Internet-oheisa­ ineiston taulukko. Valon indusoimien ja kellokoneiston avainmolekyylien yhteydet sairauksiin.

Geeni Eläinmallin ilmiasu Ihmisen sairaus

Homer1 Masennus [1] ? Psykoosi [2] Oppimishäiriöt [3] Dementia [4]

Nr4a1 Apoptoosin häiriöt [5] Masennus [26] Ylivilkkaus [6] Kaksisuuntainen mielialahäiriö [27] Sokeriaineenvaihdunnan häiriöt [7] Psykoosi [27] Ateroskleroosi [8] Akuutti myelooinen leukemia [28] Dementia [4] Rintasyöpä [29] Eturauhassyöpä [30] Melanooma [31] Alzheimerin tauti [32] Ateroskleroosi [33]

Arntl1 Hedelmättömyys [9] Kaamosmasennus [34] Sokeriaineenvaihdunnan häiriöt [10] Kaksisuuntainen mielialahäiriö [35] Rasva-aineenvaihdunnan häiriöt [11] Verenpainetauti [36] Unihäiriöt [12] Tyypin 2 diabetes [36] Artropatia [13] Krooninen myelooinen leukemia [37] Sisäisen kellon arytmia [14]

Clock Mania [15] Unihäiriöt [38] Metabolinen oireyhtymä [16] Metabolinen oireyhtymä [39] Kokaiiniriippuvuus [17] Lihavuus [39, 40] Rasvamaksa [41] Psykoosi [42]

Npas2 Sisäisen kellon joustamattomuus [18] Kaamosmasennus [34] Muistihäiriöt [19] Non-Hodgkin-lymfooma [43] Rintasyöpä [44] Eturauhassyöpä [45] Autismi [46]

Per1 Glukokortikoidituotannon häiriöt [20] Rintasyöpä [47,48] Ei-pienisoluinen keuhkosyöpä [49] Kohtusyöpä [50] Haimasyöpä [51] Krooninen myelooinen leukemia [37] Autismi [46]

Per2 Alkoholin suurkulutus [21] Kaamosmasennus [34] Pahanlaatuinen lymfooma [22] Aikaistuneen univaiheen oireyhtymä [52] Endoteelin toimintahäiriöt [23] Akuutti myelooinen leukemia [53] Krooninen myelooinen leukemia [37] Rintasyöpä [47]

Cry1, Cry2 Unihäiriöt [24] Krooninen myelooinen leukemia [37] Sokeriaineenvaihdunnan häiriöt [25] Eturauhassyöpä [45]

