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'''''FBXL3''''' is a [[gene]] in humans and mice that encodes the F-box/LRR-repeat protein 3 (FBXL3).<ref | '''''FBXL3''''' is a [[gene]] in humans and mice that encodes the F-box/LRR-repeat protein 3 (FBXL3).<ref>GRCh38: Ensembl release 89: ENSG00000005812 - [[Ensembl genome database project|Ensembl]], May 2017</ref><ref>GRCm38: Ensembl release 89: ENSMUSG00000022124 - [[Ensembl genome database project|Ensembl]], May 2017</ref> | ||
FBXL3 is a member of the [[F-box protein]] family, which constitutes one of the four subunits in the [[SCF complex|SCF]] [[ubiquitin ligase]] complex.<ref | FBXL3 is a member of the [[F-box protein]] family, which constitutes one of the four subunits in the [[SCF complex|SCF]] [[ubiquitin ligase]] complex.<ref>''"Human PubMed Reference:".''</ref> | ||
The FBXL3 protein participates in the [[negative feedback]] loop responsible for generating molecular [[circadian rhythms]] in mammals by binding to the [[CRY1]] and [[CRY2]] proteins to facilitate their [[polyubiquitination]] by the SCF complex and their subsequent degradation by the [[proteasome]].<ref name=" | The FBXL3 protein participates in the [[negative feedback]] loop responsible for generating molecular [[circadian rhythms]] in mammals by binding to the [[CRY1]] and [[CRY2]] proteins to facilitate their [[polyubiquitination]] by the SCF complex and their subsequent degradation by the [[proteasome]].<ref name=":0">{{cite journal | vauthors = Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM, Godinho SI, Draetta GF, Pagano M | title = SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins | journal = Science | volume = 316 | issue = 5826 | pages = 900–4 | date = May 2007 | pmid = 17463251 | doi = 10.1126/science.1141194 }}</ref><ref name=":1">{{cite journal | vauthors = Siepka SM, Yoo SH, Park J, Lee C, Takahashi JS | title = Genetics and neurobiology of circadian clocks in mammals | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 72 | pages = 251–259 | pmid = 18419282 | doi = 10.1101/sqb.2007.72.052 | pmc = 3749845 }}</ref><ref name=":4">{{cite journal | vauthors = Godinho SI, Maywood ES, Shaw L, Tucci V, Barnard AR, Busino L, Pagano M, Kendall R, Quwailid MM, Romero MR, O'neill J, Chesham JE, Brooker D, Lalanne Z, Hastings MH, Nolan PM | title = The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period | journal = Science | volume = 316 | issue = 5826 | pages = 897–900 | date = May 2007 | pmid = 17463252 | doi = 10.1126/science.1141138 }}</ref> | ||
==Discovery== | ==Discovery== | ||
The ''Fbxl3'' gene function was independently identified in 2007 by three groups | The ''Fbxl3'' gene function was independently identified in 2007 by three groups lead by [https://med.nyu.edu/pathology/Pagano/The_Michele_Pagano_Laboratory.html Michele Pagano], [[Joseph S. Takahashi]], Dr. Patrick Nolan and Michael Hastings, respectively. Takahashi used [[forward genetics]] [[N-ethyl-N-nitrosourea]] (ENU) [[mutagenesis]] to screen for mice with varied circadian activity which led to the discovery of the ''Overtime'' (''Ovtm'') mutant of the ''Fbxl3'' gene.<ref name=":1" /> Nolan discovered the ''Fbxl3'' mutation ''After hours'' (''Afh'') by a forward screen assessing wheel activity behavior of mutagenized mice.<ref name=":4"/> The phenotypes identified in mice were mechanistically explained by Pagano who discovered that the FBXL3 protein is necessary for the reactivation of the [[CLOCK]] and BMAL1 protein [[heterodimer]] by inducing the degradation of CRY proteins.<ref name=":0" /> | ||
===''Overtime''=== | ===''Overtime''=== | ||
