{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T10:50:32Z","timestamp":1786791032060,"version":"build-2736575974"},"reference-count":55,"publisher":"Bioscientifica","issue":"1","content-domain":{"domain":["jme.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,1,1]]},"abstract":"<jats:p>The mineralocorticoid receptor (MR) is a ligand-activated transcription factor that regulates cardiorenal physiology and disease. Ligand-dependent MR transactivation involves a conformational change in the MR and recruitment of coregulatory proteins to form a unique DNA-binding complex at the hormone response element in target gene promoters. Differences in the recruitment of coregulatory proteins can promote tissue-, ligand- or gene-specific transcriptional outputs. The goal of this study was to evaluate the circadian protein TIMELESS as a selective regulator of MR transactivation. TIMELESS has an established role in cell cycle regulation and DNA repair. TIMELESS may not be central to mammalian clock function and does not bind DNA; however, RNA and protein levels oscillate over 24 h. Co-expression of TIMELESS down-regulated MR transactivation of an MR-responsive reporter in HEK293 cells, yet enhanced transactivation mediated by other steroid receptors. TIMELESS markedly inhibited MR transactivation of synthetic and native gene promoters and expression of MR target genes in H9c2 cardiac myoblasts. Immunofluorescence showed aldosterone induces colocalisation of TIMELESS and MR, although a direct interaction was not confirmed by coimmunoprecipitation. Potential regulation of circadian clock targets cryptochrome 1 and 2 by TIMELESS was not detected. However, our data suggest that these effects may involve TIMELESS coactivation of oestrogen receptor alpha (ER\u03b1). Taken together, these data suggest that TIMELESS may contribute to MR transcriptional outputs via enhancing ER\u03b1 inhibitory actions on MR transactivation. Given the variable expression of TIMELESS in different cell types, these data offer new opportunities for the development of MR modulators with selective actions.<\/jats:p>","DOI":"10.1530\/jme-21-0279","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T12:05:56Z","timestamp":1663070756000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-6","source":"Crossref","is-referenced-by-count":5,"title":["Regulation of mineralocorticoid receptor activation by circadian protein TIMELESS"],"prefix":"10.1530","volume":"70","author":[{"given":"Colin D","family":"Clyne","sequence":"first","affiliation":[{"name":"Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin P","family":"Kusnadi","sequence":"additional","affiliation":[{"name":"Cardiovascular Endocrinology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Cowcher","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Morgan","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J","family":"Fuller","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research, Clayton, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0450-5375","authenticated-orcid":true,"given":"Morag J","family":"Young","sequence":"additional","affiliation":[{"name":"Cardiovascular Endocrinology Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia"},{"name":"University of Melbourne and Baker HDI Department of Cardiometabolic Health and Disease, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"bib1","series-title":"Australia\u2019s Health 2022: The Eighteenth Biennial Health Report of the Australian Institute of Health and Welfare","year":"2022","unstructured":"AIHW2022Australia\u2019s Health 2022: The Eighteenth Biennial Health Report of the Australian Institute of Health and Welfare. Canberra, Australia: Australian Institute of Health and Welfare."