Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
Cancer Res. 2012 Apr 15;72(8):1996-2005. doi: 10.1158/0008-5472.CAN-11-2291. Epub 2012 Feb 16.
The balance between apoptosis ("programmed cell death") and autophagy ("programmed cell survival") is important in tumor development and response to therapy. Here, we show that high mobility group box 1 (HMGB1) and p53 form a complex that regulates the balance between tumor cell death and survival. We show that knockout of p53 in HCT116 cells increases expression of cytosolic HMGB1 and induces autophagy. Conversely, knockout of HMGB1 in mouse embryonic fibroblasts increases p53 cytosolic localization and decreases autophagy. p53 is thus a negative regulator of the HMGB1/Beclin 1 complex, and HMGB1 promotes autophagy in the setting of diminished p53. HMGB1-mediated autophagy promotes tumor cell survival in the setting of p53-dependent processes. The HMGB1/p53 complex affects the cytoplasmic localization of the reciprocal binding partner, thereby regulating subsequent levels of autophagy and apoptosis. These insights provide a novel link between HMGB1 and p53 in the cross-regulation of apoptosis and autophagy in the setting of cell stress, providing insights into their reciprocal roles in carcinogenesis.
细胞凋亡（“程序性细胞死亡”）和自噬（“程序性细胞存活”）之间的平衡在肿瘤的发生和对治疗的反应中很重要。在这里，我们表明高迁移率族蛋白 B1（HMGB1）和 p53 形成一个复合物，调节肿瘤细胞死亡和存活之间的平衡。我们表明，敲除 HCT116 细胞中的 p53 会增加细胞质 HMGB1 的表达并诱导自噬。相反，在小鼠胚胎成纤维细胞中敲除 HMGB1 会增加 p53 细胞质定位并减少自噬。因此，p53 是 HMGB1/Beclin 1 复合物的负调节剂，并且 HMGB1 在 p53 减少的情况下促进自噬。HMGB1 介导的自噬促进了 p53 依赖性过程中肿瘤细胞的存活。HMGB1/p53 复合物影响相互结合伴侣的细胞质定位，从而调节随后的自噬和细胞凋亡水平。这些发现为细胞应激条件下 HMGB1 和 p53 在细胞凋亡和自噬的交叉调节中提供了一个新的联系，为它们在致癌作用中的相互作用提供了深入的了解。
