The PXDLS linear motif regulates circadian rhythmicity through protein–protein interactions

Shalev, Moran; Aviram, Rona; Adamovich, Yaarit; Kraut-Cohen, Judith; Shamia, Tal; Ben‐Dor, Shifra; Golik, Marina; Asher, Gad

doi:10.1093/nar/gku873

Cited by 12 publications

(13 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our studies indicate that the CBP KIX domain is important for regulation of gene transcription by the circadian transcription factors CLOCK and BMAL1 even though in vitro studies have suggested that CBP interactions with BMAL1 occurred in a region outside of the KIX domain in CBP [ 64 ]. We then investigated in vivo circadian rhythms in CBP KIX/KIX mice.…”

Section: Resultsmentioning

confidence: 99%

“…For phase resetting of the circadian clock, the interactions between CBP and BMAL1 at the Per1 promoter are thought to be primarily reliant upon calcium-dependent PKC signaling following resetting stimuli and not CREB [ 40 ]. CBP has been postulated to interact with BMAL1 through the PXDLS motif (Pro-X-Asp-Leu-Ser), a conserved motif in multiple circadian proteins and present in CBP [ 64 ]. Our in vivo studies differentiating the impact of KIX mutations on period length and phase resetting support the hypothesis that different signaling pathways trigger CBP involvement in these two functions.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The CBP KIX domain regulates long-term memory and circadian activity

et al. 2020

View full text Add to dashboard Cite

Background CREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding protein (CBP), a multi-domain protein that binds numerous transcription factors potentially affecting expression of thousands of genes. Identifying specific domain functions for multi-domain proteins is essential to understand processes such as cognitive function and circadian clocks. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBPKIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding. Results We found that CBPKIX/KIX mice were impaired in long-term memory, but not learning acquisition or short-term memory for the Morris water maze. Using an unbiased analysis of gene expression in the dorsal hippocampus after training in the Morris water maze or contextual fear conditioning, we discovered dysregulation of CREB, CLOCK, and BMAL1 target genes and downregulation of circadian genes in CBPKIX/KIX mice. Given our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity and phase resetting in CBPKIX/KIX mice. CBPKIX/KIX mice exhibited delayed activity peaks after light offset and longer free-running periods in constant dark. Interestingly, CBPKIX/KIX mice displayed phase delays and advances in response to photic stimulation comparable to wildtype littermates. Thus, this work delineates site-specific regulation of the circadian clock by a multi-domain protein. Conclusions These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms. Graphical abstract

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The CBP KIX domain regulates long-term memory and circadian activity

et al. 2020

View full text Add to dashboard Cite

show abstract

“…SDS/PAGE and immunoblot were performed according to standard procedures (51). Each time point included a mix of mitochondria isolated from three to four individual mice.…”

Section: Methodsmentioning

confidence: 99%

Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins

Neufeld-Cohen

Robles

Aviram

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

204

192

View full text Add to dashboard Cite

Mitochondria are major suppliers of cellular energy through nutrients oxidation. Little is known about the mechanisms that enable mitochondria to cope with changes in nutrient supply and energy demand that naturally occur throughout the day. To address this question, we applied MS-based quantitative proteomics on isolated mitochondria from mice killed throughout the day and identified extensive oscillations in the mitochondrial proteome. Remarkably, the majority of cycling mitochondrial proteins peaked during the early light phase. We found that rate-limiting mitochondrial enzymes that process lipids and carbohydrates accumulate in a diurnal manner and are dependent on the clock proteins PER1/2. In this conjuncture, we uncovered daily oscillations in mitochondrial respiration that peak during different times of the day in response to different nutrients. Notably, the diurnal regulation of mitochondrial respiration was blunted in mice lacking PER1/2 or on a high-fat diet. We propose that PERIOD proteins optimize mitochondrial metabolism to daily changes in energy supply/demand and thereby, serve as a rheostat for mitochondrial nutrient utilization.M itochondria serve as major suppliers of cellular energy through nutrient oxidation. One of the major challenges that mitochondria face is the adaptation to changes in nutrient supply and energy demand. An inability of mitochondria to deal with altered nutrient environment is associated with metabolic diseases, such as diabetes and obesity (1, 2).Mitochondria oxidize carbohydrates and lipids to generate ATP by a process known as oxidative phosphorylation. Pyruvate and fatty acids are transported from the cytoplasm into the mitochondrial matrix, where they are catabolized into acetyl CoA. Pyruvate is converted to acetyl CoA through the action of the pyruvate dehydrogenase complex (PDC), whereas fatty acids are oxidized through a cycle of reactions that trim two carbons at a time, generating one molecule of acetyl CoA in each cycle [i.e., fatty acid oxidation (FAO)]. The acetyl groups are then fed into the Krebs cycle for additional degradation, and the process culminates with the transfer of acetyl-derived high-energy electrons along the respiratory chain.Mounting evidence suggests that circadian clocks orchestrate our daily physiology and metabolism (3-6). The mammalian circadian timing system consists of a central pacemaker in the brain that is entrained by daily light-dark cycles and synchronizes subsidiary oscillators in virtually all cells of the body, in part by driving rhythmic feeding behavior. The core clock molecular circuitry relies on interlocked transcription-translation feedback loops that generate daily oscillations of gene expression in cultured cells and living animals (7). Many transcriptomes (8-12) and more recently, several proteomics (13-15) and metabolomics studies (16-21) highlighted the pervasive circadian control of metabolism.Rest-activity and feeding-fasting cycles that naturally occur throughout the day impose pronounced changes in nutrient s...

show abstract

“…Mouse liver protein nuclear extracts were prepared according to the NUN procedure as previously described (Shalev et al, 2014). Cultured fibroblasts were homogenized in RIPA buffer (150 mM NaCl, 1% NP-40, 0.5% Na-deoxycholate, 0.1% SDS, 50 mM Tris-Hcl [pH 8], 1 mM dithiothreitol) supplemented with protease inhibitors (1 mM N-(a-aminoethyl) benzene-sulfonyl fluoride, 40 mM bestatin, 15 mM E65, 20 mM leupeptin, 15 mM pepstatin; Sigma).…”

Section: Protein Extraction Gel Electrophoresis and Immunoblottingmentioning

confidence: 99%

Circadian Clock Control by Polyamine Levels through a Mechanism that Declines with Age

et al. 2015

Self Cite

View full text Add to dashboard Cite

Polyamines are essential polycations present in all living cells. Polyamine levels are maintained from the diet and de novo synthesis, and their decline with age is associated with various pathologies. Here we show that polyamine levels oscillate in a daily manner. Both clock- and feeding-dependent mechanisms regulate the daily accumulation of key enzymes in polyamine biosynthesis through rhythmic binding of BMAL1:CLOCK to conserved DNA elements. In turn, polyamines control the circadian period in cultured cells and animals by regulating the interaction between the core clock repressors PER2 and CRY1. Importantly, we found that the decline in polyamine levels with age in mice is associated with a longer circadian period that can be reversed upon polyamine supplementation in the diet. Our findings suggest a crosstalk between circadian clocks and polyamine biosynthesis and open new possibilities for nutritional interventions against the decay in clock's function with age.

show abstract

The PXDLS linear motif regulates circadian rhythmicity through protein–protein interactions

Cited by 12 publications

References 43 publications

The CBP KIX domain regulates long-term memory and circadian activity

The CBP KIX domain regulates long-term memory and circadian activity

Circadian control of oscillations in mitochondrial rate-limiting enzymes and nutrient utilization by PERIOD proteins

Circadian Clock Control by Polyamine Levels through a Mechanism that Declines with Age

Contact Info

Product

Resources

About