Mice with the homozygous mutation of ''Ovtm'', free run with an intrinsic period of 26 hours. ''Overtime'' is a loss of function mutation caused by a substitution of [[isoleucine]] to [[threonine]] in the region of FBXL3 that binds to CRY. In mice with this mutation, levels of the proteins [[PER1]] and [[PER2]] are decreased, while levels of CRY proteins do not differ from those of wild type mice. The stabilization of CRY protein levels leads to continued repression of ''Per1'' and ''Per2'' transcription and translation. <ref name=" | Mice with the homozygous mutation of ''Ovtm'', free run with an intrinsic period of 26 hours. ''Overtime'' is a loss of function mutation caused by a substitution of [[isoleucine]] to [[threonine]] in the region of FBXL3 that binds to CRY. In mice with this mutation, levels of the proteins [[PER1]] and [[PER2]] are decreased, while levels of CRY proteins do not differ from those of wild type mice. The stabilization of CRY protein levels leads to continued repression of ''Per1'' and ''Per2'' transcription and translation.<ref name=":1" /> | ||
===''After-hours''=== | ===''After-hours''=== | ||
The ''After-hours'' mutation is a substitution of [[cysteine]] to [[serine]] at position 358. Similar to ''Overtime'', the mutation occurs in the region where FBXL3 binds to CRY. Mice homozygous for the ''Afh'' mutation have a free running period of about 27 hours. The ''Afh'' mutation delays the rate of CRY protein degradation, therefore affecting the transcription of PER2 protein. <ref name=" | The ''After-hours'' mutation is a substitution of [[cysteine]] to [[serine]] at position 358. Similar to ''Overtime'', the mutation occurs in the region where FBXL3 binds to CRY. Mice homozygous for the ''Afh'' mutation have a free running period of about 27 hours. The ''Afh'' mutation delays the rate of CRY protein degradation, therefore affecting the transcription of PER2 protein.<ref name=":0" /><ref name=":4" /> | ||
===''Fbxl21''=== | ===''Fbxl21''=== | ||
The closest homologue to ''Fbxl3'' is ''Fbxl21'' as it also binds to the CRY1 and CRY2 proteins. Predominantly localized to the cytosol, ''Fbxl21'' | The closest homologue to ''Fbxl3'' is ''Fbxl21'' as it also binds to the CRY1 and CRY2 proteins. Predominantly localized to the cytosol, ''Fbxl21'' has been proposed to antagonize the action of ''Fbxl3'' through [[ubiquitination]] and stabilization of CRY proteins instead of leading it to degradation.<ref name=":2">{{cite journal | vauthors = Hirano A, Yumimoto K, Tsunematsu R, Matsumoto M, Oyama M, Kozuka-Hata H, Nakagawa T, Lanjakornsiripan D, Nakayama KI, Fukada Y | title = FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes | journal = Cell | volume = 152 | issue = 5 | pages = 1106–18 | date = February 2013 | pmid = 23452856 | doi = 10.1016/j.cell.2013.01.054 }}</ref> FBXL21 is expressed predominantly in the suprachiasmatic nucleus, which is the region in the brain that functions as the master pacemaker in mammals.<ref name="Dardente_2008">{{cite journal | vauthors = Dardente H, Mendoza J, Fustin JM, Challet E, Hazlerigg DG | title = Implication of the F-Box Protein FBXL21 in circadian pacemaker function in mammals | journal = PLOS One | volume = 3 | issue = 10 | pages = e3530 | date = 2008 | pmid = 18953409 | pmc = 2568807 | doi = 10.1371/journal.pone.0003530 }}</ref> | ||
== Characteristics == | == Characteristics == | ||
The human ''FBXL3'' gene is located on the long arm of [[chromosome 13]] at position 22.3.<ref name=" | The human ''FBXL3'' gene is located on the long arm of [[chromosome 13]] at position 22.3.<ref name=":2" /><ref name=":3">{{cite journal | vauthors = Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M, Pagano M | title = Identification of a family of human F-box proteins | journal = Current Biology | volume = 9 | issue = 20 | pages = 1177–9 | date = October 1999 | pmid = 10531035 | doi = 10.1016/S0960-9822(00)80020-2 }}</ref> The protein is composed of 428 amino acids and has a mass of 48,707 Daltons.