Affinage

PER2

Period circadian protein homolog 2 · UniProt O15055

Length
1255 aa
Mass
136.6 kDa
Annotated
2026-04-29
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PER2 is a core component of the mammalian circadian transcription–translation feedback loop that represses CLOCK–BMAL1-driven transcription while simultaneously activating Bmal1 expression, thereby sustaining oscillatory gene expression across tissues. PER2 protein abundance is governed by a CK1δ/ε-dependent phosphoswitch: priming phosphorylation at S662 stabilizes PER2 and lengthens circadian period, whereas phosphorylation at S478 creates a β-TrCP phosphodegron that targets PER2 for ubiquitin–proteasome degradation — a balance modulated by PP1 dephosphorylation, SIRT6-mediated deacetylation, and a 5′ uORF that confers temperature-dependent translational control (PMID:17218255, PMID:32354999, PMID:15767683, PMID:16813562, PMID:30782483, PMID:36882059). Nuclear entry of PER2 requires CRY proteins and is facilitated by PML, and once nuclear, PER2 acts as a transcriptional co-factor — assembling the CREB/CRTC1/CBP complex at the Per1 CRE, enhancing HIF-1α recruitment to hypoxia-response elements, and displacing CLOCK–BMAL1 from target promoters such as PCNA (PMID:35046033, PMID:22274616, PMID:34741086, PMID:28963769, PMID:31728273). Beyond timekeeping, PER2 links the clock to metabolism, vascular function, and tumor suppression by regulating glutamate transporter expression, estrogen receptor α stability, IKK/NF-κB signaling via competitive HSP90 binding, and AKT pathway activity (PMID:15608650, PMID:17599055, PMID:37914384, PMID:22905719).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2002 Medium

    Establishing PER2 as part of an interlocked feedback loop — not merely a repressor — resolved how Bmal1 transcription is sustained, showing PER2 positively drives Bmal1 expression while CLOCK–BMAL1 represses it.

    Evidence Promoter-reporter luciferase assays measuring Bmal1 transcription in the presence of PER2, CRY1, and CRY2

    PMID:11798163

    Open questions at the time
    • Mechanism by which PER2 activates Bmal1 transcription (direct DNA binding vs. cofactor role) was not resolved
    • In vivo validation not provided
  2. 2004 High

    Demonstrating that Per2 mutation reduces astrocytic glutamate transporter Eaat1 expression and increases alcohol intake established PER2 as a regulator of glutamatergic signaling and addiction-relevant behavior.

    Evidence Per2(Brdm1) mutant mice with glutamate uptake assays and pharmacological rescue by acamprosate

    PMID:15608650

    Open questions at the time
    • Whether PER2 directly regulates Eaat1 transcription or acts indirectly was not determined
    • Mechanism linking PAS domain deletion to transporter downregulation unknown
  3. 2005 High

    Identifying the CKIε→β-TrCP→proteasome degradation axis for PER2 defined the primary mechanism controlling PER2 protein clearance and linked kinase activity to circadian period length.

    Evidence Dominant-negative β-TrCP, CKIε inhibition, proteasome inhibitors, and period measurement in Rat-1 cells

    PMID:15767683

    Open questions at the time
    • Specific phosphodegron residue not yet mapped
    • Relative contributions of CKIε vs. CKIδ to PER2 degradation in vivo unresolved
  4. 2006 High

    Showing that PP1 dephosphorylates CKI-phosphorylated PER2 to stabilize it established a kinase–phosphatase balance as the tuning mechanism for PER2 half-life and, by extension, circadian period.

    Evidence Co-IP of PER2 with PP1c in HEK-293 cells, mouse liver and brain; dominant-negative PP1c and inhibitor treatment accelerated PER2 degradation

    PMID:16813562

    Open questions at the time
    • Which PP1 regulatory subunit targets PP1 to PER2 was not identified
    • Whether PP1 acts on the stabilizing or degron phosphosites was unknown
  5. 2006 High

    Per2 mutant mice specifically lacking food-anticipatory activity revealed PER2 as an essential component of a food-entrainable oscillator distinct from the SCN master clock.

    Evidence Behavioral and molecular analysis of Per2 vs. Per1 mutant mice under restricted feeding

    PMID:17055980

    Open questions at the time
    • Anatomical locus of the food-entrainable oscillator not identified
    • Molecular mechanism by which PER2 contributes to food anticipation unclear
  6. 2007 High

    The FASPS S662G mutation in PER2 established the phosphoswitch model: CKIδ-mediated phosphorylation at S662 stabilizes PER2, and loss of this phosphorylation shortens period and causes familial advanced sleep phase syndrome in humans.

    Evidence Transgenic mice carrying human PER2 S662G, in vitro CKI phosphorylation, CKIδ dosage manipulation

    PMID:17218255

    Open questions at the time
    • How S662 phosphorylation mechanistically opposes degron-directed phosphorylation was not resolved
    • Structural basis of the phosphoswitch unknown
  7. 2007 Medium

    PER2 interaction with ERα and promotion of its degradation linked the circadian clock to estrogen signaling and breast cancer cell growth control.

    Evidence Co-IP of PER2–ERα, cycloheximide chase showing enhanced ERα degradation upon PER2 overexpression, growth inhibition and apoptosis in breast cancer cells

    PMID:17599055

    Open questions at the time
    • Whether PER2 recruits a specific E3 ligase to ERα was not determined
    • Single lab; not independently confirmed
  8. 2008 Medium

    Mapping PER2 physical interactions with BMAL1 and CLOCK via distinct domains (separate from CRY interaction domains) defined the architecture of the repressive complex on E-box elements.