},{"key":"bib2","series-title":"Science","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1126\/science.3037703","article-title":"Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor","volume":"237","author":"Arriza","year":"1987","unstructured":"Arriza JLWeinberger CCerelli GGlaser TMHandelin BLHousman DEEvans RM1987Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science237268\u2013275. (https:\/\/doi.org\/10.1126\/science.3037703)10.1126\/science.3037703"},{"key":"bib3","series-title":"Science","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1126\/science.1086593","article-title":"Requirement of mammalian timeless for circadian rhythmicity","volume":"302","author":"Barnes","year":"2003","unstructured":"Barnes JWTischkau SABarnes JAMitchell JWBurgoon PWHickok JRGillette MU2003Requirement of mammalian timeless for circadian rhythmicity. Science302439\u2013442. (https:\/\/doi.org\/10.1126\/science.1086593)10.1126\/science.1086593"},{"key":"bib4","series-title":"FEBS Journal","first-page":"6559","article-title":"Timeless in animal circadian clocks and beyond","volume":"289","author":"Cai","year":"2021","unstructured":"Cai YDChiu JC2021Timeless in animal circadian clocks and beyond. FEBS Journal2896559\u20136575. (https:\/\/doi.org\/10.1111\/febs.16253)"},{"key":"bib5","series-title":"Current Biology","article-title":"CK2 inhibits TIMELESS nuclear export and modulates CLOCK transcriptional activity to regulate circadian rhythms","volume":"31","author":"Cai","year":"2021","unstructured":"Cai YDXue YTruong CCDel Carmen-Li JOchoa CVanselow JTMurphy KALi YHLiu XKunimoto BL2021CK2 inhibits TIMELESS nuclear export and modulates CLOCK transcriptional activity to regulate circadian rhythms. Current Biology31 502.e7\u2013514.e7. (https:\/\/doi.org\/10.1016\/j.cub.2020.10.061)"},{"key":"bib6","series-title":"International Journal of Oncology","doi-asserted-by":"publisher","first-page":"597","DOI":"10.3892\/ijo.2014.2751","article-title":"Protumorigenic role of Timeless in hepatocellular carcinoma","volume":"46","author":"Elgohary","year":"2015","unstructured":"Elgohary NPellegrino RNeumann OElzawahry HMSaber MMZeeneldin AAGeffers REhemann VSchemmer PSchirmacher P, 2015Protumorigenic role of Timeless in hepatocellular carcinoma. International Journal of Oncology46597\u2013606. (https:\/\/doi.org\/10.3892\/ijo.2014.2751)10.3892\/ijo.2014.2751"},{"key":"bib7","series-title":"PLoS ONE","article-title":"Mammalian TIMELESS is involved in period determination and DNA damage-dependent phase advancing of the circadian clock","volume":"8","author":"Engelen","year":"2013","unstructured":"Engelen EJanssens RCYagita KSmits VAVan Der Horst GTTamanini F2013Mammalian TIMELESS is involved in period determination and DNA damage-dependent phase advancing of the circadian clock. PLoS ONE8 e56623. (https:\/\/doi.org\/10.1371\/journal.pone.0056623)"},{"key":"bib8","series-title":"PNAS","doi-asserted-by":"publisher","first-page":"2973","DOI":"10.1073\/pnas.95.6.2973","article-title":"Subcellular localization of mineralocorticoid receptors in living cells: effects of receptor agonists and antagonists","volume":"95","author":"Fejes-T\u00f3th","year":"1998","unstructured":"Fejes-T\u00f3th GPearce DN\u00e1ray-Fejes-T\u00f3th A1998Subcellular localization of mineralocorticoid receptors in living cells: effects of receptor agonists and antagonists. PNAS952973\u20132978. (https:\/\/doi.org\/10.1073\/pnas.95.6.2973)10.1073\/pnas.95.6.2973"},{"key":"bib9","series-title":"FEBS Journal","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1111\/j.1742-4658.2006.05569.x","article-title":"Specific TSC22 domain transcripts are hypertonically induced and alternatively spliced to protect mouse kidney cells during osmotic stress","volume":"274","author":"Fiol","year":"2007","unstructured":"Fiol DFMak SKK\u00fcltz D2007Specific TSC22 domain transcripts are hypertonically induced and alternatively spliced to protect mouse kidney cells during osmotic stress. FEBS Journal274109\u2013124. (https:\/\/doi.org\/10.1111\/j.1742-4658.2006.05569.x)10.1111\/j.1742-4658.2006.05569.x"},{"key":"bib10","series-title":"Journal of Endocrinology","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1530\/JOE-18-0584","article-title":"Cardiomyocyte transcription is controlled by combined MR and circadian clock signalling","volume":"241","author":"Fletcher","year":"2019","unstructured":"Fletcher EKKanki MMorgan JRay DWDelbridge LFuller PJClyne CDYoung MJ2019Cardiomyocyte transcription is controlled by combined MR and circadian clock signalling. Journal of Endocrinology24117\u201329. (https:\/\/doi.org\/10.1530\/JOE-18-0584)10.1530\/JOE-18-0584"},{"key":"bib11","series-title":"Molecular