Nuclear envelope protein MAN1 regulates clock through BMAL1.
Bottom Line: Our knowledge of these components and pathways is far from exhaustive.In recent decades, the nuclear envelope has emerged as a global gene regulatory machine, although its role in circadian regulation has not been explored.Our results establish a novel connection between the nuclear periphery and circadian rhythmicity, therefore bridging two global regulatory systems that modulate all aspects of bodily functions.
Affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.Show MeSH
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Mentions: Previously, MAN1 has been shown to exert antagonistic regulatory functions on signal transduction through its binding to R-SMADs (Osada et al., 2003; Raju et al., 2003; Hellemans et al., 2004; Lin et al., 2005; Pan et al., 2005; Cohen et al., 2007) and two types of R-SMADs are found in mammals: TGFβ-responsive (SMAD2 and SMAD3) and BMP-responsive (SMAD1, SMAD5, and SMAD8). To determine whether R-SMADs have an effect on BMAL1 transcription, we first expressed R-SMADs individually in HEK293 cells transfected with BMAL1-Luc to determine which R-SMAD/s is/are involved in regulating BMAL1 transcription. Expressing SMAD1, SMAD5, SMAD8, and SMAD3 had no significant effect on BMAL1 transcription but SMAD2 showed significant enhancing effect, suggesting a possible regulatory function by SMAD2 in BMAL1 regulation (Figure 7A). The enhancing action of SMAD2 was then examined together with MAN1 to determine whether there is interplay between MAN1 and SMAD2 on BMAL1 promoter activity. Intriguingly, MAN1 further augmented the enhancing effect of SMAD2 on BMAL1 in an additive manner, indicating that the positive regulatory function of MAN1 and SMAD2 on BMAL1 might be independent of each other (Figure 7B).10.7554/eLife.02981.017Figure 7.MAN1 and SMAD2 enhance BMAL1 transcription.
Affiliation: Department of Neurology, University of California, San Francisco, San Francisco, United States.