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Implication of the F-Box Protein FBXL21 in Circadian Pacemaker Function in Mammals

In mammals, the circadian clock relies on interlocked feedback loops involving clock genes and their protein products. Post-translational modifications control intracellular trafficking, functionality and degradation of clock proteins and are keys to the functioning of the clock as recently exemplif...

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Autores principales: Dardente, Hugues, Mendoza, Jorge, Fustin, Jean-Michel, Challet, Etienne, Hazlerigg, David G.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2568807/
https://www.ncbi.nlm.nih.gov/pubmed/18953409
http://dx.doi.org/10.1371/journal.pone.0003530
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author Dardente, Hugues
Mendoza, Jorge
Fustin, Jean-Michel
Challet, Etienne
Hazlerigg, David G.
author_facet Dardente, Hugues
Mendoza, Jorge
Fustin, Jean-Michel
Challet, Etienne
Hazlerigg, David G.
author_sort Dardente, Hugues
collection PubMed
description In mammals, the circadian clock relies on interlocked feedback loops involving clock genes and their protein products. Post-translational modifications control intracellular trafficking, functionality and degradation of clock proteins and are keys to the functioning of the clock as recently exemplified for the F-Box protein Fbxl3. The SCF(Fbxl3) complex directs degradation of CRY1/2 proteins and Fbxl3 murine mutants have a slower clock. To assess whether the role of Fbxl3 is phylogenetically conserved, we investigated its function in the sheep, a diurnal ungulate. Our data show that Fbxl3 function is conserved and further reveal that its closest homologue, the F-Box protein Fbxl21, also binds to CRY1 which impairs its repressive action towards the transcriptional activators CLOCK/BMAL1. However, while Fbxl3 appears to be ubiquitously expressed, Fbxl21 expression is tissue-specific. Furthermore, and in sharp contrast with Fbxl3, Fbxl21 is highly expressed within the suprachiasmatic nuclei, site of the master clock, where it displays marked circadian oscillations apparently driven by members of the PAR-bZIP family. Finally, for both Fbxl3 and Fbxl21 we identified and functionally characterized novel splice-variants, which might reduce CRY1 proteasomal degradation dependent on cell context. Altogether, these data establish Fbxl21 as a novel circadian clock-controlled gene that plays a specific role within the mammalian circadian pacemaker.
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spelling pubmed-25688072008-10-27 Implication of the F-Box Protein FBXL21 in Circadian Pacemaker Function in Mammals Dardente, Hugues Mendoza, Jorge Fustin, Jean-Michel Challet, Etienne Hazlerigg, David G. PLoS One Research Article In mammals, the circadian clock relies on interlocked feedback loops involving clock genes and their protein products. Post-translational modifications control intracellular trafficking, functionality and degradation of clock proteins and are keys to the functioning of the clock as recently exemplified for the F-Box protein Fbxl3. The SCF(Fbxl3) complex directs degradation of CRY1/2 proteins and Fbxl3 murine mutants have a slower clock. To assess whether the role of Fbxl3 is phylogenetically conserved, we investigated its function in the sheep, a diurnal ungulate. Our data show that Fbxl3 function is conserved and further reveal that its closest homologue, the F-Box protein Fbxl21, also binds to CRY1 which impairs its repressive action towards the transcriptional activators CLOCK/BMAL1. However, while Fbxl3 appears to be ubiquitously expressed, Fbxl21 expression is tissue-specific. Furthermore, and in sharp contrast with Fbxl3, Fbxl21 is highly expressed within the suprachiasmatic nuclei, site of the master clock, where it displays marked circadian oscillations apparently driven by members of the PAR-bZIP family. Finally, for both Fbxl3 and Fbxl21 we identified and functionally characterized novel splice-variants, which might reduce CRY1 proteasomal degradation dependent on cell context. Altogether, these data establish Fbxl21 as a novel circadian clock-controlled gene that plays a specific role within the mammalian circadian pacemaker. Public Library of Science 2008-10-27 /pmc/articles/PMC2568807/ /pubmed/18953409 http://dx.doi.org/10.1371/journal.pone.0003530 Text en Dardente et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Dardente, Hugues
Mendoza, Jorge
Fustin, Jean-Michel
Challet, Etienne
Hazlerigg, David G.
Implication of the F-Box Protein FBXL21 in Circadian Pacemaker Function in Mammals
title Implication of the F-Box Protein FBXL21 in Circadian Pacemaker Function in Mammals
title_full Implication of the F-Box Protein FBXL21 in Circadian Pacemaker Function in Mammals
title_fullStr Implication of the F-Box Protein FBXL21 in Circadian Pacemaker Function in Mammals
title_full_unstemmed Implication of the F-Box Protein FBXL21 in Circadian Pacemaker Function in Mammals
title_short Implication of the F-Box Protein FBXL21 in Circadian Pacemaker Function in Mammals
title_sort implication of the f-box protein fbxl21 in circadian pacemaker function in mammals
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2568807/
https://www.ncbi.nlm.nih.gov/pubmed/18953409
http://dx.doi.org/10.1371/journal.pone.0003530
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