제1저자 김민경(생화학-분자생물학교실, BK21 졸업) 송지양(생화학-분자생물학교실, BK21)
교신저자 허만욱(생화학-분자생물학교실, BK21)
J Biol Chem. 2018 Nov 8. pii: jbc.RA118.004204. doi: 10.1074/jbc.RA118.004204. [Epub ahead of print]
Reciprocal negative regulation between the tumor suppressor protein p53 and B cell CLL/lymphoma 6 (BCL6) via control of caspase-1 expression.
Kim MK1, Song JY1, Koh DI1, Kim JY2, Hatano M3, Jeon BN1, Kim MY1, Cho SY1, Kim KS4, Hur MW5.
1Yonsei University School of Medicine, Korea, Republic of.2Korea Basic Science Institute.3Graduate School of Medicine, Chiba University, Japan.4Biochemistry and Molecular Biology, Yonsei University College of Medicine, Korea, Republic of.5Biochemistry and Molecular Biology, Yonsei University School of Medicine, Korea, Republic of.
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.