PER2

Period circadian clock 2
Identifiers
Symbols PER2 ; FASPS; FASPS1
External IDs OMIM: 603426 MGI: 1195265 HomoloGene: 7885 GeneCards: PER2 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 8864 18627
Ensembl ENSG00000132326 ENSMUSG00000055866
UniProt O15055 O54943
RefSeq (mRNA) NM_003894 NM_011066
RefSeq (protein) NP_073728 NP_035196
Location (UCSC) Chr 2:
238.24 – 238.29 Mb		 Chr 1:
91.42 – 91.46 Mb
PubMed search

PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.[1][2]

Discovery

The per gene was first discovered using forward genetics in Drosophilla melanogaster in 1971. This led to experiments in mammals that found Per2 in humans.

Mammalian Per2 was discovered by Albrecht U et al. in 1997 through a search for homologous CDNA sequences to PER1.[3] It is more similar to Drosophila per than its paralogs.[4]

Function

PER2 is a member of the Period family of genes and is expressed in a circadian pattern in the suprachiasmatic nucleus, the primary circadian pacemaker in the mammalian brain. Genes in this family encode components of the circadianclock, which regulates the daily rhythms of locomotor activity, metabolism, and behavior. Circadian expression of these genes and their encoded proteins in the suprachiasmatic nucleus. Human PER2 is involved human sleep disorder and cancer formation.[5] Lowered PER2 expression is common in many tumors cells within the body, suggesting PER2 is integral for proper function and decreased levels promotes tumor progression.[6][7]

PER2 contains glucocorticoid response elements (GREs) and a GRE within the core clock gene PER2 is continuously occupied during rhythmic expression and essential for glucocorticoid regulation of PER2 in vivo. Mice with a genomic deletion spanning this GRE expressed elevated leptin levels and were protected from glucose intolerance and insulin resistance on glucocorticoid treatment but not from muscle wasting. PER2 is an integral component of a particular glucocorticoid regulatory pathway and that glucocorticoid regulation of the peripheral clock is selectively required for some actions of glucocorticoids.[8]

PER2 in mice is stabilized by exposure to strong light. PER2 in turn enhances oxygen-efficient glycolysis and hence provides cardioprotection from ischemia. Therefore, it is speculated that strong light may reduce the risk of heart attacks and decrease the damage after experiencing one.[9] Moreover, PER2 has protective functions in liver diseases, as it antagonizes hepatitis C viral replication.[10]

Per2 knockout mice experience a free-running period of around 21.8 hours, compared to the normal mouse free-running period of 23.3 hours. Some of the Per2 knockout mice can also become arrhythmic under constant light conditions. PER2 has also been shown to be possibly important in the development of cancer. PER2 expression is significantly lower in human patients with lymphoma and acute myeloid leukemia.[11]

The PER2 protein seems to be important for the proliferation of osteoblasts, which aid in adding density to the bone through a pathway utilizing Myc and Ccnd1. Certain PER2 mutations have shown that they can increase the tolerance to the amount of alcohol that a mouse can intake through reduced uptake of glutamate.[12]

Main interactions

In mammals, mPER2 forms a heterodimer with mPER1, mCRY1, and mCRY2 by binding to PAS domains. The heterodimer acts to inhibit their own transcription by suppressing the CLOCK/BMAL1 complex resulting in a negative feedback loop.[13][14] This negative feedback loop is essential for maintaining a functioning circadian clock. A disruption of either both mPER1 and mPER2 genes together or both mCRY genes causes behavioural arrhythmicity when the double-knockout animals are placed in constant conditions. A third PER gene, mPer3, does not have a critical role in the maintenance of the core clock feedback loops. Molecular and behavioural rhythms are preserved in mice lacking mPer3.[15]

Interactions with CK1e

PER2 has been shown to interact with a kinase called CK1e. CK1e phosphorylates PER2 in mammals. In Syrian hamster, a mutation called tau has been discovered in the CK1e, which increases phosphorylation of homologous PER2 leading to a faster degradation and a shortened period.[16] Mutations in hPER2 can cause FASPS because of a lack of phosphorylation site in the mutated hPER2 protein.

Interaction table

Peak of mRNA Peak of Protein Protein Motifs PER1, PER3 PER1, CRY1, CRY2 PER2 binding to Clock/Bmal1 CK1E
PER2 ZT 6 ZT 12 PAS domain Binds together through

PAS domain

 Forms heterodimer to

inhibit Clock/Bmal1

 PER2 inhibits its own transcription

through inhibition of Clock/Bmal1.

 Phosphorylates PER2

Clinical significance

A genetic test from a cheek swab can use PER2 expression levels to tell whether a person is an early morning person or a "night owl".[17]

Familial Advanced Sleep Phase

Familial advanced sleep phase (FASP) is characterized as a short period (e.g. 23.3 vs 24.3hr for population) in humans. A mutation in hPER2 decreases its phosphorylation by CK1d, which causes the phenotype seen in some FASP.[18] The primary cause of these FASP is a mutation that changes amino acid 662 from serine to glycine (S662G) in PER2. The S662G mutation makes PER2 mutant protein a stronger repressor than normal PER2, decreasing cellular PER2 levels and therefore causing this form of FASP. The mutation also seems to cause an increase in the turnover rate of PER2 in the nucleus.[12]

Gene

The PER2 gene is located on the long (q) arm of chromosome 2 at position 37.3 and has 25 exons.[5]

Predicted human PER2 protein created from the PER2 gene shares 44% identity with human PER1 and 77% identity with mouse Per2. Northern blots analysis revealed that PER2 was expressed as a 7-kb mRNA in all tissues examined. An additional 1.8-kb transcript was also detected in some tissues.[19] PER2 mRNA has been shown to peak at ZT 6 in the SCN.[12]

