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Gene Review

PER1  -  period circadian clock 1

Homo sapiens

Synonyms: Circadian clock protein PERIOD 1, Circadian pacemaker protein Rigui, KIAA0482, PER, Period circadian protein homolog 1, ...
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Disease relevance of PER1

  • We hypothesize that in the absence of a fusion protein, the inactivation of PER1 or deregulation of a gene in the neighborhood of PER1 may contribute to the pathogenesis of leukemias with a t(12;17)(p13;p12-p13) [1].
  • A novel cryptic translocation t(12;17)(p13;p12-p13) in a secondary acute myeloid leukemia results in a fusion of the ETV6 gene and the antisense strand of the PER1 gene [1].
  • We used immunohistochemical staining, methylation specific PCR and direct sequencing methods to analyze molecular changes in three most important genes, namely PER1, PER2 and PER3, in circadian rhythm in 55 cases of breast cancer of Taiwanese women [2].
  • Exposure to hypoxia led to increased PER1 and CLOCK protein levels in mice [3].
  • Abnormal expression of period 1 (PER1) in endometrial carcinoma [4].

High impact information on PER1

  • The Per1 gene is a core clock factor that plays an essential role in generating circadian rhythms [5].
  • Ectopic expression of Per1 in human cancer cell lines led to significant growth reduction [5].
  • Overexpression of Per1 sensitized human cancer cells to DNA damage-induced apoptosis; in contrast, inhibition of Per1 in similarly treated cells blunted apoptosis [5].
  • The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells [5].
  • We report here that Per1 provides an important link between the circadian system and the cell cycle system [5].

Chemical compound and disease context of PER1


Biological context of PER1

  • Both PER1 and PER2 proteins share several regions of homology with the Drosophila PER protein, including the protein dimerization PAS domain [11].
  • The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation [12].
  • The PER gene deregulation is not caused by genetic mutations but most probably by methylation of the PER1 or PER2 promoter [2].
  • Both human PERIOD1 (human PER1) and mouse Period1 (mouse Per1) consisted of 23 exons spanning approximately 16 kb, and their structures showed strong similarity to each other [13].
  • These data suggest that clock gene expression, particularly PER1 and PER2, within NDNs may act to modulate diurnal rhythms of DA release from NDNs in the OVX rat [14].

Anatomical context of PER1


Associations of PER1 with chemical compounds

  • However leptomycin B, an inhibitor of nuclear export, did not alter the degradation state of hPER1 protein [16].
  • In the Syrian and Siberian hamster PT, the high amplitude Per1 rhythm associated with dawn is suppressed under short photoperiods, an effect that is mimicked by melatonin treatment [19].
  • At E20, formation of a rhythm in Per1 expression was indicated, but no rhythms in expression of other clock genes or of the AVP gene were detected [20].
  • We found that regardless of the species/strains, subjects with regular NAS and melatonin rhythms present diurnal cocaine sensitization and striatal PER1 rhythm [21].
  • Furthermore, local injection of NMDA into the SCN resulted in the induction of Per1 and Per2 mRNA in the SCN [22].

Regulatory relationships of PER1

  • Here, we show that PER3 is a stronger activator than PER2 and that it can stimulate cell-type-specific transcription when combined with PER1 [23].
  • In the PT, melatonin onset at dusk activates cryptochrone (Cry1) gene expression and melatonin offset at dawn activates period (Per1) gene expression, thus the Cry/Per interval varies directly with nightlength, and inverse to daylength [24].
  • These results suggest that NPY may induce phase shifts by mechanisms involving or resulting in reduction of Per1 and Per2 mRNA levels [25].
  • Bmal1 was prominently expressed in the fetal SCN while Per1 and Cry1 were only weakly expressed [26].

Other interactions of PER1

  • Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers [2].
  • By 3' rapid amplification of cDNA ends-polymerase chain reaction (3' RACE-PCR), a fusion transcript between exon 1 of ETV6 and the antisense strand of PER1 (period homolog 1, Drosophila), a circadian clock gene, could be identified [1].
  • Based on coimmunoprecipitation experiments that showed protein-protein interaction between PER1 and the alpha subunit of HIF-1, we suggest that these hypoxic effects may be modulated by HIF-1alpha.-Chilov, D., Hofer, T., Bauer, C., Wenger, R [3].
  • Eleven of the 35 EC tissues showed CpG methylation in the promoter sequences of PER1, PER2, or CRY1 [27].
  • When co-transfected with wild-type hCKI epsilon, in 293T cells, hPER I showed a significant increase in phosphorylation as evidenced by a shift in molecular mass [28].