<ref>{{cite journal | vauthors = Sato K, Yoshida K | title = Augmentation of the ubiquitin-mediated proteolytic system by F-box and additional motif-containing proteins (Review) | journal = International Journal of Oncology | volume = 37 | issue = 5 | pages = 1071–6 | date = November 2010 | pmid = 20878054 | doi = 10.3892/ijo_00000758 }}</ref> The FBXL3 protein contains an F-box domain, characterized by a 40 amino acid motif that mediates protein-protein interactions, and several tandem [[leucine-rich repeats]] used for substrate recognition. It has eight [[post-translational modification]] sites involving ubiquitination and four sites involving [[phosphorylation]]. The FBXL3 protein is predominantly localized to the nucleus. It is one of four subunits of a ubiquitin ligase complex called SKP1-CUL1-F-box-protein, which includes the proteins CUL1, SKP1, and RBX1.<ref name=":3" /><ref name="Entrez_Gene_FBXL3">{{cite web |url=https://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=full_report&list_uids=26224 | title = FBXL3 F-box and leucine rich repeat protein 3 [ Homo sapiens (human) ] |work = Entrez Gene | access-date = 27 April 2017 }}</ref> | ||
== Function == | == Function == | ||
The FBXL3 protein plays a role in the negative feedback loop of the mammalian molecular circadian rhythm. The PER and CRY proteins inhibit the transcription factors CLOCK and BMAL1. The degradation of PER and CRY prevent the inhibition of the CLOCK and BMAL1 protein heterodimer. In the nucleus, the FBXL3 protein targets CRY1 and CRY2 for polyubiquitination, which triggers the degradation of the proteins by the [[proteasome]].<ref name=" | The FBXL3 protein plays a role in the negative feedback loop of the mammalian molecular circadian rhythm. The PER and CRY proteins inhibit the transcription factors CLOCK and BMAL1. The degradation of PER and CRY prevent the inhibition of the CLOCK and BMAL1 protein heterodimer. In the nucleus, the FBXL3 protein targets CRY1 and CRY2 for polyubiquitination, which triggers the degradation of the proteins by the [[proteasome]].<ref name=":0" /> FBXL3 binds to CRY2 by occupying its [[flavin adenine dinucleotide]] (FAD) cofactor pocket with a [[C-terminal]] tail and buries the PER-binding interface on the CRY2 protein.<ref>{{cite journal | vauthors = Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH, Bush MF, Pagano M, Zheng N | title = SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket | journal = Nature | volume = 496 | issue = 7443 | pages = 64–8 | date = April 2013 | pmid = 23503662 | doi = 10.1038/nature11964 | pmc = 3618506 }}</ref> | ||
The FBXL3 protein is also involved in a related feedback loop that regulates the transcription of the ''Bmal1'' gene. ''Bmal1'' expression is regulated by the binding of [[Rev-ErbA alpha|REV-ERBα]] and [[RAR-related orphan receptor alpha|RORα]] proteins to retinoic acid-related orphan receptor response elements (ROREs) in the ''Bmal1'' [[promoter (genetics)|promoter]] region. The binding of the REV-ERBα protein to the promoter represses expression, while RORα binding activates expression.<ref name="Ko2006" /> FBXL3 decreases the repression of ''Bmal1'' transcription by inactivating the REV-ERBα and [[HDAC3]] repressor complex.<ref name="ShiXing2013">{{cite journal | vauthors = Shi G, Xing L, Liu Z, Qu Z, Wu X, Dong Z, Wang X, Gao X, Huang M, Yan J, Yang L, Liu Y, Ptácek LJ, Xu Y | title = Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 12 | pages = 4750–5 | date = March 2013 | pmid = 23471982 | doi = 10.1073/pnas.1302560110 }}</ref> | The FBXL3 protein is also involved in a related feedback loop that regulates the transcription of the ''Bmal1'' gene. ''Bmal1'' expression is regulated by the binding of [[Rev-ErbA alpha|REV-ERBα]] and [[RAR-related orphan receptor alpha|RORα]] proteins to retinoic acid-related orphan receptor response elements (ROREs) in the ''Bmal1'' [[promoter (genetics)|promoter]] region. The binding of the REV-ERBα protein to the promoter represses expression, while RORα binding activates expression.<ref name="Ko2006">{{cite journal | vauthors = Ko CH, Takahashi JS | title = Molecular components of the mammalian circadian clock | journal = Human Molecular Genetics | volume = 15 Spec No 2 | issue = Review Issue 2 | pages = R271-7 | date = October 2006 | pmid = 16987893 | doi = 10.1093/hmg/ddl207 | pmc = 3762864 }}</ref> FBXL3 decreases the repression of ''Bmal1'' transcription by inactivating the REV-ERBα and [[HDAC3]] repressor complex.<ref name="ShiXing2013">{{cite journal | vauthors = Shi G, Xing L, Liu Z, Qu Z, Wu X, Dong Z, Wang X, Gao X, Huang M, Yan J, Yang L, Liu Y, Ptácek LJ, Xu Y | title = Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 12 | pages = 4750–5 | date = March 2013 | pmid = 23471982 | pmc = 3606995 | doi = 10.1073/pnas.1302560110 }}</ref> | ||
