Affinage

PER2

Period circadian protein homolog 2 · UniProt O15055

Length
1255 aa
Mass
136.6 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PER2 is a core negative-arm component of the mammalian transcription-translation feedback loop, where it physically associates with the positive-arm factors BMAL1 and CLOCK through a domain distinct from its CRY-binding interface (PMID:18430226). PER2 abundance is set by a CK1δ/ε-driven phosphoswitch: CK1δ/ε first primes PER2 at sites prerequisite for downstream stabilizing phosphorylations, with the CK1 C-terminal tail and a conserved anion-binding site governing activation-loop conformation and thus which sites are modified (PMID:29784789, PMID:32043967). CK1 phosphorylation of Ser478 creates a β-TrCP phosphodegron that drives proteasomal degradation, and abolishing this site (Ser478Ala knock-in) lengthens period and accumulates PER2 along with PER1, CRY1 and CRY2 (PMID:32354999). This degradative axis is opposed by PP1, which dephosphorylates CK1-modified PER2 to extend its half-life, and by SIRT6-mediated deacetylation that prevents PER2 proteasomal turnover; SIK3 acts in the destabilizing direction (PMID:16813562, PMID:30782483, PMID:29227248). Nuclear entry of PER2 depends on CRY proteins—particularly the CRY1 C-terminal tail—and on PML, whose PER2-promoting activity is licensed by SIRT1 deacetylation of PML at K487 (PMID:35046033, PMID:22274616). Beyond timekeeping, PER2 directly represses PPARγ recruitment to target promoters to restrain adipogenesis and lipid metabolism (PMID:21035761), serves as a CREB co-factor that assembles a CREB/CRTC1/CBP complex driving light-induced Per1 transcription (PMID:34741086), facilitates HIF-1α recruitment to hypoxia-response elements under hypoxic conditions (PMID:28963769), and participates in a reciprocal regulatory loop with SIRT1 through promoter occupancy at each other's genes (PMID:27346580). PER2 also functions in chaperone-coupled signaling control, binding HSP90 via its PAS1 domain to suppress IKK/NF-κB and PD-L1 expression (PMID:37914384) and HSP70 via its C-terminus to promote AKT degradation and cuproptosis (PMID:40113747).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2006 High

    Established that PER2 stability is set by an opposing kinase-phosphatase balance, identifying PP1 as the dephosphorylating activity that protects CK1-phosphorylated PER2 from degradation.

    Evidence Xenopus egg extract degradation assays, co-IP with PP1c in HEK-293, and dominant-negative PP1 in cells

    PMID:16813562

    Open questions at the time
    • Did not define the specific PER2 residues dephosphorylated
    • PP1 regulatory subunit targeting PER2 unidentified
  2. 2008 Medium

    Mapped the architecture of PER2 within the clock complex, showing PER2 contacts BMAL1 and CLOCK at sites distinct from CRY-binding interfaces while CRY proteins are the stronger repressors.

    Evidence Mammalian two-hybrid and co-immunoprecipitation

    PMID:18430226

    Open questions at the time
    • Two-hybrid/co-IP without structural resolution of the complex
    • Functional consequence of PER2-BMAL1/CLOCK binding for repression not separated from CRY
  3. 2010 High

    Extended PER2 beyond timekeeping by showing it directly represses PPARγ transcriptional output to control adipogenesis and lipid metabolism.

    Evidence Co-IP, ChIP, microarray, adipocyte differentiation in PER2-deficient fibroblasts, and lipidomics in PER2-deficient mice

    PMID:21035761

    Open questions at the time
    • Mechanism by which PER2 blocks PPARγ promoter recruitment not resolved at residue level
    • Relationship between this metabolic role and clock phase unclear
  4. 2012 High

    Resolved how PER2 reaches the nucleus, identifying PML as a binding partner required for PER2 nuclear localization under SIRT1-dependent control.

    Evidence Co-IP, immunofluorescence in SCN neurons and MEFs, Pml-/- KO, and SIRT1 deacetylation assay

    PMID:22274616

    Open questions at the time
    • How PML physically escorts PER2 across the nuclear envelope undefined
    • Interplay between PML and CRY-driven nuclear entry not reconciled
  5. 2016 Medium

    Defined a reciprocal PER2-SIRT1 regulatory loop linking the clock to chromatin acetylation state in liver.