Analytical, diagnostic and therapeutic context of PER1

  • The PER1 and PER2 daily profiles were measured in peripheral organs by Western blotting [29].
  • Molecular oscillation of per1 and per2 genes in the rodent brain: an in situ hybridization and molecular biological study [30].
  • In this study, the expression of a circadian gene, PER1, was examined in 35 ECs and paired non-tumour tissues by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry [4].
  • RT-PCR analysis demonstrated the expression of PER1 in all 11 tissues tested, consistent with the data from other mammalian species [31].
  • Addition of NPY to the brain slices in the subjective day resulted in reduction of Per1 and Per2 mRNA levels 0.5 and 2 h after treatment [25].


  1. A novel cryptic translocation t(12;17)(p13;p12-p13) in a secondary acute myeloid leukemia results in a fusion of the ETV6 gene and the antisense strand of the PER1 gene. Penas, E.M., Cools, J., Algenstaedt, P., Hinz, K., Seeger, D., Schafhausen, P., Schilling, G., Marynen, P., Hossfeld, D.K., Dierlamm, J. Genes Chromosomes Cancer (2003) [Pubmed]
  2. Deregulated expression of the PER1, PER2 and PER3 genes in breast cancers. Chen, S.T., Choo, K.B., Hou, M.F., Yeh, K.T., Kuo, S.J., Chang, J.G. Carcinogenesis (2005) [Pubmed]
  3. Hypoxia affects expression of circadian genes PER1 and CLOCK in mouse brain. Chilov, D., Hofer, T., Bauer, C., Wenger, R.H., Gassmann, M. FASEB J. (2001) [Pubmed]
  4. Abnormal expression of period 1 (PER1) in endometrial carcinoma. Yeh, K.T., Yang, M.Y., Liu, T.C., Chen, J.C., Chan, W.L., Lin, S.F., Chang, J.G. J. Pathol. (2005) [Pubmed]
  5. The circadian gene per1 plays an important role in cell growth and DNA damage control in human cancer cells. Gery, S., Komatsu, N., Baldjyan, L., Yu, A., Koo, D., Koeffler, H.P. Mol. Cell (2006) [Pubmed]
  6. Multidrug-resistant Pseudomonas aeruginosa producing PER-1 extended-spectrum serine-beta-lactamase and VIM-2 metallo-beta-lactamase. Docquier, J.D., Luzzaro, F., Amicosante, G., Toniolo, A., Rossolini, G.M. Emerging Infect. Dis. (2001) [Pubmed]
  7. Treatment of experimental pneumonia in rats caused by a PER-1 extended-spectrum beta-lactamase-producing strain of Pseudomonas aeruginosa. Mimoz, O., Elhelali, N., Léotard, S., Jacolot, A., Laurent, F., Samii, K., Petitjean, O., Nordmann, P. J. Antimicrob. Chemother. (1999) [Pubmed]
  8. Activities of cefepime and five other antibiotics against nosocomial PER-1-type and/or OXA-10-type beta-lactamase-producing Pseudomonas aeruginosa and Acinetobacter spp. Vahaboglu, H., Saribaş, S., Akbal, H., Ozturk, R., Yucel, A. J. Antimicrob. Chemother. (1998) [Pubmed]
  9. Resistance to extended-spectrum cephalosporins, caused by PER-1 beta-lactamase, in Salmonella typhimurium from Istanbul, Turkey. Vahaboglu, H., Hall, L.M., Mulazimoglu, L., Dodanli, S., Yildirim, I., Livermore, D.M. J. Med. Microbiol. (1995) [Pubmed]
  10. PER-1- and OXA-10-like beta-lactamases in ceftazidime-resistant Pseudomonas aeruginosa isolates from intensive care unit patients in Istanbul, Turkey. Aktaş, Z., Poirel, L., Salcioğlu, M., Ozcan, P.E., Midilli, K., Bal, C., Anğ, O., Nordmann, P. Clin. Microbiol. Infect. (2005) [Pubmed]
  11. Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei. Shearman, L.P., Zylka, M.J., Weaver, D.R., Kolakowski, L.F., Reppert, S.M. Neuron (1997) [Pubmed]
  12. Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Eide, E.J., Woolf, M.F., Kang, H., Woolf, P., Hurst, W., Camacho, F., Vielhaber, E.L., Giovanni, A., Virshup, D.M. Mol. Cell. Biol. (2005) [Pubmed]
  13. The human and mouse Period1 genes: five well-conserved E-boxes additively contribute to the enhancement of mPer1 transcription. Hida, A., Koike, N., Hirose, M., Hattori, M., Sakaki, Y., Tei, H. Genomics (2000) [Pubmed]