    Evidence Mammalian two-hybrid and co-immunoprecipitation in HEK-293 cells

    PMID:18430226

    Open questions at the time
    • Stoichiometry and dynamics of the repressive complex in living cells unresolved
    • Single interaction methodology per pair
  9. 2010 Medium

    Demonstrating that PER2's PAS-B domain binds Fe(III) heme with 1:1 stoichiometry raised the possibility that PER2 senses metabolic/redox state, though functional consequences remained undefined.

    Evidence UV-Vis/CD spectroscopy, H454A mutagenesis, heme dissociation kinetics

    PMID:20887817

    Open questions at the time
    • Physiological role of heme binding in circadian regulation not established
    • In vivo relevance not tested
  10. 2012 High

    PML was identified as a nuclear import facilitator for PER2, linking PML body dynamics and SIRT1-mediated deacetylation of PML to circadian clock function in SCN neurons.

    Evidence Co-IP of PER2–PML, immunofluorescence in SCN, Pml−/− mice showing cytoplasmic PER2 redistribution, SIRT1 deacetylation of PML-K487

    PMID:22274616

    Open questions at the time
    • Whether PML acts as a direct nuclear import chaperone or indirectly through PML bodies was not distinguished
    • Relative contribution of PML vs. CRY-dependent import not quantified
  11. 2015 High

    Discovery that CLOCK–BMAL1 recruits the DDB1–CUL4 ubiquitin ligase to Per loci for rhythmic H2B monoubiquitination established a chromatin licensing step required for PER2 repressor complex recruitment to its own promoter.

    Evidence ChIP for H2Bub at Per genes, DDB1-CUL4a depletion, circadian reporter assays

    PMID:26323038

    Open questions at the time
    • Whether H2Bub is specifically required for PER2 or for the entire PER–CRY complex was not separated
    • Mechanism linking monoubiquitination to repressor docking not defined
  12. 2018 High

    Unified phosphoswitch model: CK1δ/ε serves as both priming kinase and downstream kinase on PER2, with CK1 splice variants and C-terminal tail modulating period sensitivity — resolving the paradox of how a single kinase family produces both stabilizing and destabilizing phosphorylation.

    Evidence Biochemical reconstitution of PER2 priming phosphorylation, mathematical modeling, CK1 splice-variant comparison

    PMID:29784789

    Open questions at the time
    • Full phosphosite map of endogenous PER2 in vivo not available
    • Role of other kinases (e.g., SIK3) in the phosphoswitch hierarchy unclear
  13. 2020 High

    The PER2-S478A knock-in mouse definitively identified S478 as the β-TrCP phosphodegron site in vivo, showing that blocking this single phosphorylation lengthens period, accumulates PER2 in both compartments, and disrupts temperature compensation.

    Evidence Knock-in mouse behavioral and molecular analysis, PER2::LUC fibroblast bioluminescence

    PMID:32354999

    Open questions at the time
    • Whether S478 phosphorylation is the sole degradation trigger or acts in concert with other degron sites
    • Structural basis of β-TrCP recognition of phospho-S478 peptide not determined
  14. 2020 High

    An anion binding site in CK1 controls activation loop conformation and determines which PER2 phosphosites (stabilizing vs. destabilizing) are preferentially targeted, providing a structural explanation for period-altering CK1 mutations across species.

    Evidence CK1 anion-binding-site mutagenesis, PER2 phosphorylation/stability measurements, cross-species comparison

    PMID:32043967

    Open questions at the time
    • Whether intracellular anion concentrations physiologically modulate this switch is unknown
    • No full crystal structure of CK1 bound to PER2 peptide
  15. 2021 Medium

    PER2 was shown to function as a transcriptional co-activator at the Per1 CRE by assembling the CREB/CRTC1/CBP complex, establishing that PER2 has a direct positive transcriptional role beyond its canonical repressor function.

    Evidence In vitro/in vivo CREB–CRTC1–CBP interaction assays, ChIP for H3 acetylation and RNA Pol II at Per1, light-stimulation in Per2−/− mice

    PMID:34741086

    Open questions at the time
    • Whether PER2 directly contacts CRE DNA or acts solely as a scaffold was not determined
    • Generalizability of co-activator role beyond Per1 not tested
  16. 2022 High

    CRY proteins were established as essential gatekeepers for PER2 nuclear entry in SCN neurons, with the CRY1 C-terminal tail required for relocalization — clarifying why CRY loss abolishes circadian rhythms even when PER2 is present.

    Evidence Confocal imaging and FRAP of PER2::Venus in Cry-null SCN, viral CRY1/CRY2 rescue, CRY1 tail deletion

    PMID:35046033

    Open questions at the time
    • Whether CRY masks a PER2 nuclear export signal or actively drives import is unknown
    • Relative contributions of CRY1 vs. CRY2 to PER2 import quantitatively unresolved
  17. 2023 High

    A 5′ uORF in Per2 mRNA was identified as a temperature-sensing translational switch controlled by PI3K, providing a mechanism for peripheral temperature entrainment independent of transcriptional regulation.

    Evidence uORF knock-in ablation mice, ribosome profiling, PI3K inhibition, temperature-cycle entrainment assays, wound-healing assay

    PMID:36882059

    Open questions at the time
    • Identity of the PI3K-regulated factor that modulates uORF bypass unknown
    • Whether this mechanism operates in SCN neurons not tested
  18. 2023 Medium

    PER2 was shown to suppress IKK/NF-κB signaling by competitively binding HSP90 through its PAS1 domain, promoting IKKα/β ubiquitination and reducing PD-L1 expression — extending PER2's tumor-suppressive functions to immune evasion.