    Evidence ChIP for H4K16ac at Per2 promoter, Per2 binding at Sirt1 promoter, and Sirt1-deficient mouse liver / human hepatocytes

    PMID:27346580

    Open questions at the time
    • Whether PER2 represses Sirt1 directly or via CLOCK/BMAL1 displacement not separated
    • Tissue specificity of the loop untested beyond liver
  6. 2017 Medium

    Showed PER2 couples the clock to hypoxia signaling by acting as a co-factor that facilitates HIF-1α recruitment to HREs only when N803 is unhydroxylated.

    Evidence Co-IP, HRE-reporter assays, N803A mutation, and deferoxamine treatment

    PMID:28963769

    Open questions at the time
    • Single-lab co-IP/reporter evidence without in vivo hypoxia validation
    • Whether PER2 alters HIF-1α stability or only recruitment unresolved
  7. 2018 High

    Identified CK1δ/ε itself as the priming kinase for PER2, establishing the molecular entry point of the phosphoswitch that times PER2 turnover.

    Evidence In-cell biochemical and biophysical analysis of mouse PER2 priming phosphorylation plus phosphoswitch mathematical modeling

    PMID:29784789

    Open questions at the time
    • Upstream signals that tune CK1 priming via its C-terminal tail not enumerated
    • Stoichiometry of priming vs degron phosphorylation in vivo not quantified
  8. 2020 High

    Mechanistically connected the phosphoswitch to PER2 degradation, defining Ser478 as a CK1-created β-TrCP phosphodegron and showing an anion-binding site in CK1 selects between stabilizing and destabilizing PER2 sites.

    Evidence PER2-Ser478Ala knock-in mice with behavior/protein/bioluminescence readouts; CK1 mutagenesis, in vitro kinase assays, and cross-species period-mutant analysis

    PMID:32043967 PMID:32354999

    Open questions at the time
    • How cellular signals shift CK1 between the two site preferences in vivo not defined
    • Contribution of additional degrons beyond Ser478 to period control unmeasured
  9. 2019 Medium

    Added an acetylation arm to PER2 stability control, showing SIRT6 deacetylates PER2 to prevent its proteasomal degradation and maintain circadian phase.

    Evidence Co-IP, deacetylation assay, and Sirt6-knockdown phenotype

    PMID:30782483

    Open questions at the time
    • Acetylated lysines on PER2 not mapped
    • Interplay of acetylation with the CK1 phosphodegron not dissected
  10. 2021 Medium

    Defined PER2 as a transcriptional co-factor for CREB, required to assemble the CREB/CRTC1/CBP complex that drives light-induced Per1 transcription.

    Evidence CREB/PER2 interaction assays, ChIP, luciferase reporters, KO, and light-pulse experiments in mice

    PMID:34741086

    Open questions at the time
    • Whether PER2 acts catalytically or stoichiometrically in complex assembly unclear
    • Generality beyond the Per1 CRE not established
  11. 2022 High

    Demonstrated CRY proteins, via the CRY1 C-terminal tail, drive PER2 nuclear relocalization and rhythm initiation in SCN neurons.

    Evidence Confocal imaging of endogenous PER2::Venus in CRY-null SCN, viral CRY-variant rescue, FRAP, and translational switching

    PMID:35046033

    Open questions at the time
    • How CRY-driven and PML-driven nuclear import integrate not resolved
    • Structural basis of CRY1 tail action on PER2 mobility undefined
  12. 2023 Medium

    Revealed a chaperone-coupled signaling role, with PER2 binding HSP90 through its PAS1 domain to displace IKKs, suppressing NF-κB activity and PD-L1 expression.

    Evidence Co-IP, GST pull-down, cycloheximide chase, and humanized-immune xenograft in OSCC

    PMID:37914384

    Open questions at the time
    • Single-lab/single-cancer-context evidence
    • Whether this is clock-dependent not addressed
  13. 2025 Medium

    Extended PER2 chaperone control to HSP70, showing C-terminal binding reduces HSP70-AKT interaction to promote AKT degradation and cuproptosis, with ATF3 identified as an upstream activator of PER2 transcription.

