DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbα.
DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbα.
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DOI：
10.1042/bj20121085
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发表时间：
2013-05-01
期刊：
影响因子：
--
通讯作者：
Chini EN
中科院分区：
文献类型：
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作者：
Chini CC;Escande C;Nin V;Chini EN
细胞核受体Rev-erbα是生物钟的主要调节因子，整合了生物钟和代谢。Rev-erbα控制着几个时钟基因的昼夜节律振荡，Rev-erbα蛋白降解对于维持昼夜节律振荡以及脂肪细胞分化都很重要。阐明调节Rev-erbα稳定性的机制对于我们理解这些过程至关重要。在本文中，我们报告了蛋白质DBC 1（乳腺癌1中的转录因子）是Rev-erbα的一种新的调节因子。Rev-erbα和DBC 1在细胞和体内相互作用，并且DBC 1调节Rev-erbα阻遏物功能。在细胞或DBC 1-KO（敲除）小鼠中通过siRNA（小干扰RNA）消耗DBC 1，导致Rev-erbα蛋白水平显著降低，但mRNA水平未降低。相反，DBC 1过表达通过阻止其泛素化和降解显著增强Rev-erbα蛋白的稳定性。DBC 1对Rev-erbα蛋白水平和功能的调节依赖于DBC 1的N端和C端结构域。更重要的是，在耗尽DBC 1的细胞中，Rev-erbα和BMAL 1的昼夜节律振荡急剧减少。总之，我们的数据确定了DBC 1作为昼夜节律受体Rev-erbα的重要调节剂，并提出Rev-erbα可能参与介导DBC 1的一些生理效应。
The nuclear receptor Rev-erbα has been implicated as a major regulator of the circadian clock and integrates circadian rhythm and metabolism. Rev-erbα controls circadian oscillations of several clock genes and Rev-erbα protein degradation is important for maintenance of the circadian oscillations and also for adipocyte differentiation. Elucidating the mechanisms that regulate Rev-erbα stability is essential for our understanding of these processes. In the present paper, we report that the protein DBC1 (Deleted in Breast Cancer 1) is a novel regulator of Rev-erbα. Rev-erbα and DBC1 interact in cells and in vivo, and DBC1 modulates the Rev-erbα repressor function. Depletion of DBC1 by siRNA (small interfering RNA) in cells or in DBC1-KO (knockout) mice produced a marked decrease in Rev-erbα protein levels, but not in mRNA levels. In contrast, DBC1 overexpression significantly enhanced Rev-erbα protein stability by preventing its ubiquitination and degradation. The regulation of Rev-erbα protein levels and function by DBC1 depends on both the N-terminal and C-terminal domains of DBC1. More importantly, in cells depleted of DBC1, there was a dramatic decrease in circadian oscillations of both Rev-erbα and BMAL1. In summary, our data identify DBC1 as an important regulator of the circadian receptor Rev-erbα and proposes that Rev-erbα could be involved in mediating some of the physiological effects of DBC1.