cell lymphoma. The precise function of BCL6 in germinal-centre development and lymphomagenesis is unclear because very few direct BCL6 target genes have been identified. Here we report that BCL6 suppresses the expression of the p53 (also known as tp53) tumour suppressor gene and modulates DNA damage-induced apoptotic responses in germinal-centre B cells. BCL6 represses p53 transcription by binding two specific DNA sites within the p53 promoter region and, accordingly, p53 expression is absent in germinal-centre B cells where BCL6 is highly expressed. Suppression of BCL6 expression via specific short interfering RNA leads to increased levels of p53 messenger RNA and protein both under basal conditions and in response to DNA damage. Most notably, constitutive expression of BCL6 protects B cell lines from apoptosis induced by DNA damage. These results suggest that an important function of BCL6 is to allow germinal-centre B cells to tolerate the physiological DNA breaks required for immunoglobulin class switch recombination and somatic hypermutation without inducing a p53-dependent apoptotic response. These findings also imply that deregulated BCL6 expression contributes to lymphomagenesis in part by functional inactivation of p53.