    Evidence Co-IP, GST pull-down, domain mapping, ubiquitination assay, ATF3 ChIP, and xenograft in OSCC

    PMID:40113747

    Open questions at the time
    • Single-context evidence in OSCC
    • Direct vs indirect effect of PER2 on AKT ubiquitination machinery not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple PER2 stability inputs (CK1 priming/degron, PP1, SIRT1/SIRT6, SIK3) and the two distinct nuclear-import routes (CRY1 tail vs PML/SIRT1) are quantitatively integrated to set period in vivo remains unresolved.
  • No unified kinetic model linking phosphorylation, acetylation, and import
  • Structural picture of PER2 in the repressive complex absent
  • Tissue-specific weighting of metabolic vs timekeeping functions unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140110 transcription regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-9909396 Circadian clock 4 R-HSA-74160 Gene expression (Transcription) 3
Partners
BMAL1CLOCKCRY1CSNK1DHIF1AHSP90PMLPPP1CA
Complex memberships
CLOCK/BMAL1 clock complexCREB/CRTC1/CBP transactivation complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 CK1δ/ε (including the CK1δ2 splice variant) is itself the priming kinase for PER2, phosphorylating it at sites that are prerequisite for downstream stabilizing phosphorylations; the CK1 carboxyl-terminal tail modulates this priming activity and allows cellular signaling to influence circadian period. Comprehensive biochemical and biophysical analysis of mouse PER2 priming phosphorylation in cells; phosphoswitch mathematical modeling Proceedings of the National Academy of Sciences of the United States of America High 29784789
2020 A conserved anion binding site in CK1 controls activation-loop conformation and determines which sites on PER2 are preferentially phosphorylated, thereby acting as a molecular switch that directly regulates PER2 stability; period-altering CK1 mutations in humans and Drosophila differentially modulate this switch. Integrated experimental (mutagenesis, in vitro kinase assays) and computational studies; cross-species period mutant analysis eLife High 32043967
2020 CK1-mediated phosphorylation of PER2 at Ser478 creates a phosphodegron that recruits the E3 ligase β-TrCP for proteasomal degradation; PER2-Ser478Ala knock-in mice show longer circadian period and accumulation of PER2 protein (and associated PER1, CRY1, CRY2) in both nucleus and cytoplasm, with perturbed temperature compensation. PER2-Ser478Ala knock-in mouse generation; behavioral circadian analysis; western blotting; MEF bioluminescence (PER2::LUC) assays Proceedings of the National Academy of Sciences of the United States of America High 32354999
2006 Protein phosphatase 1 (PP1) dephosphorylates CK1-phosphorylated PER2, stabilizing it against ubiquitin-proteasome degradation; PER2 co-immunoprecipitates with PP1c in mammalian cells, and dominant-negative PP1c or PP1 inhibitors accelerate PER2 degradation and shorten its half-life. Xenopus egg extract degradation assay; co-immunoprecipitation in HEK-293 cells; endogenous PP1 phosphatase assay from liver and brain; dominant-negative overexpression The Biochemical Journal High 16813562
2008 PER2 physically interacts with BMAL1 (at a distinct domain from CRY1/CRY2 binding sites) and with CLOCK, whereas CRY1 and CRY2 interact with BMAL1 but not with CLOCK; CRY proteins bind BMAL1 with higher affinity than PER2 and are stronger transcriptional repressors. Mammalian two-hybrid system; co-immunoprecipitation assays BMC Molecular Biology Medium 18430226
2010 PER2 directly and specifically represses PPARγ transcriptional activity: PER2 blocks PPARγ recruitment to target promoters, thereby suppressing adipogenesis; PER2-deficient mice display drastically altered lipid metabolism and enhanced adipocyte differentiation. PER2 targets the S112 residue of PPARγ. Co-immunoprecipitation; chromatin immunoprecipitation; whole-genome microarray profiling; adipocyte differentiation assays in PER2-deficient fibroblasts; lipidomic profiling in white adipose tissue Cell Metabolism High 21035761