Carcinogenesis","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1002\/mc.20862","article-title":"Genetic and epigenetic associations of circadian gene TIMELESS and breast cancer risk","volume":"51","author":"Fu","year":"2012","unstructured":"Fu ALeaderer DZheng THoffman AEStevens RGZhu Y2012Genetic and epigenetic associations of circadian gene TIMELESS and breast cancer risk. Molecular Carcinogenesis51923\u2013929. (https:\/\/doi.org\/10.1002\/mc.20862)10.1002\/mc.20862"},{"key":"bib12","series-title":"Hypertension","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1161\/01.HYP.0000193502.77417.17","article-title":"Mechanisms of mineralocorticoid action","volume":"46","author":"Fuller","year":"2005","unstructured":"Fuller PJYoung MJ2005Mechanisms of mineralocorticoid action. Hypertension461227\u20131235. (https:\/\/doi.org\/10.1161\/01.HYP.0000193502.77417.17)10.1161\/01.HYP.0000193502.77417.17"},{"key":"bib13","series-title":"Science","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1126\/science.2845584","article-title":"Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated","volume":"242","author":"Funder","year":"1988","unstructured":"Funder JWPearce PTSmith RSmith AI1988Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science242583\u2013585. (https:\/\/doi.org\/10.1126\/science.2845584)10.1126\/science.2845584"},{"key":"bib14","series-title":"Science","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1126\/science.270.5237.811","article-title":"Isolation of timeless by PER protein interaction: defective interaction between timeless protein and long-period mutant PERL","volume":"270","author":"Gekakis","year":"1995","unstructured":"Gekakis NSaez LDelahaye-Brown AMMyers MPSehgal AYoung MWWeitz CJ1995Isolation of timeless by PER protein interaction: defective interaction between timeless protein and long-period mutant PERL. Science270811\u2013815. (https:\/\/doi.org\/10.1126\/science.270.5237.811)10.1126\/science.270.5237.811"},{"key":"bib15","series-title":"Endocrinology","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1210\/en.2005-0860","article-title":"Development of a panel of monoclonal antibodies against the mineralocorticoid receptor","volume":"147","author":"Gomez-Sanchez","year":"2006","unstructured":"Gomez-Sanchez CEDe Rodriguez AFRomero DGEstess JWarden MPGomez-Sanchez MTGomez-Sanchez EP2006Development of a panel of monoclonal antibodies against the mineralocorticoid receptor. Endocrinology1471343\u20131348. (https:\/\/doi.org\/10.1210\/en.2005-0860)10.1210\/en.2005-0860"},{"key":"bib16","series-title":"Nature Neuroscience","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1038\/77653","article-title":"A time-less function for mouse timeless","volume":"3","author":"Gotter","year":"2000","unstructured":"Gotter ALManganaro TWeaver DRKolakowski Jr LFPossidente BSriram SMaclaughlin DTReppert SM2000A time-less function for mouse timeless. Nature Neuroscience3755\u2013756. (https:\/\/doi.org\/10.1038\/77653)10.1038\/77653"},{"key":"bib17","series-title":"Journal of Molecular Biology","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.jmb.2006.10.097","article-title":"Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors","volume":"366","author":"Gotter","year":"2007","unstructured":"Gotter ALSuppa CEmanuel BS2007Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors. Journal of Molecular Biology36636\u201352. (https:\/\/doi.org\/10.1016\/j.jmb.2006.10.097)10.1016\/j.jmb.2006.10.097"},{"key":"bib18","series-title":"Science","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1126\/science.286.5440.768","article-title":"Light-independent role of CRY1 and CRY2 in the mammalian circadian clock","volume":"286","author":"Griffin","year":"1999","unstructured":"Griffin Jr EAStaknis DWeitz CJ1999Light-independent role of CRY1 and CRY2 in the mammalian circadian clock. Science286768\u2013771. (https:\/\/doi.org\/10.1126\/science.286.5440.768)10.1126\/science.286.5440.768"},{"key":"bib19","series-title":"Current Biology","doi-asserted-by":"publisher","first-page":"R714","DOI":"10.1016\/j.cub.2005.08.019","article-title":"The circadian timekeeping system of Drosophila","volume":"15","author":"Hardin","year":"2005","unstructured":"Hardin PE2005The