The FBXL3 protein has also been found to cooperatively degrade [[c-MYC]] when bound to CRY2. The c-MYC protein is a [[transcription factor]] important in regulating [[cell proliferation]]. The CRY2 protein can function as a co-factor for the FBXL3 ligase complex and interacts with [[phosphorylated]] c-MYC. This interaction promotes the ubiquitination and degradation of the c-MYC protein. <ref name="HuberPapp2016">{{cite journal | vauthors = Huber AL, Papp SJ, Chan AB, Henriksson E, Jordan SD, Kriebs A, Nguyen M, Wallace M, Li Z, Metallo CM, Lamia KA | title = CRY2 and FBXL3 Cooperatively Degrade c-MYC | journal = Molecular Cell | volume = 64 | issue = 4 | pages = 774–789 | date = November 2016 | pmid = 27840026 | doi = 10.1016/j.molcel.2016.10.012 }}</ref> | The FBXL3 protein has also been found to cooperatively degrade [[c-MYC]] when bound to CRY2. The c-MYC protein is a [[transcription factor]] important in regulating [[cell proliferation]]. The CRY2 protein can function as a co-factor for the FBXL3 ligase complex and interacts with [[phosphorylated]] c-MYC. This interaction promotes the ubiquitination and degradation of the c-MYC protein.<ref name="HuberPapp2016">{{cite journal | vauthors = Huber AL, Papp SJ, Chan AB, Henriksson E, Jordan SD, Kriebs A, Nguyen M, Wallace M, Li Z, Metallo CM, Lamia KA | title = CRY2 and FBXL3 Cooperatively Degrade c-MYC | journal = Molecular Cell | volume = 64 | issue = 4 | pages = 774–789 | date = November 2016 | pmid = 27840026 | pmc = 5123859 | doi = 10.1016/j.molcel.2016.10.012 }}</ref> | ||
== Interactions == | == Interactions == | ||
FBXL3 has been shown to [[Protein-protein interaction|interact]] with: | FBXL3 has been shown to [[Protein-protein interaction|interact]] with: | ||
* [[SKP1A]]<ref name= | * [[SKP1A]]<ref name=":3"/> | ||
* [[CRY1]] <ref name="Ko2006" /> | |||
* [[CRY2]] <ref name="HuberPapp2016" /><ref name="XingBusino2013">{{cite journal | vauthors = Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH, Bush MF, Pagano M, Zheng N | title = SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket | journal = Nature | volume = 496 | issue = 7443 | pages = 64–8 | date = April 2013 | pmid = 23503662 | pmc = 3618506 | doi = 10.1038/nature11964 }}</ref> | |||
* [[Rev-ErbA alpha|REV-ERBα]] <ref name="ShiXing2013" /> | * [[Rev-ErbA alpha|REV-ERBα]] <ref name="ShiXing2013" /> | ||
* [[HDAC3]] <ref name="ShiXing2013" /> | * [[HDAC3]] <ref name="ShiXing2013" /> | ||
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== References == | == References == | ||
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FBXL3 is a gene in humans and mice that encodes the F-box/LRR-repeat protein 3 (FBXL3).[1][2] FBXL3 is a member of the F-box protein family, which constitutes one of the four subunits in the SCF ubiquitin ligase complex.[3]
The FBXL3 protein participates in the negative feedback loop responsible for generating molecular circadian rhythms in mammals by binding to the CRY1 and CRY2 proteins to facilitate their polyubiquitination by the SCF complex and their subsequent degradation by the proteasome.[4][5][6]
Discovery
The Fbxl3 gene function was independently identified in 2007 by three groups lead by Michele Pagano, Joseph S. Takahashi, Dr. Patrick Nolan and Michael Hastings, respectively. Takahashi used forward genetics N-ethyl-N-nitrosourea (ENU) mutagenesis to screen for mice with varied circadian activity which led to the discovery of the Overtime (Ovtm) mutant of the Fbxl3 gene.[5] Nolan discovered the Fbxl3 mutation After hours (Afh) by a forward screen assessing wheel activity behavior of mutagenized mice.[6] The phenotypes identified in mice were mechanistically explained by Pagano who discovered that the FBXL3 protein is necessary for the reactivation of the CLOCK and BMAL1 protein heterodimer by inducing the degradation of CRY proteins.[4]