2012 PML (promyelocytic leukaemia) protein physically interacts with PER2 and is required for PER2 nuclear localization; in Pml−/− cells, PER2 is predominantly perinuclear/cytoplasmic. SIRT1 deacetylates PML at K487, and this deacetylation promotes PML-mediated nuclear localization of PER2. Co-immunoprecipitation; immunofluorescence localization in SCN neurons and MEFs; genetic KO (Pml−/−); SIRT1 deacetylation assay The EMBO Journal High 22274616
2017 PER2 functions as a co-factor that facilitates recruitment of HIF-1α to hypoxia-response elements (HREs); PER2 physically interacts with HIF-1α via co-immunoprecipitation, and its enhancement of HIF-1 transcriptional activity requires the HIF-1α N803 asparagine to be unhydroxylated (hypoxic conditions). Co-immunoprecipitation; forced PER2 expression; HRE-reporter (VEGF promoter) assays; N803A point mutation; deferoxamine (N803-dioxygenase inhibitor) treatment The FEBS Journal Medium 28963769
2021 PER2 acts as a co-factor of CREB to facilitate formation of a CREB/CRTC1/CBP transactivation complex on the CRE element of the Per1 gene in response to light or forskolin; absence of PER2 abolishes the CREB–CBP interaction and reduces histone H3 acetylation and RNA Pol II recruitment to the Per1 promoter. In vitro and in vivo CREB/PER2 interaction assays; chromatin immunoprecipitation; luciferase reporter assays; genetic KO; light-pulse experiments in mice Scientific Reports Medium 34741086
2016 SIRT1 and PER2 constitute a reciprocal negative regulatory loop in the liver: SIRT1 deficiency leads to enhanced H4K16 acetylation at the Per2 promoter, causing Per2 overexpression; in turn, PER2 suppresses Sirt1 transcription by binding to its promoter at the CLOCK/BMAL1 site. ChIP for H4K16 acetylation at Per2 promoter; Per2 promoter binding assay; Sirt1-deficient mouse liver analysis; human hepatocyte experiments Scientific Reports Medium 27346580
2017 SIK3 (salt-inducible kinase 3) facilitates phosphorylation-dependent destabilization of PER2 protein; SIK3 knockdown elevates PER2 protein levels while SIK3 overexpression decreases them, and PER2 accumulates in Sik3-deficient fibroblasts and liver. Sik3 knockout mouse; SIK3 knockdown/overexpression in cultured cells; bioluminescence rhythm monitoring; protein level assessment by western blotting eLife Medium 29227248
2019 SIRT6 interacts with and deacetylates PER2, thereby preventing its proteasomal degradation; loss of Sirt6 jeopardizes circadian phase, and this is linked to PER2 acetylation status. Co-immunoprecipitation; deacetylation assay; Sirt6-knockdown circadian phenotype analysis Biochemical and Biophysical Research Communications Medium 30782483
2004 Per2(Brdm1) mutant mice (PAS domain deletion) display lowered expression of the glutamate transporter Eaat1 in astrocytes, leading to reduced glutamate uptake and elevated extracellular glutamate, which is mechanistically linked to increased alcohol intake; acamprosate normalizes glutamate levels and alcohol consumption in these mice. Per2 mutant mouse analysis; Eaat1 expression profiling; extracellular glutamate measurement; pharmacological rescue with acamprosate Nature Medicine Medium 15608650
2022 CRY proteins are required for nuclear localization of PER2 in SCN neurons: in the absence of CRY, PER2 is predominantly cytoplasmic and more mobile (by FRAP); virally expressed CRY1 or CRY2 relocalize PER2 to the nucleus and initiate circadian rhythms; the CRY1 C-terminal tail is necessary for this nuclear relocalization. Confocal imaging of endogenous PER2::Venus in SCN of CRY-null 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