circadian timekeeping system of Drosophila. Current Biology15R714\u2013R722. (https:\/\/doi.org\/10.1016\/j.cub.2005.08.019)10.1016\/j.cub.2005.08.019"},{"key":"bib20","series-title":"Current Opinion in Pharmacology","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.coph.2020.10.007","article-title":"Corticosteroids and circadian rhythms in the cardiovascular system","volume":"57","author":"Kanki","year":"2021","unstructured":"Kanki MYoung MJ2021Corticosteroids and circadian rhythms in the cardiovascular system. Current Opinion in Pharmacology5721\u201327. (https:\/\/doi.org\/10.1016\/j.coph.2020.10.007)10.1016\/j.coph.2020.10.007"},{"key":"bib21","series-title":"FEBS Letters","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/S0014-5793(98)01597-X","article-title":"Identification of the mammalian homologues of the Drosophila timeless gene, Timeless","volume":"441","author":"Koike","year":"1998","unstructured":"Koike NHida ANumano RHirose MSakaki YTei H1998Identification of the mammalian homologues of the Drosophila timeless gene, Timeless. FEBS Letters441427\u2013431. (https:\/\/doi.org\/10.1016\/s0014-5793(9801597-x)10.1016\/S0014-5793(98)01597-X"},{"key":"bib22","series-title":"Trends in Cell Biology","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.tcb.2007.07.001","article-title":"Circadian proteins in the regulation of cell cycle and genotoxic stress responses","volume":"17","author":"Kondratov","year":"2007","unstructured":"Kondratov RVAntoch MP2007Circadian proteins in the regulation of cell cycle and genotoxic stress responses. Trends in Cell Biology17311\u2013317. (https:\/\/doi.org\/10.1016\/j.tcb.2007.07.001)10.1016\/j.tcb.2007.07.001"},{"key":"bib23","series-title":"Journal of Cell Science","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1242\/jcs.057984","article-title":"Human Timeless and Tipin stabilize replication forks and facilitate sister-chromatid cohesion","volume":"123","author":"Leman","year":"2010","unstructured":"Leman ARNoguchi CLee CYNoguchi E2010Human Timeless and Tipin stabilize replication forks and facilitate sister-chromatid cohesion. Journal of Cell Science123660\u2013670. (https:\/\/doi.org\/10.1242\/jcs.057984)10.1242\/jcs.057984"},{"key":"bib24","series-title":"Journal of Molecular Biology","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1016\/j.jmb.2018.03.008","article-title":"Timeless is a novel estrogen receptor co-activator involved in multiple signaling pathways in MCF-7 cells","volume":"430","author":"Magne Nde","year":"2018","unstructured":"Magne Nde CBCasas Gimeno GDocanto MKnower KCYoung MJBuehn JSayed EClyne CD2018Timeless is a novel estrogen receptor co-activator involved in multiple signaling pathways in MCF-7 cells. Journal of Molecular Biology4301531\u20131543. (https:\/\/doi.org\/10.1016\/j.jmb.2018.03.008)10.1016\/j.jmb.2018.03.008"},{"key":"bib25","series-title":"BMC Cancer","article-title":"Potential cancer-related role of circadian gene TIMELESS suggested by expression profiling and in vitro analyses","volume":"13","author":"Mao","year":"2013","unstructured":"Mao YFu ALeaderer DZheng TChen KZhu Y2013Potential cancer-related role of circadian gene TIMELESS suggested by expression profiling and in vitro analyses. BMC Cancer13 498. (https:\/\/doi.org\/10.1186\/1471-2407-13-498)"},{"key":"bib26","series-title":"Biomedicine and Pharmacotherapy","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.biopha.2011.11.007","article-title":"Altered expression of the clock gene machinery in kidney cancer patients","volume":"66","author":"Mazzoccoli","year":"2012","unstructured":"Mazzoccoli GPiepoli ACarella MPanza APazienza VBenegiamo GPalumbo ORanieri E2012Altered expression of the clock gene machinery in kidney cancer patients. Biomedicine and Pharmacotherapy66175\u2013179. (https:\/\/doi.org\/10.1016\/j.biopha.2011.11.007)10.1016\/j.biopha.2011.11.007"},{"key":"bib27","series-title":"Frontiers in Endocrinology","article-title":"Importance of the sequence-directed DNA shape for specific binding site recognition by the estrogen-related receptor","volume":"8","author":"Mohideen-Abdul","year":"2017","unstructured":"Mohideen-Abdul KTazibt KBourguet MHazemann ILebars ITakacs MCianferani SKlaholz