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. Bcl11bKO/+p53KO/+ doubly heterozygous mice, but not Bcl11bKO/+ 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 Bcl11bKO/+p53KO/+ mouse thymocytes.