2007 PER2 binds ERα and enhances ERα degradation; conversely, suppression of PER2 levels leads to ERα stabilization; PER2 expression is itself estrogen-inducible in breast cancer cells, suggesting a feedback mechanism to attenuate estrogen stimulation. Co-immunoprecipitation; PER2 overexpression and suppression in breast cancer cells; ERα protein stability assays; estrogen induction experiments Oncogene Medium 17599055
2023 PER2 binds HSP90 through its PAS1 domain and reduces the interaction of HSP90 with IKKs, promoting ubiquitination of IKKα/β and thereby suppressing IKK/NF-κB pathway activity and PD-L1 expression in oral squamous cell carcinoma cells. Co-immunoprecipitation; GST pull-down; cycloheximide chase assay; western blotting; overexpression/knockdown; in vivo xenograft humanized immune model Journal for Immunotherapy of Cancer Medium 37914384
2025 PER2 binds HSP70 through its C-terminal domain, reducing the HSP70–AKT interaction and promoting AKT ubiquitination and degradation, which upregulates cuproptosis-related proteins (DLAT, PDHB, SLC31A1) and promotes cuproptosis in OSCC cells. ATF3 is an upstream transcriptional activator of PER2, binding the PER2 promoter at −807 to −796 bp. Co-immunoprecipitation; GST pull-down; domain deletion mapping; ubiquitination assay; ATF3 ChIP/promoter analysis; in vivo xenograft Cell Death & Disease Medium 40113747
2021 Per2 (together with Per1) is required for activation of Igf2 transcription during myoblast differentiation; Per proteins are recruited to the Igf2 promoter and enhancer, driving dynamic histone modifications and promoter-enhancer looping that create a circadian time window for myoblast differentiation initiation. Per1/Per2 depletion in myoblasts; in vivo muscle regeneration assay; RNA Pol II ChIP; histone modification ChIP; chromatin conformation capture (promoter-enhancer interaction); Per2 KO mice The Journal of Cell Biology Medium 34009269
2008 Estrogen (17β-estradiol) directly shortens the period of PER2::LUC circadian rhythms in uterine tissue explants but not in SCN explants; this effect is blocked by the ER antagonist raloxifene, indicating an estrogen-receptor-mediated direct modulation of the peripheral (uterine) molecular clock. Tissue explant bioluminescence assays from PER2::LUC knock-in mice; ovariectomy and estradiol/raloxifene treatment American Journal of Physiology. Endocrinology and Metabolism Medium 18728223
2014 Sevoflurane anesthesia reduces CLOCK binding to the E'-box of the Per2 promoter and decreases histone H4 acetylation at the proximal Per2 promoter region, leading to suppressed Per2 expression in the SCN; this occurs independently of NAD+ concentration. Chromatin immunoprecipitation (anti-acetylated-histone H4 and anti-CLOCK); quantitative in situ hybridization; LC-MS measurement of NAD+ PloS One Medium 24498074
2016 Per2 is activated predominantly in lymphoid-biased haematopoietic stem cells (HSCs) under DNA damage and ageing conditions, where it stimulates DNA damage signalling and p53-dependent apoptosis; Per2 deletion ameliorates replication stress, improves maintenance of Ly-biased HSCs, and extends lifespan without increasing DNA damage accumulation. Batf/p53-dependent HSC differentiation induction persists in Per2-deficient mice. In vivo RNAi screening; Per2 conditional KO mouse; HSC isolation and transplantation; DNA damage signalling analysis; lifespan measurement Nature Cell Biology Medium 27088856
2008 Per2 mutation causes Akt-dependent increase in endothelial cell senescence and impairs ischemia-induced EPC mobilization and revascularization; bone marrow transplantation or infusion of wild-type EPCs rescues blood flow recovery in Per2 mutant mice. Per2 mutant mouse; endothelial cell Akt signaling analysis; hind-limb ischemia model; bone marrow transplantation; matrigel neovascularization assay Circulation Medium 18981300