BPMoras DBillas IML2017Importance of the sequence-directed DNA shape for specific binding site recognition by the estrogen-related receptor. Frontiers in Endocrinology8 140. (https:\/\/doi.org\/10.3389\/fendo.2017.00140)"},{"key":"bib28","series-title":"Molecular Endocrinology","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1210\/mend.16.3.0787","article-title":"A negative coregulator for the human ER","volume":"16","author":"Norris","year":"2002","unstructured":"Norris JDFan DSherk AMcdonnell DP2002A negative coregulator for the human ER. Molecular Endocrinology16459\u2013468. (https:\/\/doi.org\/10.1210\/mend.16.3.0787)10.1210\/mend.16.3.0787"},{"key":"bib29","series-title":"Nature Reviews: Molecular Cell Biology","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/s41580-019-0179-2","article-title":"Molecular mechanisms and physiological importance of circadian rhythms","volume":"21","author":"Patke","year":"2020","unstructured":"Patke AYoung MWAxelrod S2020Molecular mechanisms and physiological importance of circadian rhythms. Nature Reviews: Molecular Cell Biology2167\u201384. (https:\/\/doi.org\/10.1038\/s41580-019-0179-2)10.1038\/s41580-019-0179-2"},{"key":"bib30","series-title":"New England Journal of Medicine","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1056\/NEJM199909023411001","article-title":"The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators","volume":"341","author":"Pitt","year":"1999","unstructured":"Pitt BZannad FRemme WJCody RCastaigne APerez APalensky JWittes J1999The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. New England Journal of Medicine341709\u2013717. (https:\/\/doi.org\/10.1056\/NEJM199909023411001)10.1056\/NEJM199909023411001"},{"key":"bib31","series-title":"New England Journal of Medicine","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1056\/NEJMoa030207","article-title":"Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction","volume":"348","author":"Pitt","year":"2003","unstructured":"Pitt BRemme WZannad FNeaton JMartinez FRoniker BBittman RHurley SKleiman JGatlin M, 2003Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. New England Journal of Medicine3481309\u20131321. (https:\/\/doi.org\/10.1056\/NEJMoa030207)10.1056\/NEJMoa030207"},{"key":"bib32","series-title":"Journal of Gastrointestinal Surgery","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1007\/s11605-012-2112-2","article-title":"Circadian gene expression and clinicopathologic correlates in pancreatic cancer","volume":"17","author":"Relles","year":"2013","unstructured":"Relles DSendecki JChipitsyna GHyslop TYeo CJArafat HA2013Circadian gene expression and clinicopathologic correlates in pancreatic cancer. Journal of Gastrointestinal Surgery17443\u2013450. (https:\/\/doi.org\/10.1007\/s11605-012-2112-2)10.1007\/s11605-012-2112-2"},{"key":"bib33","series-title":"Investigative Ophthalmology and Visual Science","doi-asserted-by":"publisher","first-page":"8093","DOI":"10.1167\/iovs.12-10419","article-title":"Proteolytic processing of connective tissue growth factor in normal ocular tissues and during corneal wound healing","volume":"53","author":"Robinson","year":"2012","unstructured":"Robinson PMSmith TSPatel DDave MLewin ASPi LScott EWTuli SSSchultz GS2012Proteolytic processing of connective tissue growth factor in normal ocular tissues and during corneal wound healing. Investigative Ophthalmology and Visual Science538093\u20138103. (https:\/\/doi.org\/10.1167\/iovs.12-10419)10.1167\/iovs.12-10419"},{"key":"bib34","series-title":"Nature Reviews: Drug Discovery","first-page":"287","article-title":"Circadian rhythm as a therapeutic target","volume":"20","author":"Ruan","year":"2021","unstructured":"Ruan WYuan XEltzschig HK2021Circadian rhythm as a therapeutic target. Nature Reviews: Drug Discovery20287\u2013307. (https:\/\/doi.org\/10.1038\/s41573-020-00109-w)"},{"key":"bib35","series-title":"Neuron","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1016\/S0896-6273(00)80627-3","article-title":"Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription","volume":"21","author":"Sangoram","year":"1998","unstructured":"Sangoram AMSaez LAntoch MPGekakis NStaknis DWhiteley AFruechte EMVitaterna MHShimomura KKing DP, 