Rev-erbα protein levels decrease significantly upon depletion.
Rev-erbα is a key regulator of the circadian clock and metabolism.
DBC1 interacts with Rev-erbα and regulates its repressor function.
Depletion of DBC1 results in reduced Rev-erbα protein levels without affecting mRNA levels.
Overexpression of DBC1 enhances Rev-erbα protein stability by inhibiting its degradation.
Loss of DBC1 leads to a marked decrease in circadian oscillations of Rev-erbα and BMAL1.
Simplified
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 (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.
Key numbers
significantly lower levels
Decrease in Rev-erbα Protein Levels
Observed in NIH 3T3 cells treated with siRNA.
1.5 h
Increase in Rev-erbα Half-Life
Half-life increased from approximately 30 min to 1.5 h with overexpression.
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