2012 PER2 regulates AKT activity; cells with downregulated PER2 show prolonged elevated AKT T308 phosphorylation after growth factor stimulation or DNA damage, and PER2 downregulation delays DNA-damage-induced Chk2 activation while overriding apoptosis and cell cycle arrest. PER2 knockdown and overexpression in cancer cells; western blotting for AKT T308 phosphorylation and Chk2 activation after growth factor and DNA damage stimuli Biochemistry and Cell Biology Low 22905719
2013 TNF-α inhibits Per2 transcription in rheumatoid synovial cells through D-box 1 and D-box 2 motifs in the Per2 promoter, acting via the D-box binding transcriptional activators DBP, HLF, and TEF (which are downregulated by TNF-α) and the repressor E4BP4 (which is upregulated). Site-directed mutagenesis of Per2 D-box motifs; luciferase reporter assay; real-time PCR in primary human synovial cells treated with TNF-α Scandinavian Journal of Rheumatology Medium 23496259
2022 IL-1β induces PER2 upregulation in primary human chondrocytes via NMDA receptor activation → CREB phosphorylation; CREB knockdown or inhibition prevents IL-1β-induced PER2 increase. IL-1β simultaneously reduces BMAL1 via NF-κB activation; NF-κB inhibition prevents BMAL1 reduction and partially mitigates PER2 increase. NMDAR antagonist (MK801); CREB knockdown; NF-κB inhibitor; phosphorylation assays (GluN1, CREB, p65) in primary human chondrocytes Cellular Signalling Medium 34481895
2022 EGR1 transcription factor binds the PER2 promoter and promotes IL-4-induced transcriptional activation of PER2 in human keratinocytes; this is required for normal circadian oscillation of PER2 under IL-4 exposure. IL-4 uses both MAPK and JAK signaling pathways to induce EGR1-mediated PER2 expression. Promoter-reporter assay; EMSA; DNA affinity precipitation; ChIP; Egr1−/− mouse atopic dermatitis model; real-time bioluminescence oscillation assay The Journal of Investigative Dermatology Medium 35398375
2008 Per2 mutation is associated with endothelial dysfunction involving decreased NO production and reduced vasodilatory prostaglandins, combined with increased cyclooxygenase-1-derived vasoconstrictors; COX-1 protein is upregulated in aortas of Per2 mutant mice without changes in eNOS or M3 receptor expression. Aortic ring organ-bath relaxation studies; indomethacin (COX inhibitor) pharmacology; COX-1/COX-2 and eNOS western blotting Circulation Medium 17404161
2021 Deletion of Per2 specifically in glial cells (but not neurons) reduces glutamate levels in the nucleus accumbens and increases GAT2/Slc6a13 and Drd3 mRNA, leading to reduced despair and anxiety behaviors; neuronal Per2 deletion reduces despair but not anxiety; glial Bmal1 deletion has no effect on either behavior. Conditional Cre-lox genetic deletion of Per2 in glia or neurons; AAV-mediated deletion in NAc glia; neurotransmitter measurement; qRT-PCR for transporter/receptor expression; behavioral tests Scientific Reports Medium 34112905
2004 In Xenopus photoreceptors, xPer2 is directly responsive to both light and dopamine (via quinpirole, a D2 agonist), with light-induced xPer2 upregulation not blocked by cAMP analogue but dopamine-induced upregulation blocked by pCPT-cAMP; both signals act specifically in photoreceptors. In situ hybridization; pharmacological manipulation (quinpirole, pCPT-cAMP); cellular localization in retinal sections The European Journal of Neuroscience Medium 15245489
2008 Per2 null mice show enhanced UCP2 expression in the liver, leading to decreased intracellular ATP and increased production of toxic CCl4 derivatives; the absence of Per2 causes elevated CLOCK expression, which drives Ucp2 through a Clock-controlled PPARα signal transduction pathway. Per2-null mouse hepatotoxicity model; Ucp2 mRNA quantification; ATP measurement; Clock and PPARα expression analysis in Per2-null liver The American Journal of Pathology Medium 19056852