  14. Anatomical and functional characterization of clock gene expression in neuroendocrine dopaminergic neurons. Sellix, M.T., Egli, M., Poletini, M.O., McKee, D.T., Bosworth, M.D., Fitch, C.A., Freeman, M.E. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2006) [Pubmed]
  15. Temporal and spatial distribution of immunoreactive PER1 and PER2 proteins in the suprachiasmatic nucleus and peri-suprachiasmatic region of the diurnal grass rat (Arvicanthis niloticus). Ramanathan, C., Nunez, A.A., Martinez, G.S., Schwartz, M.D., Smale, L. Brain Res. (2006) [Pubmed]
  16. Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts. Miyazaki, K., Nagase, T., Mesaki, M., Narukawa, J., Ohara, O., Ishida, N. Biochem. J. (2004) [Pubmed]
  17. Up-regulation of per mRNA expression by parathyroid hormone through a protein kinase A-CREB-dependent mechanism in chondrocytes. Hinoi, E., Ueshima, T., Hojo, H., Iemata, M., Takarada, T., Yoneda, Y. J. Biol. Chem. (2006) [Pubmed]
  18. Tetrodotoxin administration in the suprachiasmatic nucleus prevents NMDA-induced reductions in pineal melatonin without influencing Per1 and Per2 mRNA levels. Paul, K.N., Gamble, K.L., Fukuhara, C., Novak, C.M., Tosini, G., Albers, H.E. Eur. J. Neurosci. (2004) [Pubmed]
  19. Clock genes in calendar cells as the basis of annual timekeeping in mammals--a unifying hypothesis. Lincoln, G.A., Andersson, H., Loudon, A. J. Endocrinol. (2003) [Pubmed]
  20. Expression of clock and clock-driven genes in the rat suprachiasmatic nucleus during late fetal and early postnatal development. Kováciková, Z., Sládek, M., Bendová, Z., Illnerová, H., Sumová, A. J. Biol. Rhythms (2006) [Pubmed]
  21. Diurnal rhythms in cocaine sensitization and in Period1 levels are common across rodent species. Akhisaroglu, M., Ahmed, R., Kurtuncu, M., Manev, H., Uz, T. Pharmacol. Biochem. Behav. (2004) [Pubmed]
  22. Correlative association between N-methyl-D-aspartate receptor-mediated expression of period genes in the suprachiasmatic nucleus and phase shifts in behavior with photic entrainment of clock in hamsters. Moriya, T., Horikawa, K., Akiyama, M., Shibata, S. Mol. Pharmacol. (2000) [Pubmed]
  23. Transcriptional activation of the neuronal peripherin-encoding gene depends on a G + C-rich element that binds Sp1 in vitro and in vivo. Ferrari, N., Desmarais, D., Royal, A. Gene (1995) [Pubmed]
  24. Decoding the nightly melatonin signal through circadian clockwork. Lincoln, G.A. Mol. Cell. Endocrinol. (2006) [Pubmed]
  25. Neuropeptide Y rapidly reduces Period 1 and Period 2 mRNA levels in the hamster suprachiasmatic nucleus. Fukuhara, C., Brewer, J.M., Dirden, J.C., Bittman, E.L., Tosini, G., Harrington, M.E. Neurosci. Lett. (2001) [Pubmed]
  26. Developmental expression of clock genes in the Syrian hamster. Li, X., Davis, F.C. Brain Res. Dev. Brain Res. (2005) [Pubmed]
  27. Promoter methylation in circadian genes of endometrial cancers detected by methylation-specific PCR. Shih, M.C., Yeh, K.T., Tang, K.P., Chen, J.C., Chang, J.G. Mol. Carcinog. (2006) [Pubmed]
  28. Phosphorylation and destabilization of human period I clock protein by human casein kinase I epsilon. Keesler, G.A., Camacho, F., Guo, Y., Virshup, D., Mondadori, C., Yao, Z. Neuroreport (2000) [Pubmed]
  29. Photoperiodic regulation of PER1 and PER2 protein expression in rat peripheral tissues. Bendov??, Z., Sumov??, S. Physiological research / Academia Scientiarum Bohemoslovaca (2006) [Pubmed]
  30. Molecular oscillation of per1 and per2 genes in the rodent brain: an in situ hybridization and molecular biological study. Matsui, D., Takekida, S., Okamura, H. The Kobe journal of medical sciences. (2005) [Pubmed]
  31. Genetic and physical mapping, expression analysis and partial sequence of porcine PER1. Skinner, T.M., Lopez-Corrales, N.L., Anderson, S.I., Loudon, A.S., Lowden, S., Haley, C.S., Archibald, A.L. Cytogenet. Cell Genet. (2001) [Pubmed]
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