    Evidence GST pull-down, co-IP, PAS1 deletion mutant, IKK ubiquitination assay, xenograft model in oral squamous cell carcinoma

    PMID:37914384

    Open questions at the time
    • Whether PER2–HSP90 interaction is circadian-gated not tested
    • Single cancer type; generalizability to other tissues unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the full structural basis of the CK1–PER2 phosphoswitch complex, how PER2 coordinates its dual repressor and co-activator transcriptional roles genome-wide, the identity of the food-entrainable oscillator circuit in which PER2 is essential, and whether heme binding to the PAS-B domain has a physiological signaling role.
  • No high-resolution structure of full-length PER2 in complex with CK1 or CRY
  • Genome-wide map of PER2 co-activator vs. repressor targets unavailable
  • Anatomical and molecular identity of PER2-dependent food-entrainable oscillator undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-9909396 Circadian clock 7 R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3
Partners
BMAL1BTRCCLOCKCRY1CRY2CSNK1DCSNK1EPML
Complex memberships
CLOCK–BMAL1–PER2 complexPER–CRY repressor complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 CKIε phosphorylates PER2, recruiting the ubiquitin E3 ligase adapter β-TrCP to a specific phosphodegron site, leading to PER2 ubiquitination and 26S proteasome-mediated degradation; CKIε inhibition slows PER2 degradation and lengthens circadian period in Rat-1 cells. Cell-based PER2 degradation assay, dominant-negative β-TrCP overexpression, proteasome inhibitors, CKIε inhibition, circadian period measurement in synchronized cells Molecular and cellular biology High 15767683
2007 Phosphorylation of PER2 at S662 by CKIδ stabilizes PER2 and increases Per2 transcription; the FASPS S662G mutation causes PER2 hypophosphorylation at this site and advanced sleep phase; CKIδ dosage modulates the S662 phenotype, demonstrating CKIδ regulates period through PER2 in vivo. Transgenic mice carrying human FASPS PER2 S662G mutation, in vitro CKI phosphorylation assay, behavioral circadian analysis, CKIδ dosage manipulation Cell High 17218255
2008 β-TrCP2 (as well as β-TrCP1) directly targets PER2 for degradation via a specific binding site (m2) on PER2; siRNA-mediated knockdown of β-TrCP1 and/or β-TrCP2 attenuates circadian oscillations in NIH3T3 cells. In vitro ubiquitin ligase assay, Luciferase-PER2 fusion stability assay, siRNA knockdown, real-time circadian reporter assay Journal of biochemistry High 18782782
2006 Protein phosphatase 1 (PP1) dephosphorylates CKI-phosphorylated PER2, stabilizing it against ubiquitin-proteasome degradation; PER2 co-immunoprecipitates with PP1c in HEK-293 cells, mouse liver, and mouse brain; dominant-negative PP1c or PP1 inhibitors accelerate PER2 degradation and shorten PER2 half-life. Co-immunoprecipitation, Xenopus egg extract degradation assay, dominant-negative PP1c overexpression, PP1 inhibitor treatment, pulse-chase half-life measurement The Biochemical journal High 16813562
2018 CK1δ/ε (including the CK1δ2 splice variant) serves as both the priming kinase and the downstream kinase for PER2; priming phosphorylation by CK1δ/ε initiates the phosphoswitch that stabilizes PER2 and lengthens circadian period; the CK1 C-terminal tail modulates period sensitivity to cellular signaling. Comprehensive biochemical and biophysical analysis of mPER2 priming phosphorylation in cells, mathematical phosphoswitch modeling, splice-variant comparison Proceedings of the National Academy of Sciences of the United States of America High 29784789
2020 Phosphorylation of PER2 at Ser478 by CK1 creates a β-TrCP phosphodegron; PER2-S478A knock-in mice show longer circadian period, accumulation of PER2 protein in nucleus and cytoplasm of liver, increased nuclear PER1/CRY1/CRY2, and perturbed three-phase decay and temperature compensation of circadian period in fibroblasts. PER2-S478A knock-in mouse generation, behavioral circadian analysis, western blot, PER2::LUC bioluminescence in mouse embryonic fibroblasts Proceedings of the National Academy of Sciences of the United States of America High 32354999
2020 A conserved anion binding site in CK1 controls activation loop conformation and determines which sites on PER2 (stabilizing vs. destabilizing) are preferentially phosphorylated; period-altering CK1 mutations from humans to Drosophila differentially modulate this activation loop switch to elicit predictable changes in PER2 stability. Integrated experimental and computational studies, mutagenesis of CK1 anion binding site, measurement of PER2 phosphorylation and stability eLife High 32043967