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 463 15608650
2010 PER2 controls lipid metabolism by direct regulation of PPARγ. Cell metabolism 394 21035761
2005 Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Carcinogenesis 313 15790588
2007 Mutation of the circadian clock gene Per2 alters vascular endothelial function. Circulation 193 17404161
2007 The clock gene Per2 links the circadian system to the estrogen receptor. Oncogene 165 17599055
2012 CLOCK, PER2 and BMAL1 DNA methylation: association with obesity and metabolic syndrome characteristics and monounsaturated fat intake. Chronobiology international 138 23003921
2007 Expression of the circadian clock genes Per1 and Per2 in sporadic and familial breast tumors. Neoplasia (New York, N.Y.) 132 17971899
2018 CK1δ/ε protein kinase primes the PER2 circadian phosphoswitch. Proceedings of the National Academy of Sciences of the United States of America 128 29784789
2002 Gradients in the circadian expression of Per1 and Per2 genes in the rat suprachiasmatic nucleus. The European journal of neuroscience 127 11982626
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 114 18728223
2008 Increased vascular senescence and impaired endothelial progenitor cell function mediated by mutation of circadian gene Per2. Circulation 111 18981300
2016 Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging. Scientific reports 79 27346580
2011 The circadian mutation PER2(S662G) is linked to cell cycle progression and tumorigenesis. Cell death and differentiation 78 21818120
2012 Persistent cell-autonomous circadian oscillations in fibroblasts revealed by six-week single-cell imaging of PER2::LUC bioluminescence. PloS one 74 22479387
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 70 28963769
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
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
2006 Protein phosphatase 1 regulates the stability of the circadian protein PER2. The Biochemical journal 65 16813562
2015 The Mammalian circadian clock gene per2 modulates cell death in response to oxidative stress. Frontiers in neurology 62 25628599
2010 The clock gene PER2 and sleep problems: association with alcohol consumption among Swedish adolescents. Upsala journal of medical sciences 62 20187847
2020 Casein kinase 1 dynamics underlie substrate selectivity and the PER2 circadian phosphoswitch. eLife 60 32043967
2007 The multiple facets of Per2. Cold Spring Harbor symposia on quantitative biology 60 18419266
2020 Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch. Proceedings of the National Academy of Sciences of the United States of America 59 32354999
2009 Per2 inhibits k562 leukemia cell growth in vitro and in vivo through cell cycle arrest and apoptosis induction. Pathology oncology research : POR 59 19957060
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
2018 Circadian clock gene Per2 downregulation in non‑small cell lung cancer is associated with tumour progression and metastasis. Oncology reports 54 30226549
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
2016 Per2 induction limits lymphoid-biased haematopoietic stem cells and lymphopoiesis in the context of DNA damage and ageing. Nature cell biology 51 27088856
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 50 22274616
2012 Influence of aging on Bmal1 and Per2 expression in extra-SCN oscillators in hamster brain. Brain research 50 23159832
2019 Expression of miR-34a-5p is up-regulated in human colorectal cancer and correlates with survival and clock gene PER2 expression. PloS one 49 31658284
2018 Neurobiological Functions of the Period Circadian Clock 2 Gene, Per2. Biomolecules & therapeutics 45 29223143
2017 Loss of the clock gene PER2 is associated with cancer development and altered expression of important tumor-related genes in oral cancer. International journal of oncology 44 29115399
2015 Circadian genes Per1 and Per2 increase radiosensitivity of glioma in vivo. Oncotarget 43 25760074
2000 Inhibitory action of brotizolam on circadian and light-induced per1 and per2 expression in the hamster suprachiasmatic nucleus. British journal of pharmacology 43 11139454
2020 PER2 inhibits proliferation and stemness of glioma stem cells via the Wnt/β‑catenin signaling pathway. Oncology reports 42 32468039
2009 Combined PER2 and CRY1 expression predicts outcome in chronic lymphocytic leukemia. European journal of haematology 41 19500131
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 39 37914384
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 38 22261359
2009 Motivational Modulation of Rhythms of the Expression of the Clock Protein PER2 in the Limbic Forebrain. Biological psychiatry 38 19200536
2015 Melatonin Entrains PER2::LUC Bioluminescence Circadian Rhythm in the Mouse Cornea. Investigative ophthalmology & visual science 36 26207312
2021 Per1/Per2-Igf2 axis-mediated circadian regulation of myogenic differentiation. The Journal of cell biology 35 34009269
2019 Bisphenol A Alters Bmal1, Per2, and Rev-Erba mRNA and Requires Bmal1 to Increase Neuropeptide Y Expression in Hypothalamic Neurons. Endocrinology 35 30500912
2008 The protective role of Per2 against carbon tetrachloride-induced hepatotoxicity. The American journal of pathology 33 19056852
2020 Overexpression of the clock gene Per2 suppresses oral squamous cell carcinoma progression by activating autophagy via the PI3K/AKT/mTOR pathway. Journal of Cancer 32 32284762
2019 Chronotype Genetic Variant in PER2 is Associated with Intrinsic Circadian Period in Humans. Scientific reports 31 30926824
2019 Systems approach reveals photosensitivity and PER2 level as determinants of clock-modulator efficacy. Molecular systems biology 31 31353796
