Reciprocal negative regulation between the tumor suppressor protein p53 and B cell CLL/lymphoma 6 (BCL6) via control of caspase-1 expression
Reciprocal negative regulation between the tumor suppressor protein p53 and B cell CLL/lymphoma 6 (BCL6) via control of caspase-1 expression
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DOI：
10.1074/jbc.ra118.004204
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发表时间：
2019-01-04
影响因子：
4.8
通讯作者：
Hur, Man-Wook
中科院分区：
文献类型：
--
作者：
Kim, Min-Kyeong;Song, Ji-Yang;Hur, Man-Wook
即使面对生理性DNA损伤或肿瘤抑制蛋白p53的表达，B细胞CLL/淋巴瘤6（BCL 6）也增加增殖并拮抗B细胞中的凋亡反应。BCL 6抑制TP 53的转录，也似乎在蛋白质水平上抑制p53，另外的发现表明BCL 6和p53之间的负相互调节。在此，使用Bcl 6（-/-）敲除小鼠、HEK 293 A和HCT 116 p53（-/-）细胞以及定点诱变，我们发现BCL 6与p53相互作用，从而抑制p53中Lys-132被E1 A结合蛋白p300（p300）乙酰化，一种通常在DNA损伤诱导的细胞应激时发生的修饰，并且其被BCL 6消除减少了p53靶基因的转录激活，包括编码半胱天冬酶-1的基因。相反，我们还发现BCL 6蛋白通过p53诱导的、半胱天冬酶介导的蛋白水解切割以及BCL 6-p53-半胱天冬酶-1复合物的形成而降解。我们的研究结果表明，p53可能会阻止致癌转化通过减少BCL-6的稳定性，通过caspase-1的上调，而异常BCL-6表达失活的p53靶基因的反式激活，无论是通过抑制p300或抑制TP 53基因转录的p53乙酰化。这些发现对B细胞的发育和淋巴瘤的发生有意义。
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.