Deleted in Breast Cancer-1 (DBC1) modulates the stability and function of the nuclear receptor Rev-erb{alpha}

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 regulates Rev-erbα stability is essential for our understanding of these processes. Here we report that the protein Deleted in Breast Cancer 1 (DBC1) 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 in cells or in DBC1 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 identifies 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.

Source: BJ Cell - February 12, 2013 Category: Biochemistry Authors: C CS Chini, C Escande, V Nin, E N Chini Tags: BJ Cell Source Type: research