Abstract
Even in the face of physiological DNA damage or expression of the tumor suppressor protein p53, B cell CLL/lymphoma 6 (BCL6) increases proliferation and antagonizes apoptotic responses in B cells. BCL6 represses TP53 transcription and also appears to inactivate p53 at the protein level, and additional findings have suggested negative mutual regulation between BCL6 and p53. Here, using Bcl6-/- knockout mice, HEK293A and HCT116 p53-/- cells, and site-directed mutagenesis, we found that BCL6 interacts with p53 and thereby inhibits acetylation of Lys-132 in p53 by E1A-binding protein p300 (p300), a modification that normally occurs upon DNA damage-induced cellular stress and whose abrogation by BCL6 diminished transcriptional activation of p53 target genes, including that encoding caspase-1. Conversely, we also found that BCL6 protein is degraded via p53-induced, caspase-mediated proteolytic cleavage, and the formation of a BCL6-p53-caspase-1 complex. Our results suggest that p53 may block oncogenic transformation by decreasing BCL6 stability via caspase-1 up-regulation, whereas aberrant BCL6 expression inactivates transactivation of p53 target genes, either by inhibiting p53 acetylation by p300 or repressing TP53 gene transcription. These findings have implications for B cell development and lymphomagenesis.
Highlights
Even in the face of physiological DNA damage or expression of the tumor suppressor protein p53, B cell CLL/lymphoma 6 (BCL6) increases proliferation and antagonizes apoptotic responses in B cells
Using Bcl6؊/؊ knockout mice, HEK293A and HCT116 p53؊/؊ cells, and site-directed mutagenesis, we found that BCL6 interacts with p53 and thereby inhibits acetylation of Lys-132 in p53 by E1A-binding protein p300 (p300), a modification that normally occurs upon DNA damage–induced cellular stress and whose abrogation by BCL6 diminished transcriptional activation of p53 target genes, including that encoding caspase-1
Our results suggest that p53 may block oncogenic transformation by decreasing BCL6 stability via caspase-1 up-regulation, whereas aberrant BCL6 expression inactivates transactivation of p53 target genes, either by inhibiting p53 acetylation by p300 or repressing TP53 gene transcription
Summary
We first investigated whether ectopic BCL6 could repress TP53, the transcriptional coactivator p300, and p53 target genes regulating cell cycle and apoptosis. The assays showed that ectopic BCL6 expression increased cell proliferation, p53 significantly decreased cell proliferation These results suggest that BCL6 might inhibit p53 activity important for transcriptional activation of p53 target genes, thereby blocking apoptosis and cell-cycle arrest (Fig. 1D). BCL6 could repress the transcriptional activation of p53 target genes controlling the cell cycle or apoptosis by decreasing p300mediated acetylation of p53 Lys-132 following DNA damage. BCL6 modulates acetylation of p53 by p300 and decreases p53 acetylation at Lys-132, attenuating p53 transactivation of its target genes involved in cell-cycle arrest and/or apoptosis and instead stimulating cell proliferation Another interesting finding of our study is that p53 can decrease BCL6 protein expression via caspase-1. Dr Masahiko Hatano of the Chiba University and Center for Animal Resource and Development (CARD) of Kumamoto University provided Bcl6Ϫ/Ϫ knockout C57BL/6J mouse populations
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