Overtime
Mice with the homozygous mutation of Ovtm, free run with an intrinsic period of 26 hours. Overtime is a loss of function mutation caused by a substitution of isoleucine to threonine in the region of FBXL3 that binds to CRY. In mice with this mutation, levels of the proteins PER1 and PER2 are decreased, while levels of CRY proteins do not differ from those of wild type mice. The stabilization of CRY protein levels leads to continued repression of Per1 and Per2 transcription and translation.[5]
After-hours
The After-hours mutation is a substitution of cysteine to serine at position 358. Similar to Overtime, the mutation occurs in the region where FBXL3 binds to CRY. Mice homozygous for the Afh mutation have a free running period of about 27 hours. The Afh mutation delays the rate of CRY protein degradation, therefore affecting the transcription of PER2 protein.[4][6]
Fbxl21
The closest homologue to Fbxl3 is Fbxl21 as it also binds to the CRY1 and CRY2 proteins. Predominantly localized to the cytosol, Fbxl21 has been proposed to antagonize the action of Fbxl3 through ubiquitination and stabilization of CRY proteins instead of leading it to degradation.[7] FBXL21 is expressed predominantly in the suprachiasmatic nucleus, which is the region in the brain that functions as the master pacemaker in mammals.[8]
Characteristics
The human FBXL3 gene is located on the long arm of chromosome 13 at position 22.3.[7][9] The protein is composed of 428 amino acids and has a mass of 48,707 Daltons.[10] The FBXL3 protein contains an F-box domain, characterized by a 40 amino acid motif that mediates protein-protein interactions, and several tandem leucine-rich repeats used for substrate recognition. It has eight post-translational modification sites involving ubiquitination and four sites involving phosphorylation. The FBXL3 protein is predominantly localized to the nucleus. It is one of four subunits of a ubiquitin ligase complex called SKP1-CUL1-F-box-protein, which includes the proteins CUL1, SKP1, and RBX1.[9][11]
Function
The FBXL3 protein plays a role in the negative feedback loop of the mammalian molecular circadian rhythm. The PER and CRY proteins inhibit the transcription factors CLOCK and BMAL1. The degradation of PER and CRY prevent the inhibition of the CLOCK and BMAL1 protein heterodimer. In the nucleus, the FBXL3 protein targets CRY1 and CRY2 for polyubiquitination, which triggers the degradation of the proteins by the proteasome.[4] FBXL3 binds to CRY2 by occupying its flavin adenine dinucleotide (FAD) cofactor pocket with a C-terminal tail and buries the PER-binding interface on the CRY2 protein.[12]
The FBXL3 protein is also involved in a related feedback loop that regulates the transcription of the Bmal1 gene. Bmal1 expression is regulated by the binding of REV-ERBα and RORα proteins to retinoic acid-related orphan receptor response elements (ROREs) in the Bmal1 promoter region. The binding of the REV-ERBα protein to the promoter represses expression, while RORα binding activates expression.[13] FBXL3 decreases the repression of Bmal1 transcription by inactivating the REV-ERBα and HDAC3 repressor complex.[14]
The FBXL3 protein has also been found to cooperatively degrade c-MYC when bound to CRY2. The c-MYC protein is a transcription factor important in regulating cell proliferation. The CRY2 protein can function as a co-factor for the FBXL3 ligase complex and interacts with phosphorylated c-MYC. This interaction promotes the ubiquitination and degradation of the c-MYC protein.[15]
Interactions
FBXL3 has been shown to interact with:
References
- ↑ GRCh38: Ensembl release 89: ENSG00000005812 - Ensembl, May 2017
- ↑ GRCm38: Ensembl release 89: ENSMUSG00000022124 - Ensembl, May 2017
- ↑ "Human PubMed Reference:".