1998Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription. Neuron211101\u20131113. (https:\/\/doi.org\/10.1016\/s0896-6273(0080627-3)10.1016\/S0896-6273(00)80627-3"},{"key":"bib36","series-title":"Biochemical and Biophysical Research Communications","doi-asserted-by":"publisher","first-page":"2784","DOI":"10.1016\/j.bbrc.2018.08.040","article-title":"Loss of circadian protein TIMELESS accelerates the progression of cellular senescence","volume":"503","author":"Shen","year":"2018","unstructured":"Shen XLi MMao ZYu W2018Loss of circadian protein TIMELESS accelerates the progression of cellular senescence. Biochemical and Biophysical Research Communications5032784\u20132791. (https:\/\/doi.org\/10.1016\/j.bbrc.2018.08.040)10.1016\/j.bbrc.2018.08.040"},{"key":"bib37","series-title":"Cellular Physiology and Biochemistry","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1159\/000110432","article-title":"Differential regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) splice variants based on alternative initiation of transcription","volume":"20","author":"Simon","year":"2007","unstructured":"Simon PSchneck MHochstetter TKoutsouki EMittelbronn MMerseburger AWeigert CNiess ALang F2007Differential regulation of serum- and glucocorticoid-inducible kinase 1 (SGK1) splice variants based on alternative initiation of transcription. Cellular Physiology and Biochemistry20715\u2013728. (https:\/\/doi.org\/10.1159\/000110432)10.1159\/000110432"},{"key":"bib38","series-title":"Cell Cycle","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.4161\/cc.10.10.15613","article-title":"Timeless functions independently of the Tim-Tipin complex to promote sister chromatid cohesion in normal human fibroblasts","volume":"10","author":"Smith-Roe","year":"2011","unstructured":"Smith-Roe SLPatel SSSimpson DAZhou YCRao SIbrahim JGKaiser-Rogers KACordeiro-Stone MKaufmann WK2011Timeless functions independently of the Tim-Tipin complex to promote sister chromatid cohesion in normal human fibroblasts. Cell Cycle101618\u20131624. (https:\/\/doi.org\/10.4161\/cc.10.10.15613)10.4161\/cc.10.10.15613"},{"key":"bib39","series-title":"Genes to Cells","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1046\/j.1365-2443.1999.00238.x","article-title":"A mammalian ortholog of Drosophila timeless, highly expressed in SCN and retina, forms a complex with mPER1","volume":"4","author":"Takumi","year":"1999","unstructured":"Takumi TNagamine YMiyake SMatsubara CTaguchi KTakekida SSakakida YNishikawa KKishimoto TNiwa S, 1999A mammalian ortholog of Drosophila timeless, highly expressed in SCN and retina, forms a complex with mPER1. Genes to Cells467\u201375. (https:\/\/doi.org\/10.1046\/j.1365-2443.1999.00238.x)10.1046\/j.1365-2443.1999.00238.x"},{"key":"bib40","series-title":"Seminars in Cell and Developmental Biology","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.semcdb.2017.06.011","article-title":"The clock is ticking. Ageing of the circadian system: from physiology to cell cycle","volume":"70","author":"Terzibasi-Tozzini","year":"2017","unstructured":"Terzibasi-Tozzini EMartinez-Nicolas ALucas-Sanchez A2017The clock is ticking. Ageing of the circadian system: from physiology to cell cycle. Seminars in Cell and Developmental Biology70164\u2013176. (https:\/\/doi.org\/10.1016\/j.semcdb.2017.06.011)10.1016\/j.semcdb.2017.06.011"},{"key":"bib41","series-title":"Hormone Research","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1159\/000201107","article-title":"Role of steroid hormone coregulators in health and disease","volume":"71","author":"Thakur","year":"2009","unstructured":"Thakur MKParamanik V2009Role of steroid hormone coregulators in health and disease. Hormone Research71194\u2013200. (https:\/\/doi.org\/10.1159\/000201107)10.1159\/000201107"},{"key":"bib42","series-title":"Cold Spring Harbor Perspectives in Biology","doi-asserted-by":"publisher","first-page":"a033589","DOI":"10.1101\/cshperspect.a033589","article-title":"Coordination between differentially regulated circadian clocks generates rhythmic behavior","volume":"10","author":"Top","year":"2018","unstructured":"Top DYoung MW2018Coordination between differentially regulated circadian clocks generates rhythmic behavior. Cold Spring