2017 Salt-inducible kinase 3 regulates the mammalian circadian clock by destabilizing PER2 protein. eLife 31 29227248
2014 Epigenetic suppression of mouse Per2 expression in the suprachiasmatic nucleus by the inhalational anesthetic, sevoflurane. PloS one 31 24498074
2023 PER2 integrates circadian disruption and pituitary tumorigenesis. Theranostics 30 37215573
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
2016 Per2 participates in AKT-mediated drug resistance in A549/DDP lung adenocarcinoma cells. Oncology letters 29 28123577
2021 Deletion of the clock gene Period2 (Per2) in glial cells alters mood-related behavior in mice. Scientific reports 28 34112905
2018 PER2 regulation of mammary gland development. Development (Cambridge, England) 28 29490985
2011 A fear-inducing odor alters PER2 and c-Fos expression in brain regions involved in fear memory. PloS one 28 21655193
2021 Knockout of the circadian gene, Per2, disrupts corticosterone secretion and results in depressive-like behaviors and deficits in startle responses. BMC neuroscience 27 33509094
2018 The circadian gene, Per2, influences methamphetamine sensitization and reward through the dopaminergic system in the striatum of mice. Addiction biology 27 30091820
2004 Regulation of photoreceptor Per1 and Per2 by light, dopamine and a circadian clock. The European journal of neuroscience 27 15245489
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 26 35046033
2018 Zebrafish Lacking Circadian Gene per2 Exhibit Visual Function Deficiency. Frontiers in behavioral neuroscience 26 29593513
2021 PER2 mediates CREB-dependent light induction of the clock gene Per1. Scientific reports 25 34741086
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
2019 Sirt6 deacetylase activity regulates circadian rhythms via Per2. Biochemical and biophysical research communications 23 30782483
2015 Circadian variations of clock gene Per2 and cell cycle genes in different stages of carcinogenesis in golden hamster buccal mucosa. Scientific reports 23 25950458
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
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
2022 Bmal1- and Per2-mediated regulation of the osteogenic differentiation and proliferation of mouse bone marrow mesenchymal stem cells by modulating the Wnt/β-catenin pathway. Molecular biology reports 19 35386071
2021 PER2 Circadian Oscillation Sensitizes Esophageal Cancer Cells to Chemotherapy. Biology 19 33810377
2015 Diurnal Expression of the Per2 Gene and Protein in the Lateral Habenular Nucleus. International journal of molecular sciences 19 26213916
2015 Real-Time Recording of Circadian Per1 and Per2 Expression in the Suprachiasmatic Nucleus of Freely Moving Rats. Journal of biological rhythms 18 26656624
2022 Per1/Per2 Disruption Reduces Testosterone Synthesis and Impairs Fertility in Elderly Male Mice. International journal of molecular sciences 17 35806403
2021 PER2-mediated ameloblast differentiation via PPARγ/AKT1/β-catenin axis. International journal of oral science 16 34011974
2016 Differential localization of PER1 and PER2 in the brain master circadian clock. The European journal of neuroscience 16 27740710
2025 PER2 interaction with HSP70 promotes cuproptosis in oral squamous carcinoma cells by decreasing AKT stability. Cell death & disease 15 40113747
2022 Characterization of Affective Behaviors and Motor Functions in Mice With a Striatal-Specific Deletion of Bmal1 and Per2. Frontiers in physiology 15 35755440
2021 Targeting circadian PER2 as therapy in myocardial ischemia and reperfusion injury. Chronobiology international 15 34034593
2021 Dopamine D1 Receptor-Mediated Regulation of Per1, Per2, CLOCK, and BMAL1 Expression in the Suprachiasmatic Nucleus in Adult Male Rats. Journal of molecular neuroscience : MN 15 34751875
2009 Behavioral and hormonal regulation of expression of the clock protein, PER2, in the central extended amygdala. Progress in neuro-psychopharmacology & biological psychiatry 15 19376186
2008 Deregulated expression of the per2 gene in human colorectal carcinoma. Molecular medicine reports 15 21479457
2022 Involvement of Npas2 and Per2 modifications in zinc-induced acute diurnal toxicity in mice. The Journal of toxicological sciences 14 36450499
2021 Targeted modification of the Per2 clock gene alters circadian function in mPer2luciferase (mPer2Luc) mice. PLoS computational biology 14 34048425
2020 Downregulation of PER2 Promotes Tumor Progression by Enhancing Glycolysis via the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway in Oral Squamous Cell Carcinoma. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 14 32615095
2014 The analysis of deregulated expression and methylation of the PER2 genes in gliomas. Journal of cancer research and therapeutics 14 25313752
2024 More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα. The Journal of physiology 13 38850551
2022 Per2 Expression Regulates the Spatial Working Memory of Mice through DRD1-PKA-CREB Signaling. Molecular neurobiology 13 35508866
2021 IL-1β induces changes in expression of core circadian clock components PER2 and BMAL1 in primary human chondrocytes through the NMDA receptor/CREB and NF-κB signalling pathways. Cellular signalling 13 34481895
2020 Aberrant Expression and Subcellular Localization of PER2 Promote the Progression of Oral Squamous Cell Carcinoma. BioMed research international 13 32185221
2014 Correlation between deregulated expression of PER2 gene and degree of glioma malignancy. Tumori 13 25688509
2022 Transcription Factor EGR1 Regulates the Expression of the Clock Gene PER2 under IL-4 Stimulation in Human Keratinocytes. The Journal of investigative dermatology 12 35398375

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