Abstract
Circadian clocks coordinate the timing of important biological processes. Interconnected transcriptional and post-translational feedback loops based on a set of clock genes generate and maintain these rhythms with a period of about 24 hours. Many clock proteins undergo circadian cycles of post-translational modifications. Among these modifications, protein phosphorylation plays an important role in regulating activity, stability and intracellular localization of clock components. Several protein kinases were characterized as regulators of the circadian clock. However, the function of protein phosphatases, which balance phosphorylation events, in the mammalian clock mechanism is less well understood. Here, we identify protein phosphatase 1 (PP1) as regulator of period and light-induced resetting of the mammalian circadian clock. Down-regulation of PP1 activity in cells by RNA interference and in vivo by expression of a specific inhibitor in the brain of mice tended to lengthen circadian period. Moreover, reduction of PP1 activity in the brain altered light-mediated clock resetting behavior in mice, enhancing the phase shifts in either direction. At the molecular level, diminished PP1 activity increased nuclear accumulation of the clock component PER2 in neurons. Hence, PP1, may reduce PER2 phosphorylation thereby influencing nuclear localization of this protein. This may at least partially influence period and phase shifting properties of the mammalian circadian clock.
Highlights
Many behavioral, physiological and metabolic functions are temporally organized and show daily rhythms, even in the absence of external timing cues
To get insights in the function of phosphatase 1 (PP1) in the mammalian clock mechanism, we reduced the expression of various catalytic subunits of PP1 in human osteosarcoma U-2 OS cells by RNA interference
The expression of PPP1CA, PPP1CB or PPP1CC was reduced by lentiviral infection of U-2 OS reporter cells with RNAi constructs specific for the respective subunits with more than 75% knock-down efficiency at the mRNA level (Figure S1A)
Summary
Physiological and metabolic functions are temporally organized and show daily rhythms, even in the absence of external timing cues. Temporal coordination of biological processes separates biochemically incompatible reactions, optimizes an organism’s energy expenditure, and may improve overall performance. Circadian ( = ‘about a day’) oscillations are based on an autonomous clock mechanism that is phase-controlled and synchronized with the environment by external time cues, such as light or food. The central circadian pacemaker is located in the suprachiasmatic nucleus (SCN), a structure in the ventral hypothalamus. Light, which serves as strong timing cue or Zeitgeber, directly impinges on the cellular oscillators of SCN neurons via the retinohypothalamic tract. The SCN can integrate this temporal information and coordinate all body clocks to establish and maintain adequate phase-relationships between different tissue clocks (reviewed in [1])
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