2002 PER2 activates transcription of BMAL1; CRY1, CRY2, and PER2 together upregulate BMAL1 expression while BMAL1-CLOCK heterodimers repress it, forming an interlocked feedback loop in the mammalian circadian clock. Promoter-reporter luciferase assay, genomic structure characterization of mBmal1 Biochemical and biophysical research communications Medium 11798163
2008 PER2 physically interacts with BMAL1 and CLOCK (but not CRY1/CRY2 with CLOCK); CRY proteins interact with BMAL1 at different domains than PER2; together PER2 and CRY proteins inhibit BMAL1-CLOCK transcriptional activation. Mammalian two-hybrid system, co-immunoprecipitation BMC molecular biology Medium 18430226
2012 PML (promyelocytic leukemia protein) physically interacts with PER2 and promotes PER2 nuclear localization in SCN neurons; loss of PML shifts PER2 to a predominantly perinuclear/cytoplasmic distribution and disrupts clock gene rhythms; SIRT1 deacetylates PML at K487 to regulate PML control of PER2 nuclear localization. Co-immunoprecipitation, immunofluorescence localization, Pml-/- mouse analysis, SIRT1 deacetylation assay The EMBO journal High 22274616
2022 CRY proteins are required for PER2 nuclear localization in SCN neurons; in the absence of CRY, PER2 is predominantly cytoplasmic and more mobile (measured by FRAP); virally expressed CRY1 or CRY2 relocalized PER2 to the nucleus and initiated SCN circadian rhythms; the C-terminal tail of CRY1 is necessary for PER2 nuclear relocalization. Confocal imaging of PER2::Venus reporter mice, viral vector expression of CRY variants, FRAP, translational switching to control CRY1 abundance Proceedings of the National Academy of Sciences of the United States of America High 35046033
2017 PER2 interacts with HIF-1α via co-immunoprecipitation and facilitates recruitment of HIF-1α to the hypoxia-response element (HRE) of the VEGF promoter; this requires that HIF-1α N803 is unhydroxylated; PER2 enhances HIF-1 transcriptional activity without changing HIF-1α protein or mRNA levels. Co-immunoprecipitation, chromatin immunoprecipitation/HRE binding assay, N803A point mutant of HIF-1α, deferoxamine treatment The FEBS journal Medium 28963769
2017 SIK3 promotes phosphorylation-dependent destabilization of PER2 protein; SIK3 knockdown increases PER2 protein levels while SIK3 overexpression decreases them; Sik3-deficient mice show elevated PER2 in fibroblasts and liver and lengthened circadian period. Sik3 knockout and knockdown in cells, western blot for PER2 protein levels, bioluminescence rhythm recording, liver fractionation eLife Medium 29227248
2016 SIRT1 and PER2 form a reciprocal negative regulation loop: SIRT1 deficiency leads to enhanced H4K16 acetylation at the Per2 promoter causing Per2 overexpression; in turn, PER2 suppresses Sirt1 transcription by binding to the Sirt1 promoter at the Clock/Bmal1 site. Sirt1-deficient mouse model, ChIP assay for H4K16 acetylation at Per2 promoter, chromatin binding of PER2 at Sirt1 promoter, human hepatocyte validation Scientific reports Medium 27346580
2019 SIRT6 interacts with and deacetylates PER2, preventing its proteasomal degradation; loss of Sirt6 disrupts circadian phase. Co-immunoprecipitation, deacetylation assay, Sirt6-knockout cells, circadian phase analysis Biochemical and biophysical research communications Medium 30782483
2015 Clock-Bmal1 recruits the Ddb1-Cullin-4 ubiquitin ligase to Per1 and Per2 gene loci; rhythmic H2B monoubiquitination at Per genes depends on Bmal1, Ddb1, and Cullin-4a; this chromatin mark facilitates subsequent recruitment of the Per repressor complex to Clock-Bmal1 on DNA. ChIP for H2B monoubiquitination, depletion of Ddb1-Cullin-4a, circadian reporter assay, Co-IP of Per complex with Clock-Bmal1 Nature structural & molecular biology High 26323038
2021 PER2 acts as a co-factor of CREB to facilitate assembly of the CREB/CRTC1/CBP transactivation complex on the CRE element of the Per1 gene regulatory region in response to light or forskolin; absence of PER2 abolishes CBP-CREB interaction, reduces histone H3 acetylation at the Per1 gene, and decreases RNA Pol II recruitment. In vitro and in vivo CREB/CRTC1/CBP interaction assays, ChIP for H3 acetylation and RNA Pol II, Per2-/- mouse light-stimulation experiments Scientific reports Medium 34741086
2010 The PAS-B domain of mouse PER2 binds Fe(III) heme with 1:1 stoichiometry using His454 as an axial ligand; heme binding is pH-sensitive and shows faster dissociation kinetics than myoglobin, distinct from the PAS-A domain properties. Spectroscopic characterization (UV-Vis, CD), diethylpyrocarbonate treatment, H454A point mutant, heme dissociation kinetics Biochimica et biophysica acta Medium 20887817
