Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):12036-41. doi: 10.1073/pnas.1108125108. Epub 2011 Jun 20.
In mice and humans the circadian rhythm of many biochemical reactions, physiology, and behavior is generated by a transcriptional-translation feedback loop (TTFL) made up of the so-called core clock genes/proteins. The circadian system interfaces with most signaling pathways including those involved in cell proliferation and inflammation. Cryptochrome (CRY) is a core clock protein that plays an essential role in the repressive arm of the TTFL. It was recently reported that mutation of CRY in p53-null mice delayed the onset of cancer. It was therefore suggested that CRY mutation may activate p53-independent apoptosis pathways, which eliminate premalignant and malignant cells and thus delay overt tumor formation. Here we show that CRY mutation sensitizes p53 mutant and oncogenically transformed cells to tumor necrosis factor α (TNFα)-initiated apoptosis by interfacing with the NF-κB signaling pathway through the GSK3β kinase and alleviating prosurvival NF-κB signaling. These findings provide a mechanistic foundation for the delayed onset of tumorigenesis in clock-disrupted p53 mutant mice and suggest unique therapeutic strategies for treating cancers associated with p53 mutation.
在老鼠和人类中，许多生化反应、生理学和行为的昼夜节律是由一个转录-翻译反馈环（TTFL）产生的，该环由所谓的核心时钟基因/蛋白组成。昼夜节律系统与大多数信号通路相互作用，包括那些涉及细胞增殖和炎症的信号通路。CRY 是核心时钟蛋白，在 TTFL 的抑制臂中发挥着重要作用。最近有报道称，CRY 在 p53 缺失的小鼠中的突变延迟了癌症的发生。因此，有人认为 CRY 突变可能会激活 p53 非依赖性细胞凋亡途径，从而消除癌前和恶性细胞，从而延迟明显的肿瘤形成。在这里，我们通过 GSK3β 激酶与 NF-κB 信号通路相互作用并减轻促生存 NF-κB 信号，表明 CRY 突变通过与 NF-κB 信号通路相互作用，使 p53 突变和致癌转化细胞对肿瘤坏死因子 α（TNFα）引发的细胞凋亡敏感。这些发现为时钟中断的 p53 突变小鼠中肿瘤发生延迟提供了机制基础，并为治疗与 p53 突变相关的癌症提供了独特的治疗策略。