42 INTERNET-OHEISAINEISTON LÄHTEET 14) Bunger M, Wilsbacher L,Moran S, ym. receptors Nr4a3 and Nr4a1 leads to de- 1) Orsetti M, Di Brisco F, Canonico PL, Mop3 is an essential component of the velopment of acute myeloid leukemia. Genazzani AA, Ghi P. Gene regulation master circadian pacemaker in mam- Nat Med 2007;13:730–5. in the frontal cortex of rats exposed to mals. Cell 200;103:1009–17. 29) Pärssinen J, Alarmo EL, Khan S, Karhu the chronic mild stress paradigm, an 15) Roybal K, Theobold D, Graham A, ym. R, Vihinen M, Kallioniemi A. Identifica- animal model of human depression. Mania-like behavior induced by disrup- tion of differentially expressed genes Eur J Neurosci 2008;27:2156–64. tion of CLOCK. Proc Natl Acad Sci U S A after PPM1D silencing in breast cancer. 2) Szumlinski KK, Lominac KD, Kleschen 2007;104:6406–1. Cancer Lett 2008;259:61–70. MJ, ym. Behavioral and neurochemical 16) Turek FW, Joshu C, Kohsaka A, ym. 30) Tamura K, Furihata M, Tsunoda T, ym. phenotyping of Homer1 mutant mice: Obesity and metabolic syndrome in Molecular features of hormone-refrac- possible relevance to schizophrenia. circadian Clock mutant mice. Science tory prostate cancer cells by genome- Genes Brain Behav 2005;4:273–88. 2005;308:1043–5. wide gene expression profiles. Cancer 3) Jaubert PJ, Golub MS, Lo YY, Ger- 17) McClung CA, Sidiropoulou K, Vitaterna Res 2007;67:5117–25. mann SL, ym. Complex, multimodal M, Takahashi JS, White FJ, Cooper DC, 31) Yu H, Kumar SM, Fang D, Acs G, Xu ­behavioral profile of the Homer1 Nestler EJ. Regulation of dopaminer- X. Nuclear orphan TR3/Nur77 knockout mouse. Genes Brain Behav gic transmission and cocaine reward mediates melanoma cell apoptosis. 2007;6:141–54. by the Clock gene. Proc Natl Acad Sci Cancer Biol Ther 2007;6:405–12. 4) Dickey CA, Loring JF, Montgomery J, U S A 2005;102:9377–8. 32) Newman SJ, Bond B, Crook B, Darker Gordon MN, Eastman PS, Morgan 18) Dudley CA, Erbel-Sieler C, Estill SJ, ym. J, Edge C, Maycox PR. Neuron-specific D. Selectively reduced expression of Altered patterns of sleep and behav- localisation of the TR3 death recep- synaptic plasticity-related genes in ioral adaptability in NPAS2-deficient tor in Alzheimer’s disease. Brain Res amyloid precursor protein + preseni- mice. Science 2003;301;379–83. 2000;857:131–40. lin-1 transgenic mice. J Neurosci. 2003 19) Garcia JA, Zhang D, Estill SJ, ym. Im- 33) Bonta PI, van Tiel CM, Vos M, ym. Nu- 15;23:5219–26. paired cued and contextual memory clear receptors Nur77, Nurr1, and NOR- 5) Kim S, Ono K, Tobias P, Han, J. Orphan in NPAS2-deficient mice. Science 1 expressed in atherosclerotic lesion Nur77 is involved in 2000;288:2226–30. macrophages reduce lipid loading and caspase-independent macrophage cell 20) Dallmann R, Touma C, Palme R, Albre- inflammatory responses. Arterioscler death. J Exp Med 2003;197:1441–52. cht U, Steinlechner S. Impaired daily Thromb Vasc Biol 2006;26:2288–94. 6) Gilbert F, Morissette M, St-Hilaire glucocorticoid rhythm in Per1 (Brd) 34) Partonen T, Treutlein J, Alpman A, ym. M, ym. Nur77 gene knockout alters mice. J Comp Physiol 2006;192:769– Three circadian genes Per2, Arntl, dopamine neuron biochemical activity 75. and Npas2 contribute to winter depres- and dopamine turnover. Biol Psychiatry 21) Spanagel R, Pendyala G, Abarca C, sion. Ann Med 2007;39:229–38. 2006;60:538–47. ym. The clock gene Per2 influences 35) Nievergelt CM, Kripke DF, Barrett TB, 7) Fu Y, Luo L, Luo N, Zhu X, Garvey the glutamatergic system and modu- ym. Suggestive evidence for associa- WT. NR4A orphan nuclear recep- lates alcohol consumption. Nat Med tion of the circadian genes PERIOD3 tors modulate insulin action and the 2005;11:35–42. and ARNTL with bipolar disorder. Am glucose transport system: potential 22) Fu, L, Pelicano H, Liu J, Huang P, Lee J Med Genet B Neuropsychiatr Genet role in insulin resistance. J Biol Chem C. The circadian gene Period2 plays an 2006;141B:234–41. 