2004 Per2(Brdm1) mutant mice (with PAS domain deletion) show reduced expression of glutamate transporter Eaat1 in astrocytes, leading to decreased glutamate uptake, elevated extracellular glutamate, and increased alcohol consumption; acamprosate normalizes glutamate levels and alcohol intake in these mice. Per2 mutant mouse analysis, glutamate transporter expression and glutamate uptake assays, acamprosate pharmacological rescue, alcohol consumption measurement Nature medicine High 15608650
2007 PER2 physically interacts with ERα (estrogen receptor-alpha); PER2 binding enhances ERα degradation, while Per2 suppression stabilizes ERα; PER2 overexpression in breast cancer cells causes growth inhibition, loss of clonogenic ability, and apoptosis; Per2 itself is estrogen-inducible suggesting a feedback loop. Co-immunoprecipitation, Per2 overexpression/knockdown, ERα stability (cycloheximide chase), colony formation and apoptosis assays Oncogene Medium 17599055
2014 KSRP promotes decay of Per2 mRNA through direct RNA-protein interaction with the AU-rich element in the Per2 3' UTR; KSRP ablation increases Per2 expression and delays circadian phase of clock genes in liver, leading to reduced lipogenic gene expression. RNA-protein interaction assay, heterologous mRNA reporter with Per2 3' UTR, Ksrp-/- mice, primary hepatocyte culture, qRT-PCR Journal of lipid research Medium 25514904
2023 PER2 binds to HSP90 through its PAS1 domain, reducing the interaction of HSP90 with IKKα/β; this promotes IKKα/β ubiquitination and inhibits IKK/NF-κB pathway activity, thereby suppressing PD-L1 expression in oral squamous cell carcinoma. Co-immunoprecipitation, GST pull-down, CHX chase assay, PAS1 domain deletion mutant, IKK ubiquitination assay, in vivo xenograft model Journal for immunotherapy of cancer Medium 37914384
2021 Per1 and Per2 are required for activation of Igf2 (an autocrine promoter of myoblast differentiation); Per1/Per2 depletion suppresses RNA Pol II recruitment, reduces dynamic histone modifications at the Igf2 promoter and enhancer, and disrupts promoter-enhancer interaction, thereby impairing myoblast differentiation and muscle regeneration. Per1/Per2 siRNA depletion in myoblasts, ChIP for histone modifications and RNA Pol II, chromatin conformation capture, in vivo muscle regeneration after cardiotoxin injury The Journal of cell biology High 34009269
2013 TNF-α inhibits Per2 transcription in rheumatoid synovial cells through D-box binding proteins DBP, HLF, TEF (activators) and E4BP4 (repressor); mutation of D-box 1 and D-box 2 motifs in the Per2 promoter abolished TNF-α-mediated transcriptional inhibition. Site-directed mutagenesis of Per2 promoter D-box motifs, luciferase reporter assay, qRT-PCR in primary synovial cells Scandinavian journal of rheumatology Medium 23496259
2023 A minimal upstream open reading frame (uORF) in the 5' UTR of Per2 mediates temperature-dependent translational upregulation of PER2 protein without affecting Per2 transcription; PI3K lies upstream of this uORF-mediated translation; genetic ablation of the Per2 uORF impairs entrainment of cells to physiological body temperature cycles and delays wound healing in vivo. Genetic uORF ablation (knock-in mice), ribosome profiling, PI3K inhibition, cell entrainment to temperature cycles, wound healing assay Cell reports High 36882059
2013 Egr1 binds directly to two Egr1-binding sites (EBS) in the Per2 promoter (positions -180 to -100) and mediates lithium-induced Per2 transcription; lithium activates the ERK1/2/Elk1 pathway to induce Egr1, which then drives Per2 expression; Egr1-/- mice show attenuated Per2 induction by lithium in frontal cortex. Serial promoter deletion reporter assays, EBS point mutation, EMSA, ChIP, Egr1 siRNA and Egr1-/- mouse Biochimica et biophysica acta High 23816566
2014 Sevoflurane anesthesia reduces CLOCK binding to the E'-box in the Per2 promoter and decreases histone H4 acetylation at the proximal Per2 promoter region, suppressing Per2 expression in the SCN; this occurs independently of NAD+ levels in the SCN. ChIP with anti-acetylated histone H4 and anti-CLOCK antibodies, LC-MS for SCN NAD+ levels, in vitro SCN explant culture with Per2-dLuc reporter PloS one Medium 24498074
2012 PER2 regulates AKT activity; cells with downregulated PER2 show prolonged high-level AKT T308 phosphorylation after growth factor stimulation or DNA damage; PER2 knockdown also delays DNA damage-induced Chk2 activation and overrides DNA damage-induced apoptosis and cell cycle arrest. PER2 siRNA knockdown, western blot for p-AKT T308 and p-Chk2, DNA damage assays, apoptosis and cell cycle analysis Biochemistry and cell biology Medium 22905719