Harbor Perspectives in Biology10a033589. (https:\/\/doi.org\/10.1101\/cshperspect.a033589)10.1101\/cshperspect.a033589"},{"key":"bib43","series-title":"Molecular and Cellular Biology","doi-asserted-by":"publisher","first-page":"3109","DOI":"10.1128\/MCB.25.8.3109-3116.2005","article-title":"Coupling of human circadian and cell cycles by the timeless protein","volume":"25","author":"Unsal-Ka\u00e7maz","year":"2005","unstructured":"Unsal-Ka\u00e7maz KMullen TEKaufmann WKSancar A2005Coupling of human circadian and cell cycles by the timeless protein. Molecular and Cellular Biology253109\u20133116. (https:\/\/doi.org\/10.1128\/MCB.25.8.3109-3116.2005)10.1128\/MCB.25.8.3109-3116.2005"},{"key":"bib44","series-title":"Journal of Biological Chemistry","doi-asserted-by":"publisher","first-page":"8777","DOI":"10.1074\/jbc.M806103200","article-title":"Timeless maintains genomic stability and suppresses sister chromatid exchange during unperturbed DNA replication","volume":"284","author":"Urtishak","year":"2009","unstructured":"Urtishak KASmith KDChanoux RAGreenberg RAJohnson FBBrown EJ2009Timeless maintains genomic stability and suppresses sister chromatid exchange during unperturbed DNA replication. Journal of Biological Chemistry2848777\u20138785. (https:\/\/doi.org\/10.1074\/jbc.M806103200)10.1074\/jbc.M806103200"},{"key":"bib45","series-title":"Seminars in Ophthalmology","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1080\/08820538.2016.1228418","article-title":"Systemic mineralocorticoid antagonists in the treatment of central serous chorioretinopathy","volume":"32","author":"Yang","year":"2017","unstructured":"Yang DEliott D2017Systemic mineralocorticoid antagonists in the treatment of central serous chorioretinopathy. Seminars in Ophthalmology3236\u201342. (https:\/\/doi.org\/10.1080\/08820538.2016.1228418)10.1080\/08820538.2016.1228418"},{"key":"bib46","series-title":"Journal of Molecular Endocrinology","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1677\/JME-09-0031","article-title":"The mineralocorticoid receptor and its coregulators","volume":"43","author":"Yang","year":"2009","unstructured":"Yang JYoung MJ2009The mineralocorticoid receptor and its coregulators. Journal of Molecular Endocrinology4353\u201364. (https:\/\/doi.org\/10.1677\/JME-09-0031)10.1677\/JME-09-0031"},{"key":"bib47","series-title":"Current Opinion in Pharmacology","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.coph.2016.02.005","article-title":"Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences","volume":"27","author":"Yang","year":"2016","unstructured":"Yang JYoung MJ2016Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences. Current Opinion in Pharmacology2778\u201385. (https:\/\/doi.org\/10.1016\/j.coph.2016.02.005)10.1016\/j.coph.2016.02.005"},{"key":"bib48","series-title":"Journal of Biological Chemistry","doi-asserted-by":"publisher","first-page":"3030","DOI":"10.1074\/jbc.M109.050237","article-title":"Mammalian TIMELESS is required for ATM-dependent CHK2 activation and G2\/M checkpoint control","volume":"285","author":"Yang","year":"2010","unstructured":"Yang XWood PAHrushesky WJM2010Mammalian TIMELESS is required for ATM-dependent CHK2 activation and G2\/M checkpoint control. Journal of Biological Chemistry2853030\u20133034. (https:\/\/doi.org\/10.1074\/jbc.M109.050237)10.1074\/jbc.M109.050237"},{"key":"bib49","series-title":"Molecular Endocrinology","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1210\/me.2010-0193","article-title":"Identification of ligand-selective peptide antagonists of the mineralocorticoid receptor using phage display","volume":"25","author":"Yang","year":"2011","unstructured":"Yang JChang CYSafi RMorgan JMcdonnell DPFuller PJClyne CDYoung MJ2011Identification of ligand-selective peptide antagonists of the mineralocorticoid receptor using phage display. Molecular Endocrinology2532\u201343. (https:\/\/doi.org\/10.1210\/me.2010-0193)10.1210\/me.2010-0193"},{"key":"bib50","series-title":"Journal of Biological Chemistry","doi-asserted-by":"publisher","first-page":"2729","DOI":"10.1074\/jbc.M605596200","article-title":"Human Tim\/Timeless-interacting protein, Tipin, is required for efficient progression of S phase and DNA replication