2007;282:31525–33. important role in tumor suppression 36) Woon PY, Kaisaki PJ, Bragança J, ym. 8) Pols TW, Bonta PI, de Vries CJ. NR4A and DNA damage response in vivo. Cell Aryl hydrocarbon receptor nuclear nuclear orphan receptors: protective 2002;111:41–50. translocator-like (BMAL1) is associated in vascular disease? Curr Opin Lipidol 23) Viswambharan H, Carvas JM, Antic V, with susceptibility to hypertension and 2007;18:515–20. ym. Mutation of the circadian clock type 2 diabetes. Proc Natl Acad Sci U S 9) Alvarez JD, Hansen A, Ord T, ym. The gene Per2 alters vascular endothelial A 2007;104:14412–7. circadian clock protein BMAL1 is nec- function. Circulation 2007;115:2188– 37) Yang MY, Chang JG, Lin PM, ym. Down- essary for fertility and proper testo­ 95. regulation of circadian clock genes in sterone production in mice. J Biol 24) Wisor JP, O’Hara BF, Terao A, ym. A role chronic myeloid leukemia: alternative Rhythms 2008;23:26–36. for cryptochromes in sleep regulation. methylation pattern in hPER3. Cancer 10) Rudic RD, McNamara P, Curtis AM, BMC Neurosci 2002;3:20. Sci 2006;97:1298–307. ym. BMAL1 and CLOCK, two essential 25) Ikeda H, Yong Q, Kurose T, ym. Clock 38) Naylor E, Bergmann BM, Krauski K, components of the circadian clock, are gene defect disrupts light-dependency ym. The circadian clock mutation al- involved in glucose homeostasis. PLoS of autonomic nerve activity. Biochem ters sleep homeostasis in the mouse. Biol 2004;2:e377. Biophys Res Commun 2007;364:457– J Neurosci 2000;20:8138–43. 11) Shimba S, Ishii N, Ohta Y, ym. Brain and 63. 39) Scott EM, Carter AM, Grant PJ. As- muscle Arnt-like protein-1 (BMAL1), a 26) Vawter MP, Tomita H, Meng F, ym. sociation between polymorphisms in component of the molecular clock, reg- Mitochondrial-related gene expression the Clock gene, obesity and the met- ulates adipogenesis. Proc Natl Acad Sci changes are sensitive to agonal-pH abolic syndrome in man. Int J Obes U S A 2005;102:12071–6. state: implications for brain disorders. 2008;32:658–62. 12) Laposky A, Easton A, Dugovic C, Wal- Mol Psychiatry 2006;11:663–79. 40) Sookoian S, Gemma C, Gianotti TF, isser J, Bradfield C, Turek F. Deletion of 27) Xing G, Zhang L, Russell S, Post R. Burgueño A, Castaño G, Pirola CJ. Ge- the mammalian circadian clock gene Reduction of dopamine-related tran- netic variants of clock transcription BMAL1/Mop3 alters baseline sleep scription factors Nurr1 and NGFI-B in factor are associated with individual ­architecture and the response to sleep the prefrontal cortex in schizophrenia susceptibility to obesity. Am J Clin Nutr deprivation. Sleep 2005;28:395–409. and bipolar disorders. Schizophr Res 2008;87:1606–15. 13) Bunger MK, Walisser JA, Sullivan R, ym. 2006;84:36–56. 41) Sookoian S, Castaño G, Gemma C, Gi- Progressive arthropathy in mice with a 28) Mullican SE, Zhang S, Konopleva M, anotti TF, Pirola CJ. Common genetic targeted disruption of the Mop3/Bmal- Ruvolo V, Andreeff M, Milbrandt J, variations in CLOCK transcription fac- 1 locus.Genesis 2005;41:122–32. Conneely OM. Abrogation of nuclear tor are associated with nonalcoholic 43 fatty liver disease. World J Gastroen- China. Prostate Cancer Prostatic Dis small cell lung cancer. Clin Cancer Res terol 2007;13:4242–8. 2008;11:342–8. 2007;13:1399–404. 42) Takao T, Tachikawa H, Kawanishi Y, 46) Nicholas B, Rudrasingham V, Nash S, 50) Yeh KT, Yang MY, Liu TC, ym. Abnor- Mizukami K, Asada T. CLOCK gene Kirov G, Owen MJ, Wimpory DC. Asso- mal expression of period 1 (PER1) T3111C polymorphism is associated ciation of Per1 and Npas2 with autistic in endometrial carcinoma. J Pathol with Japanese schizophrenics: a pre- disorder: support for the clock genes/ 2005;206:111–20. liminary study. Eur Neuropsychophar- social timing hypothesis. Mol Psychia- 51) Pogue-Geile KL, Lyons-Weiler J, Whit- macol 2007;17:273–6. try 2007;12:581–92. comb DC. Molecular overlap of fly cir- 43) ZhuY, Leaderer D, Guss C, ym. Ala- 47) Chen ST, Choo K, Hou M, ym. Derugu- cadian rhythms and human pancreatic 394Thr polymorphism in the clock lated expression of the PER1, PER2 and cancer. Cancer Lett 2006;243:55–7. gene NPAS2: a circadian modifier for PER3 in breast cancers. Carsinogenesis 52) Toh KL, Jones CR, He Y, ym An hPer2 the risk of non-Hodgkin’s lymphoma. 2005;26:1241–6. phosphorylation site mutation in fa- Int J Cancer 2006;120:432–5. 48) Gery S, Komatsu N, Baldjyan L, Yu A, milial advanced sleep phase syndrome. 44) Zhu Y, Stevens RG, Leaderer D, ym. Koo D, Koeffler HP. The circadian Science 2001;291:1040–3. Non-synonymous polymorphisms in gene plays an important role in 53) Gery S, Gombert AF,Yi WS, Koeffler C, the circadian gene NPAS2 and breast cell growth and DNA damage con- Holfman WK, Koeffler PH. Transcrip- cancer risk. Breast Cancer Res Treat trol in human cancer cells. Mol Cell tion profiling of C/EBP targets identifies 2008;107:421–5. 2006;22:375–82. Per2 as a gene implicated in myeloid 45) Chu LW, Zhu Y, Yu K, ym. Variants 49) Gery S, Komatsu N, Kawamata N, ym. leukemia. Blood 2005;106:2827–36. in circadian genes and prostate can- Epigenetic silencing of the candidate cer risk: a population-based study in tumor suppressor gene Per1 in non-

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