Abstract:CLOCK and BMAL1 are bHLH-PAS-containing transcription factors that bind to E-box elements and are indispensable for expression of core circadian clock components such as the Per and Cry genes. A key step in expression is the heterodimerization of CLOCK and BMAL1 and their accumulation in the nucleus with an approximately 24-h periodicity. We show here that nucleocytoplasmic shuttling of BMAL1 is essential for transactivation and for degradation of the CLOCK/BMAL1 heterodimer. Using serial deletions and point m… Show more
“…In this study, we demonstrate that CCA1 and LHY have similar expression patterns, bind to a similar region of the Lhcb1*3 promoter, colocalize in the nucleus, and that they can physically interact both in vitro and in plants. These findings are consistent with the evidence showing the involvement of dimerization between core oscillator components in the mammalian system (Kwon et al, 2006) and in Drosophila (Meyer et al, 2006), suggesting that homodimerization and heterodimerization might be conserved aspects in the regulation of eukaryotic circadian clocks.…”
The circadian clock is an endogenous mechanism that coordinates biological processes with daily and seasonal changes in the environment. Heterodimerization of central clock components is an important way of controlling clock function in several different circadian systems. CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) are Myb-related proteins that function in or close to the central oscillator in Arabidopsis (Arabidopsis thaliana). Single mutants of cca1 and lhy have a phenotype of short-period rhythms. cca1 lhy double mutants show an even shorter period phenotype than the cca1 single mutant, suggesting that CCA1 and LHY are only partially functionally redundant. To determine whether CCA1 and LHY act in parallel or synergistically in the circadian clock, we examined their expression in both light-grown and etiolated seedlings. We have shown that LHY and CCA1 bind to the same region of the promoter of a Light-harvesting chlorophyll a/b protein (Lhcb, also known as CAB). CCA1 and LHY can form homodimers, and they also colocalize in the nucleus and heterodimerize in vitro and in vivo. In Arabidopsis, CCA1 and LHY physically interact in a manner independent of photoperiod. Moreover, results from gel filtration chromatography indicate that CCA1 and LHY are present in the same large complex in plants. Taken together, these results imply that CCA1 and LHY function synergistically in regulating circadian rhythms of Arabidopsis.
“…In this study, we demonstrate that CCA1 and LHY have similar expression patterns, bind to a similar region of the Lhcb1*3 promoter, colocalize in the nucleus, and that they can physically interact both in vitro and in plants. These findings are consistent with the evidence showing the involvement of dimerization between core oscillator components in the mammalian system (Kwon et al, 2006) and in Drosophila (Meyer et al, 2006), suggesting that homodimerization and heterodimerization might be conserved aspects in the regulation of eukaryotic circadian clocks.…”
The circadian clock is an endogenous mechanism that coordinates biological processes with daily and seasonal changes in the environment. Heterodimerization of central clock components is an important way of controlling clock function in several different circadian systems. CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) are Myb-related proteins that function in or close to the central oscillator in Arabidopsis (Arabidopsis thaliana). Single mutants of cca1 and lhy have a phenotype of short-period rhythms. cca1 lhy double mutants show an even shorter period phenotype than the cca1 single mutant, suggesting that CCA1 and LHY are only partially functionally redundant. To determine whether CCA1 and LHY act in parallel or synergistically in the circadian clock, we examined their expression in both light-grown and etiolated seedlings. We have shown that LHY and CCA1 bind to the same region of the promoter of a Light-harvesting chlorophyll a/b protein (Lhcb, also known as CAB). CCA1 and LHY can form homodimers, and they also colocalize in the nucleus and heterodimerize in vitro and in vivo. In Arabidopsis, CCA1 and LHY physically interact in a manner independent of photoperiod. Moreover, results from gel filtration chromatography indicate that CCA1 and LHY are present in the same large complex in plants. Taken together, these results imply that CCA1 and LHY function synergistically in regulating circadian rhythms of Arabidopsis.
“…Next, we tested the role of the adrenal peripheral clock in producing the daily CS rhythm in vivo by ablating the molecular clockwork specifically in the adrenal CS-producing cells. We chose BMAL1 as a target for knockdown because our previous studies show that it plays the determining role in posttranslational regulation and function of the CLOCK:BMAL1 heterodimer (24,25) and, more importantly, CLOCK has an overlapping role with NPAS2, another member of core clock components (26). We generated a transgenic (TG) mouse line in which a part of the BMAL1 coding region was expressed in an antisense orientation under tissue-specific control by using the 1.3-kb ACTH receptor (MC2R) promoter (MC2R-AS-BMAL1; see Figs.…”
Section: Circadian Rhythms Of Cs Production and Adrenal Steroidogenicmentioning
Glucocorticoid (GC) is an adrenal steroid with diverse physiological effects. It undergoes a robust daily oscillation, which has been thought to be driven by the master circadian clock in the suprachiasmatic nucleus of the hypothalamus via the hypothalamuspituitary-adrenal axis. However, we show that the adrenal gland has its own clock and that the peripheral clockwork is tightly linked to steroidogenesis by the steroidogenic acute regulatory protein.Examination of mice with adrenal-specific knockdown of the canonical clock protein BMAL1 reveals that the adrenal clock machinery is required for circadian GC production. Furthermore, behavioral rhythmicity is drastically affected in these animals, together with altered expression of Period1, but not Period2, in several peripheral organs. We conclude that the adrenal peripheral clock plays an essential role in harmonizing the mammalian circadian timing system by generating a robust circadian GC rhythm.adrenal gland ͉ steroidogenic acute regulatory protein ͉ BMAL1
“…The mechanism of PER/CRYdependent repression is complex and is not yet well understood. It has been shown that CRYs regulate posttranslational modifications, nuclear/cytoplasmic distribution and stability of CLOCK and BMAL1 proteins as well as the interaction of the CLOCK/BMAL1 complex with chromatin modifying enzymes [19][20][21]. All these activities are likely to contribute to CRYdependent inhibition of CLOCK/BMAL1 functional activity.…”
Circadian clocks are molecular time-keeping systems that underlie daily fluctuations in multiple physiological and biochemical processes. It is well recognized now that dysfunctions of the circadian system (both genetically and environmentally induced) are associated with the development of various pathological conditions. Here we describe the application of high throughput screening approach designed to search for small molecules capable of pharmacological modulation of the molecular clock. We provide evidence for the feasibility and value of this approach for both scientific and therapeutic purposes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.