2010 Per2 deficiency enhances Ucp2 gene expression in the liver; absence of Per2 causes elevated Clock expression which drives Ucp2 upregulation via a Clock-controlled PPARα signal transduction pathway, leading to decreased intracellular ATP and increased susceptibility to CCl4-induced hepatotoxicity. Per2-null mice, qRT-PCR and protein analysis of Ucp2/Clock/PPARα, ATP measurement, histological analysis of liver injury The American journal of pathology Medium 19056852
2019 PER2 periodically suppresses PCNA transcription by displacing the CLOCK-BMAL1 heterodimer from the PCNA promoter in a CRY1/2-dependent manner, thereby impeding oxaliplatin-induced DNA adduct repair in oral squamous cell carcinoma cells. Chromatin immunoprecipitation (pulldown) of CLOCK-BMAL1 from PCNA promoter, PER2 overexpression/knockdown, CRY1/2-dependent co-expression experiments, DNA adduct repair assays Advanced science Medium 31728273
2021 PER2-mediated ameloblast differentiation operates through the PPARγ/AKT1/β-catenin signaling axis; Per2 knockdown decreases PPARγ expression and AKT1 phosphorylation and alters β-catenin localization; overexpression of PPARγ partially rescues Per2 knockdown phenotypes. Per2 knockdown by RNAi in ameloblast-lineage cells (ALC), overexpression of PPARγ as rescue, western blot for pathway components, in vivo circadian disruption mouse model with PPARγ agonist rescue International journal of oral science Medium 34011974
2010 Endogenous dopamine regulates the daily rhythm of PER2 expression in the dorsal striatum through daily activation of D2 (but not D1) dopamine receptors; depletion of striatal dopamine (6-OHDA or α-methyl-para-tyrosine) or D2 receptor blockade blunts the PER2 rhythm; timed D2 receptor activation restores and entrains PER2 rhythm in dopamine-depleted striatum. 6-OHDA and AMPT dopamine depletion, receptor-specific pharmacology (raclopride D2 blockade, D1/D2 agonists), immunohistochemistry for PER2 in rat brain regions The Journal of neuroscience Medium 20962226
2008 Estrogen directly affects the circadian clock in the uterus: 17β-estradiol (E2) applied to explanted uterus cultures shortens the period of PER2::LUC expression; this effect is attenuated by raloxifene (estrogen receptor antagonist), indicating estrogen acts via estrogen receptors to modulate PER2 rhythms in the uterus but not the SCN. PER2::LUC tissue explant culture from ovariectomized knockin mice, estrogen/raloxifene treatment, bioluminescence recording American journal of physiology. Endocrinology and metabolism Medium 18728223
2006 Per2 mutant mice lack food-anticipatory activity under restricted feeding conditions, while Per1 mutants and wild-type mice show normal food anticipation; peripheral phase shifts of clock-gene expression in response to timed food restriction are comparable across all genotypes, placing PER2 specifically in a central food-entrainable oscillator pathway but not peripheral feeding synchronization. Per2 and Per1 mutant mouse behavioral analysis (rest-activity, body temperature rhythms), clock-gene expression in SCN and peripheral tissues under restricted feeding Current biology High 17055980
2017 Per2 mutation in mice (PAS domain deletion) is associated with increased cyclooxygenase-1 (but not COX-2) protein levels in aorta, decreased NO production, and altered prostaglandin production, leading to impaired endothelium-dependent relaxation; endothelial dysfunction is not associated with hypertension or dyslipidemia. Organ chamber studies with aortic rings, Western blot for COX-1/COX-2/eNOS, pharmacological dissection with indomethacin, Per2 mutant mouse model Circulation Medium 17404161
2015 Per2 mutation in MEFs increases resistance to ROS-induced cytotoxicity; this is paralleled by altered Bcl-2 expression; elevated survival and altered NADH/NAD+ ratio in mutant cells is reversed by reintroduction of wild-type Per2; clock-synchronized cells display time-dependent sensitivity to paraquat. Per2 mutant MEFs, ROS (paraquat) treatment, cell viability assay, Bcl-2 expression, NADH/NAD+ measurement, wild-type Per2 rescue Frontiers in neurology Medium 25628599
2023 PER2 enhances HIF-1α transcriptional activity to induce cell cycle genes Ccnb2, Cdc20, and Espl1 in pituitary cells; PER2 upregulation in jet-lagged mice accelerates pituitary adenoma growth, while Per2 loss protects against estrogen-induced pituitary adenoma; SR8278 (which decreases PER2 expression) has anti-tumor effects. RNA-seq, in vivo jet-lag and estrogen-induced pituitary adenoma models, PER2 overexpression/KO, HIF-1α ChIP, luciferase reporter for HIF-1α target genes Theranostics Medium 37215573