checkpoint","volume":"282","author":"Yoshizawa-Sugata","year":"2007","unstructured":"Yoshizawa-Sugata NMasai H2007Human Tim\/Timeless-interacting protein, Tipin, is required for efficient progression of S phase and DNA replication checkpoint. Journal of Biological Chemistry2822729\u20132740. (https:\/\/doi.org\/10.1074\/jbc.M605596200)10.1074\/jbc.M605596200"},{"key":"bib51","series-title":"Essays in Biochemistry","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1042\/EBC20210006","article-title":"Mineralocorticoid receptor actions in cardiovascular development and disease","volume":"65","author":"Young","year":"2021","unstructured":"Young MJClyne CD2021Mineralocorticoid receptor actions in cardiovascular development and disease. Essays in Biochemistry65901\u2013911. (https:\/\/doi.org\/10.1042\/EBC20210006)10.1042\/EBC20210006"},{"key":"bib52","series-title":"Cell Reports","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.celrep.2015.09.017","article-title":"TIMELESS forms a complex with PARP1 distinct from its complex with TIPIN and plays a role in the DNA damage response","volume":"13","author":"Young","year":"2015","unstructured":"Young LMMarzio APerez-Duran PReid DAMeredith DNRoberti DStar ARothenberg EUeberheide BPagano M2015TIMELESS forms a complex with PARP1 distinct from its complex with TIPIN and plays a role in the DNA damage response. Cell Reports13451\u2013459. (https:\/\/doi.org\/10.1016\/j.celrep.2015.09.017)10.1016\/j.celrep.2015.09.017"},{"key":"bib53","series-title":"New England Journal of Medicine","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1056\/NEJMoa1009492","article-title":"Eplerenone in patients with systolic heart failure and mild symptoms","volume":"364","author":"Zannad","year":"2011","unstructured":"Zannad FMcmurray JJVKrum HVan Veldhuisen DJSwedberg KShi HVincent JPocock SJPitt B & EMPHASIS-HF Study Group2011Eplerenone in patients with systolic heart failure and mild symptoms. New England Journal of Medicine36411\u201321. (https:\/\/doi.org\/10.1056\/NEJMoa1009492)10.1056\/NEJMoa1009492"},{"key":"bib55","series-title":"FASEB Journal","doi-asserted-by":"publisher","first-page":"3936","DOI":"10.1096\/fj.09-134759","article-title":"Cnksr3 is a direct mineralocorticoid receptor target gene and plays a key role in the regulation of the epithelial sodium channel","volume":"23","year":"2009","unstructured":"Ziera TIrlbacher HFromm ALatouche CKrug SMFromm MJaisser F & Borden SA2009Cnksr3 is a direct mineralocorticoid receptor target gene and plays a key role in the regulation of the epithelial sodium channel. FASEB Journal233936\u20133946. (https:\/\/doi.org\/10.1096\/fj.09-134759)10.1096\/fj.09-134759"},{"key":"bib54","series-title":"Molecular Therapy","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.ymthe.2019.08.015","article-title":"Timeless-stimulated miR-5188-FOXO1\/beta-Catenin-c-Jun feedback loop promotes stemness via ubiquitination of beta-catenin in breast cancer","volume":"28","author":"Zou","year":"2020","unstructured":"Zou YLin XBu JLin ZChen YQiu YMo HTang YFang WWu Z2020Timeless-stimulated miR-5188-FOXO1\/beta-Catenin-c-Jun feedback loop promotes stemness via ubiquitination of beta-catenin in breast cancer. Molecular Therapy28313\u2013327. (https:\/\/doi.org\/10.1016\/j.ymthe.2019.08.015)10.1016\/j.ymthe.2019.08.015"}],"container-title":["Journal of Molecular Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/jme.bioscientifica.com\/view\/journals\/jme\/70\/1\/JME-21-0279.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/jme.bioscientifica.com\/downloadpdf\/journals\/jme\/70\/1\/JME-21-0279.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/jme.bioscientifica.com\/downloadpdf\/journals\/jme\/70\/1\/JME-21-0279.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:54:10Z","timestamp":1784555650000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/jme\/article\/14570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,1]]},"references-count":55,"journal-issue":{"issue":"1"},"URL":"https:\/\/doi.org\/10.1530\/jme-21-0279","relation":{},"ISSN":["0952-5041","1479-6813"],"issn-type":[{"value":"0952-5041","type":"print"},{"value":"1479-6813","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,1]]}}}