title: BCL11B tumor suppressor inhibits HDM2 expression in a p53-dependent manner.
abstract: BCL11B is a C2H2 zinc finger transcription factor that acts as a haploinsufficient tumor suppressor. Mutations and deletion in the human orthologue BCL11B have been identified in human T-cell acute lymphoblastic leukemia (T-ALL) and a mouse model of thymic lymphomas. Bcl11b(KO/+)p53(KO/+) doubly heterozygous mice, but not Bcl11b(KO/+) heterozygous mice, spontaneously develop thymic lymphomas at a high frequency, suggesting cooperativity of BCL11B and p53 in cancer development. In this study, we have examined whether or not BCL11B directly affects the p53 signaling pathway including HDM2, a ubiquitin ligase for p53 degradation. The p53 pathway regulates cell proliferation and the response to DNA damages to maintain genome integrity. Here we show that BCL11B binds to human HDM2-P2 promoter by ChIP (chromatin immuno-precipitation) assay and inhibits HDM2 expression in a p53-dependent manner. Deletion of the distal p53 responsive element in HDM2 promoter region or the lack of p53 in HCT116 cells greatly reduced the repressive effect of BCL11B on HDM2-P2 promoter activity. The repressive activity was alleviated in γ-ray induced DNA damage conditions that activate p53, suggesting interaction between BCL11B and p53 for HDM2 expression. These date suggest that BCL11B affects the activity of the p53-HDM2 feedback loop in basal and irradiated conditions. This may be a mechanism underlying the leukemic transformation in T-ALL and in Bcl11b(KO/+)p53(KO/+) mouse thymocytes.
authors.affiliation: Department of Molecular Genetics, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Obata
authors.forename: Ryo
authors.initials: R
authors.lastname: Kominami
authors.forename: Yukio
authors.initials: Y
authors.lastname: Mishima
mesh_terms: D002460:Cell Line; D004249:DNA Damage; D005720:Gamma Rays; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: C479740:BCL11B protein, human; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D049410:Luciferases, Renilla; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2