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nature medicine 462 15608650
2005 Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Molecular and cellular biology 403 15767683
2007 Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell 316 17218255
2005 Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 311 15790588
2010 Endogenous dopamine regulates the rhythm of expression of the clock protein PER2 in the rat dorsal striatum via daily activation of D2 dopamine receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 190 20962226
2007 Mutation of the circadian clock gene Per2 alters vascular endothelial function. Circulation 190 17404161
2006 Lack of food anticipation in Per2 mutant mice. Current biology : CB 171 17055980
2007 The clock gene Per2 links the circadian system to the estrogen receptor. Oncogene 164 17599055
2005 Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia. Blood 127 15985538
2002 Gradients in the circadian expression of Per1 and Per2 genes in the rat suprachiasmatic nucleus. The European journal of neuroscience 127 11982626
2018 CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch. Proceedings of the National Academy of Sciences of the United States of America 122 29784789
2008 Inter-individual differences in habitual sleep timing and entrained phase of endogenous circadian rhythms of BMAL1, PER2 and PER3 mRNA in human leukocytes. Sleep 119 18517031
2002 Interactivating feedback loops within the mammalian clock: BMAL1 is negatively autoregulated and upregulated by CRY1, CRY2, and PER2. Biochemical and biophysical research communications 117 11798163
2008 Interaction of circadian clock proteins PER2 and CRY with BMAL1 and CLOCK. BMC molecular biology 115 18430226
2008 Estrogen directly modulates circadian rhythms of PER2 expression in the uterus. American journal of physiology. Endocrinology and metabolism 110 18728223
2006 Evening exposure to blue light stimulates the expression of the clock gene PER2 in humans. The European journal of neuroscience 101 16519674
2016 Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging. Scientific reports 77 27346580
2012 Persistent cell-autonomous circadian oscillations in fibroblasts revealed by six-week single-cell imaging of PER2::LUC bioluminescence. PloS one 72 22479387
2010 Role of mutation of the circadian clock gene Per2 in cardiovascular circadian rhythms. American journal of physiology. Regulatory, integrative and comparative physiology 67 20053965
2010 Deregulated expression of the Per1 and Per2 in human gliomas. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 67 20481271
2017 A circadian clock gene, PER2, activates HIF-1 as an effector molecule for recruitment of HIF-1α to promoter regions of its downstream genes. The FEBS journal 66 28963769
2008 The role of {beta}-TrCP1 and {beta}-TrCP2 in circadian rhythm generation by mediating degradation of clock protein PER2. Journal of biochemistry 65 18782782
2006 The expression of the clock protein PER2 in the limbic forebrain is modulated by the estrous cycle. Proceedings of the National Academy of Sciences of the United States of America 65 16554373
2013 Cardiac Per2 functions as novel link between fatty acid metabolism and myocardial inflammation during ischemia and reperfusion injury of the heart. PloS one 64 23977055
2006 Protein phosphatase 1 regulates the stability of the circadian protein PER2. The Biochemical journal 64 16813562
2010 The clock gene PER2 and sleep problems: association with alcohol consumption among Swedish adolescents. Upsala journal of medical sciences 62 20187847
2015 The Mammalian circadian clock gene per2 modulates cell death in response to oxidative stress. Frontiers in neurology 61 25628599
2007 The multiple facets of Per2. Cold Spring Harbor symposia on quantitative biology 60 18419266
2012 Per2 mutation recapitulates the vascular phenotype of diabetes in the retina and bone marrow. Diabetes 58 23193187
2013 The circadian Per1 and Per2 genes influence alcohol intake, reinforcement, and blood alcohol levels. Behavioural brain research 57 23608482
2020 Casein kinase 1 dynamics underlie substrate selectivity and the PER2 circadian phosphoswitch. eLife 56 32043967
2020 Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch. Proceedings of the National Academy of Sciences of the United States of America 56 32354999
2016 Clock gene Per2 as a controller of liver carcinogenesis. Oncotarget 54 27494874
2013 TNF-α modulates expression of the circadian clock gene Per2 in rheumatoid synovial cells. Scandinavian journal of rheumatology 54 23496259
2015 Histone monoubiquitination by Clock-Bmal1 complex marks Per1 and Per2 genes for circadian feedback. Nature structural & molecular biology 50 26323038
2013 Fibroblast PER2 circadian rhythmicity depends on cell density. Journal of biological rhythms 50 23735497
2012 PML regulates PER2 nuclear localization and circadian function. The EMBO journal 49 22274616
2012 Influence of aging on Bmal1 and Per2 expression in extra-SCN oscillators in hamster brain. Brain research 49 23159832
2018 Neurobiological Functions of the Period Circadian Clock 2 Gene, Per2. Biomolecules & therapeutics 44 29223143
2015 Circadian genes Per1 and Per2 increase radiosensitivity of glioma in vivo. Oncotarget 43 25760074
2020 PER2 inhibits proliferation and stemness of glioma stem cells via the Wnt/β‑catenin signaling pathway. Oncology reports 42 32468039
2017 Intense light-elicited upregulation of miR-21 facilitates glycolysis and cardioprotection through Per2-dependent mechanisms. PloS one 42 28448534
2009 Combined PER2 and CRY1 expression predicts outcome in chronic lymphocytic leukemia. European journal of haematology 40 19500131
2019 Periodic Oxaliplatin Administration in Synergy with PER2-Mediated PCNA Transcription Repression Promotes Chronochemotherapeutic Efficacy of OSCC. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 39 31728273
2009 Motivational Modulation of Rhythms of the Expression of the Clock Protein PER2 in the Limbic Forebrain. Biological psychiatry 38 19200536
2012 Deletion of clock gene Per2 exacerbates cholestatic liver injury and fibrosis in mice. Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie 37 22261359
2015 Melatonin Entrains PER2::LUC Bioluminescence Circadian Rhythm in the Mouse Cornea. Investigative ophthalmology & visual science 35 26207312
2006 Pinealectomy does not affect diurnal PER2 expression in the rat limbic forebrain. Neuroscience letters 35 16488540
2023 PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression. Journal for immunotherapy of cancer 34 37914384
2021 Per1/Per2-Igf2 axis-mediated circadian regulation of myogenic differentiation. The Journal of cell biology 33 34009269
2008 The protective role of Per2 against carbon tetrachloride-induced hepatotoxicity. The American journal of pathology 33 19056852
2019 Chronotype Genetic Variant in PER2 is Associated with Intrinsic Circadian Period in Humans. Scientific reports 31 30926824