- ↑ 4.0 4.1 4.2 4.3 Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM, Godinho SI, Draetta GF, Pagano M (May 2007). "SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins". Science. 316 (5826): 900–4. doi:10.1126/science.1141194. PMID 17463251.
- ↑ 5.0 5.1 5.2 Siepka SM, Yoo SH, Park J, Lee C, Takahashi JS. "Genetics and neurobiology of circadian clocks in mammals". Cold Spring Harbor Symposia on Quantitative Biology. 72: 251–259. doi:10.1101/sqb.2007.72.052. PMC 3749845. PMID 18419282.
- ↑ 6.0 6.1 6.2 Godinho SI, Maywood ES, Shaw L, Tucci V, Barnard AR, Busino L, Pagano M, Kendall R, Quwailid MM, Romero MR, O'neill J, Chesham JE, Brooker D, Lalanne Z, Hastings MH, Nolan PM (May 2007). "The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period". Science. 316 (5826): 897–900. doi:10.1126/science.1141138. PMID 17463252.
- ↑ 7.0 7.1 Hirano A, Yumimoto K, Tsunematsu R, Matsumoto M, Oyama M, Kozuka-Hata H, Nakagawa T, Lanjakornsiripan D, Nakayama KI, Fukada Y (February 2013). "FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes". Cell. 152 (5): 1106–18. doi:10.1016/j.cell.2013.01.054. PMID 23452856.
- ↑ Dardente H, Mendoza J, Fustin JM, Challet E, Hazlerigg DG (2008). "Implication of the F-Box Protein FBXL21 in circadian pacemaker function in mammals". PLOS One. 3 (10): e3530. doi:10.1371/journal.pone.0003530. PMC 2568807. PMID 18953409.
- ↑ 9.0 9.1 9.2 Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M, Pagano M (October 1999). "Identification of a family of human F-box proteins". Current Biology. 9 (20): 1177–9. doi:10.1016/S0960-9822(00)80020-2. PMID 10531035.
- ↑ Sato K, Yoshida K (November 2010). "Augmentation of the ubiquitin-mediated proteolytic system by F-box and additional motif-containing proteins (Review)". International Journal of Oncology. 37 (5): 1071–6. doi:10.3892/ijo_00000758. PMID 20878054.
- ↑ "FBXL3 F-box and leucine rich repeat protein 3 [ Homo sapiens (human) ]". Entrez Gene. Retrieved 27 April 2017.
- ↑ Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH, Bush MF, Pagano M, Zheng N (April 2013). "SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket". Nature. 496 (7443): 64–8. doi:10.1038/nature11964. PMC 3618506. PMID 23503662.
- ↑ 13.0 13.1 Ko CH, Takahashi JS (October 2006). "Molecular components of the mammalian circadian clock". Human Molecular Genetics. 15 Spec No 2 (Review Issue 2): R271–7. doi:10.1093/hmg/ddl207. PMC 3762864. PMID 16987893.
- ↑ 14.0 14.1 14.2 Shi G, Xing L, Liu Z, Qu Z, Wu X, Dong Z, Wang X, Gao X, Huang M, Yan J, Yang L, Liu Y, Ptácek LJ, Xu Y (March 2013). "Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock". Proceedings of the National Academy of Sciences of the United States of America. 110 (12): 4750–5. doi:10.1073/pnas.1302560110. PMC 3606995. PMID 23471982.
- ↑ 15.0 15.1 15.2 Huber AL, Papp SJ, Chan AB, Henriksson E, Jordan SD, Kriebs A, Nguyen M, Wallace M, Li Z, Metallo CM, Lamia KA (November 2016). "CRY2 and FBXL3 Cooperatively Degrade c-MYC". Molecular Cell. 64 (4): 774–789. doi:10.1016/j.molcel.2016.10.012. PMC 5123859. PMID 27840026.
- ↑ Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH, Bush MF, Pagano M, Zheng N (April 2013). "SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket". Nature. 496 (7443): 64–8. doi:10.1038/nature11964. PMC 3618506. PMID 23503662.