DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erba.

CHINI, Claudia C. S.; ESCANDE, Carlos; NIN, Veronica; CHINI, Eduardo N.

The nuclear receptor Rev-erba has been implicated as a major regulator of the circadian clock and integrates circadian rhythm and metabolism. Rev-erba controls circadian oscillations of several clock genes and Rev-erba protein degradation is important for maintenance of the circadian oscillations and also for adipocyte differentiation. Elucidating the mechanisms that regulate Rev-erba 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 Reverba. Rev-erba and DBC1 interact in cells and in vivo, and DBC1 modulates the Rev-erba repressor function. Depletion of DBC1 by siRNA (small interfering RNA) in cells or in DBC1-KO (knockout) mice produced a marked decrease in Reverba protein levels, but not in mRNA levels. In contrast, DBC1 overexpression significantly enhanced Rev-erba protein stability by preventing its ubiquitination and degradation. The regulation of Rev-erba protein levels and function byDBC1 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-erba and BMAL1. In summary, our data identify DBC1 as an important regulator of the circadian receptor Rev-erba and proposes that Rev-erba could be involved in mediating some of the physiological effects of DBC1

NUCLEAR receptors (Biochemistry); CIRCADIAN rhythms; BIODEGRADATION; PROTEOLYSIS; UBIQUITINATION; GENETIC regulation

Biochemical Journal, 2013, Vol 451, Issue 3, p453

0264-6021

Academic Journal

10.1042/BJ20121085