2014 Epigenetic suppression of mouse Per2 expression in the suprachiasmatic nucleus by the inhalational anesthetic, sevoflurane. PloS one 31 24498074
2019 Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy. Molecular systems biology 30 31353796
2017 Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein. eLife 30 29227248
2012 Fibroblast circadian rhythms of PER2 expression depend on membrane potential and intracellular calcium. Chronobiology international 30 22734566
2008 Region-specific modulation of PER2 expression in the limbic forebrain and hypothalamus by nighttime restricted feeding in rats. Neuroscience letters 30 18541376
2011 A fear-inducing odor alters PER2 and c-Fos expression in brain regions involved in fear memory. PloS one 28 21655193
2004 Regulation of photoreceptor Per1 and Per2 by light, dopamine and a circadian clock. The European journal of neuroscience 27 15245489
2023 PER2 integrates circadian disruption and pituitary tumorigenesis. Theranostics 26 37215573
2018 Zebrafish Lacking Circadian Gene per2 Exhibit Visual Function Deficiency. Frontiers in behavioral neuroscience 26 29593513
2018 The circadian gene, Per2, influences methamphetamine sensitization and reward through the dopaminergic system in the striatum of mice. Addiction biology 26 30091820
2017 The circadian clock gene PER2 plays an important role in tumor suppression through regulating tumor-associated genes in human oral squamous cell carcinoma. Oncology reports 26 28535015
2003 Light exposure during daytime modulates expression of Per1 and Per2 clock genes in the suprachiasmatic nuclei of mice. Journal of neuroscience research 26 12749028
2021 Deletion of the clock gene Period2 (Per2) in glial cells alters mood-related behavior in mice. Scientific reports 25 34112905
2013 Circadian clock gene Per2 is not necessary for the photoperiodic response in mice. PloS one 25 23505514
2013 Direct and specific effect of sevoflurane anesthesia on rat Per2 expression in the suprachiasmatic nucleus. PloS one 25 23555676
2013 Organ-specific development characterizes circadian clock gene Per2 expression in rats. American journal of physiology. Regulatory, integrative and comparative physiology 25 24133102
2023 Minimal upstream open reading frame of Per2 mediates phase fitness of the circadian clock to day/night physiological body temperature rhythm. Cell reports 24 36882059
2022 Cryptochrome proteins regulate the circadian intracellular behavior and localization of PER2 in mouse suprachiasmatic nucleus neurons. Proceedings of the National Academy of Sciences of the United States of America 24 35046033
2021 Core circadian clock genes Per1 and Per2 regulate the rhythm in photoreceptor outer segment phagocytosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 34160105
2021 PER2 mediates CREB-dependent light induction of the clock gene Per1. Scientific reports 24 34741086
2016 Association of CLOCK, ARNTL, PER2, and GNB3 polymorphisms with diurnal preference in a Korean population. Chronobiology international 24 27660894
2013 Egr1 regulates lithium-induced transcription of the Period 2 (PER2) gene. Biochimica et biophysica acta 24 23816566
2006 Human clock, PER1 and PER2 polymorphisms: lack of association with cocaine dependence susceptibility and cocaine-induced paranoia. Psychiatric genetics 24 17106427
2010 Heme-binding characteristics of the isolated PAS-B domain of mouse Per2, a transcriptional regulatory factor associated with circadian rhythms. Biochimica et biophysica acta 23 20887817
2007 Biochemical characterization of PER-2 and genetic environment of blaPER-2. Antimicrobial agents and chemotherapy 23 17438050
2019 Sirt6 deacetylase activity regulates circadian rhythms via Per2. Biochemical and biophysical research communications 22 30782483
2018 Temporal dynamics of cortisol-associated changes in mRNA expression of glucocorticoid responsive genes FKBP5, GILZ, SDPR, PER1, PER2 and PER3 in healthy humans. Psychoneuroendocrinology 22 30522007
2011 Light responsiveness of clock genes, Per1 and Per2, in the olfactory bulb of mice. Biochemical and biophysical research communications 22 21624349
2019 Analyses of BMAL1 and PER2 Oscillations in a Model of Breast Cancer Progression Reveal Changes With Malignancy. Integrative cancer therapies 21 30943793
2018 Histone deacetylase inhibitors induce the expression of tumor suppressor genes Per1 and Per2 in human gastric cancer cells. Oncology letters 21 30008892
2015 IA Channels Encoded by Kv1.4 and Kv4.2 Regulate Circadian Period of PER2 Expression in the Suprachiasmatic Nucleus. Journal of biological rhythms 21 26152125
2023 Lycium barbarum glycopeptide targets PER2 to inhibit lipogenesis in glioblastoma by downregulating SREBP1c. Cancer gene therapy 20 37069338
2022 Attenuation by Time-Restricted Feeding of High-Fat and High-Fructose Diet-Induced NASH in Mice Is Related to Per2 and Ferroptosis. Oxidative medicine and cellular longevity 20 36285301
2018 The Interaction between Bmal1 and Per2 in Mouse BMSC Osteogenic Differentiation. Stem cells international 20 29765408
2012 Mammalian PER2 regulates AKT activation and DNA damage response. Biochemistry and cell biology = Biochimie et biologie cellulaire 20 22905719
2010 The clock gene Per2 is required for normal platelet formation and function. Thrombosis research 20 21186050
2015 Real-Time Recording of Circadian Per1 and Per2 Expression in the Suprachiasmatic Nucleus of Freely Moving Rats. Journal of biological rhythms 18 26656624
2014 KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression. Journal of lipid research 18 25514904
2022 Per1/Per2 Disruption Reduces Testosterone Synthesis and Impairs Fertility in Elderly Male Mice. International journal of molecular sciences 17 35806403
2017 Effect of lipopolysaccharide on circadian clock genes Per2 and Bmal1 in mouse ovary. The journal of physiological sciences : JPS 17 28213822
2016 Differential localization of PER1 and PER2 in the brain master circadian clock. The European journal of neuroscience 16 27740710
2014 Crystal structure of the extended-spectrum β-lactamase PER-2 and insights into the role of specific residues in the interaction with β-lactams and β-lactamase inhibitors. Antimicrobial agents and chemotherapy 16 25070104
2022 Loss of thyroid gland circadian PER2 rhythmicity in aged mice and its potential association with thyroid cancer development. Cell death & disease 15 36284088
2021 PER2-mediated ameloblast differentiation via PPARγ/AKT1/β-catenin axis. International journal of oral science 15 34011974
2008 Deregulated expression of the per2 gene in human colorectal carcinoma. Molecular medicine reports 15 21479457
2022 Characterization of Affective Behaviors and Motor Functions in Mice With a Striatal-Specific Deletion of Bmal1 and Per2. Frontiers in physiology 14 35755440
2021 Targeted modification of the Per2 clock gene alters circadian function in mPer2luciferase (mPer2Luc) mice. PLoS computational biology 14 34048425
2014 The analysis of deregulated expression and methylation of the PER2 genes in gliomas. Journal of cancer research and therapeutics 14 25313752