See also

References

  1. ↑ Shearman LP, Zylka MJ, Weaver DR, Kolakowski LF, Reppert SM (Dec 1997). "Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei". Neuron 19 (6): 1261–9. doi:10.1016/S0896-6273(00)80417-1. PMID 9427249.
  2. ↑ Xu Y, Toh KL, Jones CR, Shin JY, Fu YH, Ptácek LJ (Jan 2007). "Modeling of a human circadian mutation yields insights into clock regulation by PER2". Cell 128 (1): 59–70. doi:10.1016/j.cell.2006.11.043. PMC 1828903. PMID 17218255.
  3. ↑ Buhr ED, Takahashi JS (2013). "Molecular components of the Mammalian circadian clock". Handbook of Experimental Pharmacology (217): 3–27. doi:10.1007/978-3-642-25950-0_1. PMC 3762864. PMID 23604473.
  4. ↑ Shearman LP, Zylka MJ, Weaver DR, Kolakowski LF, Reppert SM (Dec 1997). "Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei". Neuron 19 (6): 1261–1269. doi:10.1016/s0896-6273(00)80417-1. PMID 9427249.
  5. 1 2 "Entrez Gene: PER2 period homolog 2 (Drosophila)".
  6. ↑ Winter SL, Bosnoyan-Collins L, Pinnaduwage D, Andrulis IL (Oct 2007). "Expression of the circadian clock genes Per1 and Per2 in sporadic and familial breast tumors". Neoplasia 9 (10): 797–800. doi:10.1593/neo.07595. PMC 2040206. PMID 17971899.
  7. ↑ Liu B, Xu K, Jiang Y, Li X (2014-10-15). "Aberrant expression of Per1, Per2 and Per3 and their prognostic relevance in non-small cell lung cancer". International Journal of Clinical and Experimental Pathology 7 (11): 7863–7871. PMC 4270614. PMID 25550826.
  8. ↑ So AY, Bernal TU, Pillsbury ML, Yamamoto KR, Feldman BJ (Oct 2009). "Glucocorticoid regulation of the circadian clock modulates glucose homeostasis". Proceedings of the National Academy of Sciences of the United States of America 106 (41): 17582–7. doi:10.1073/pnas.0909733106. PMC 2757402. PMID 19805059.
  9. ↑ Eckle T, Hartmann K, Bonney S, Reithel S, Mittelbronn M, Walker LA, Lowes BD, Han J, Borchers CH, Buttrick PM, Kominsky DJ, Colgan SP, Eltzschig HK (May 2012). "Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia". Nature Medicine 18 (5): 774–82. doi:10.1038/nm.2728. PMID 22504483. Lay summary – Medical Daily.
  10. ↑ Benegiamo G, Mazzoccoli G, Cappello F, Rappa F, Scibetta N, Oben J, Greco A, Williams R, Andriulli A, Vinciguerra M, Pazienza V (2013). "Mutual antagonism between circadian protein period 2 and hepatitis C virus replication in hepatocytes". PLOS ONE 8 (4): e60527. doi:10.1371/journal.pone.0060527. PMID 23593233.
  11. ↑ Ko CH, Takahashi JS (Oct 2006). "Molecular components of the mammalian circadian clock". Human Molecular Genetics. 15 Spec No 2 (suppl 2): R271–R277. doi:10.1093/hmg/ddl207. PMID 16987893.
  12. 1 2 3 Takahashi JS, Hong HK, Ko CH, McDearmon EL (Oct 2008). "The genetics of mammalian circadian order and disorder: implications for physiology and disease". Nature Reviews. Genetics 9 (10): 764–775. doi:10.1038/nrg2430. PMC 3758473. PMID 18802415.
  13. ↑ Griffin EA, Staknis D, Weitz CJ (Oct 1999). "Light-independent role of CRY1 and CRY2 in the mammalian circadian clock". Science 286 (5440): 768–71. doi:10.1126/science.286.5440.768. PMID 10531061.
  14. ↑ Miyazaki K, Mesaki M, Ishida N (Oct 2001). "Nuclear entry mechanism of rat PER2 (rPER2): role of rPER2 in nuclear localization of CRY protein". Molecular and Cellular Biology 21 (19): 6651–9. doi:10.1128/MCB.21.19.6651-6659.2001. PMC 99810. PMID 11533252.
  15. ↑ Reppert SM, Weaver DR (Aug 2002). "Coordination of circadian timing in mammals". Nature 418 (6901): 935–941. doi:10.1038/nature00965. PMID 12198538.
  16. ↑ Knippschild U, Krüger M, Richter J, Xu P, García-Reyes B, Peifer C, Halekotte J, Bakulev V, Bischof J (2014). "The CK1 Family: Contribution to Cellular Stress Response and Its Role in Carcinogenesis". Frontiers in Oncology 4: 96. doi:10.3389/fonc.2014.00096. PMC 4032983. PMID 24904820.
  17. ↑ Roger Highfield (2008-06-06). "Swab test to tell if you're a late sleeper or early riser". Telegraph. Retrieved 2008-06-07.
  18. ↑ Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptácek LJ, Fu YH (Feb 2001). "An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome". Science 291 (5506): 1040–1043. doi:10.1126/science.1057499. PMID 11232563.
  19. ↑ "OMIM Entry - * 603426 - PERIOD, DROSOPHILA, HOMOLOG OF, 2; PER2". www.omim.org. Retrieved 2015-04-20.

Further reading

External links

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