{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T11:33:01Z","timestamp":1790940781424,"version":"4.1.0"},"reference-count":34,"publisher":"The Endocrine Society","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,8,1]]},"abstract":"<jats:p>Ectopic ACTH syndrome (EAS) accounts for 10\u201315% of cases of Cushing\u2019s syndrome and is mostly caused by small cell lung cancers or thymic carcinoids. EAS is characterized by tumoral cortisol resistance, whose underlying mechanism remains unknown. In this study, we reported that silencing mediator of retinoic acid and thyroid hormone receptors (SMRT), a major nuclear corepressor, was aberrantly expressed in ACTH-secreting thymic carcinoids. Overexpression and knockdown of SMRT in the ACTH-secreting AtT-20 cell line demonstrated that SMRT participated in the negative feedback of dexamethasone-mediated suppression of proopiomelanocortin. Posttranslational modification by the small ubiquitin-like modifiers (SUMO), i.e. SUMOylation plays an important role in fine-tuning transcriptional activities. SUMOylation of SMRT was observed in dexamethasone-resistant cell lines. Moreover, overexpression of the deSUMOylation enzyme enhanced the suppression of proopiomelanocortin by dexamethasone in AtT-20 cells. An evolutionarily conserved consensus SUMOylation site was identified close to the histone deacetylase 3 recruiting domain of SMRT, which might interfere with the recruiting process. These results suggested that aberrant expression and modification of SMRT might be involved in the pathogenesis of tumoral cortisol resistance. A therapeutic approach targeting SMRT SUMOylation might be developed for EAS patients.<\/jats:p>","DOI":"10.1210\/en.2010-0335","type":"journal-article","created":{"date-parts":[[2010,6,17]],"date-time":"2010-06-17T02:52:56Z","timestamp":1276743176000},"page":"3697-3705","source":"Crossref","is-referenced-by-count":4,"title":["Aberrant Expression and Modification of Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptors Involved in the Pathogenesis of Tumoral Cortisol Resistance"],"prefix":"10.1210","volume":"151","author":[{"given":"Jingjing","family":"Jiang","sequence":"first","affiliation":[{"name":"Shanghai Clinical Center for Endocrine and Metabolic Diseases (J.J., N.L., X.W., Y.L., Y.B., W.W., X.L., G.N.), E-Institute of Shanghai Universities, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Clinical Center for Endocrine and Metabolic Diseases (J.J., N.L., X.W., Y.L., Y.B., W.W., X.L., G.N.), E-Institute of Shanghai Universities, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Clinical Center for Endocrine and Metabolic Diseases (J.J., N.L., X.W., Y.L., Y.B., W.W., X.L., G.N.), E-Institute of Shanghai Universities, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Lu","sequence":"additional","affiliation":[{"name":"Shanghai Clinical Center for Endocrine and Metabolic Diseases (J.J., N.L., X.W., Y.L., Y.B., W.W., X.L., G.N.), E-Institute of Shanghai Universities, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufang","family":"Bi","sequence":"additional","affiliation":[{"name":"Shanghai Clinical Center for Endocrine and Metabolic Diseases (J.J., N.L., X.W., Y.L., Y.B., W.W., X.L., G.N.), E-Institute of Shanghai Universities, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Shanghai Clinical Center for Endocrine and Metabolic Diseases (J.J., N.L., X.W., Y.L., Y.B., W.W., X.L., G.N.), E-Institute of Shanghai Universities, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Li","sequence":"additional","affiliation":[{"name":"Shanghai Clinical Center for Endocrine and Metabolic Diseases (J.J., N.L., X.W., Y.L., Y.B., W.W., X.L., G.N.), E-Institute of Shanghai Universities, Shanghai 200025, China"},{"name":"Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, and The Key Laboratory of Endocrine Tumors and the Division of Endocrine and Metabolic Diseases (X.L., G.N.), E-Institute of Shanghai Universities, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Ning","sequence":"additional","affiliation":[{"name":"Shanghai Clinical Center for Endocrine and Metabolic Diseases (J.J., N.L., X.W., Y.L., Y.B., W.W., X.L., G.N.), E-Institute of Shanghai Universities, Shanghai 200025, China"},{"name":"Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, and The Key Laboratory of Endocrine Tumors and the Division of Endocrine and Metabolic Diseases (X.L., G.N.), E-Institute of Shanghai Universities, Shanghai 200025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2010,6,16]]},"reference":[{"key":"2020071613272379800_R1","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/BF03344098","article-title":"Six cases of ectopic ACTH syndrome caused by thymic carcinoid.","volume":"29","author":"Wang","year":"2006","journal-title":"J Endocrinol Invest"},{"key":"2020071613272379800_R2","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1677\/joe.1.05963","article-title":"Hypomethylation in the promoter region of POMC gene correlates with ectopic overexpression in thymic carcinoids.","volume":"185","author":"Ye","year":"2005","journal-title":"J Endocrinol"},{"key":"2020071613272379800_R3","doi-asserted-by":"crossref","first-page":"e001","DOI":"10.1621\/nrs.01001","article-title":"Nuclear receptor corepressors","volume":"1","author":"Lazar","year":"2003","journal-title":"Nucl Recept Signal"},{"key":"2020071613272379800_R4","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1093\/emboj\/cdg326","article-title":"A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation.","volume":"22","author":"Yu","year":"2003","journal-title":"EMBO J"},{"key":"2020071613272379800_R5","doi-asserted-by":"crossref","first-page":"6091","DOI":"10.1128\/MCB.21.18.6091-6101.2001","article-title":"The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3.","volume":"21","author":"Guenther","year":"2001","journal-title":"Mol Cell Biol"},{"key":"2020071613272379800_R6","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1101\/gad.1214604","article-title":"SUMO and ubiquitin in the nucleus: different functions, similar mechanisms?","volume":"18","author":"Gill","year":"2004","journal-title":"Genes Dev"},{"key":"2020071613272379800_R7","doi-asserted-by":"crossref","first-page":"27233","DOI":"10.1074\/jbc.M402273200","article-title":"A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus.","volume":"279","author":"Bohren","year":"2004","journal-title":"J Biol Chem"},{"key":"2020071613272379800_R8","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev.biochem.73.011303.074118","article-title":"Protein modification by SUMO.","volume":"73","author":"Johnson","year":"2004","journal-title":"Annu Rev Biochem"},{"key":"2020071613272379800_R9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molcel.2005.03.012","article-title":"SUMO: a history of modification.","volume":"18","author":"Hay","year":"2005","journal-title":"Mol Cell"},{"key":"2020071613272379800_R10","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1091\/mbc.e05-07-0610","article-title":"SUMOylation of the corepressor N-CoR modulates its capacity to repress transcription.","volume":"17","author":"Tiefenbach","year":"2006","journal-title":"Mol Biol Cell"},{"key":"2020071613272379800_R11","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1677\/ERC-08-0325","article-title":"Gene expression profiles of thymic neuroendocrine tumors (carcinoids) with ectopic ACTH syndrome reveal novel molecular mechanism.","volume":"16","author":"Bi","year":"2009","journal-title":"Endocr Relat Cancer"},{"key":"2020071613272379800_R12","doi-asserted-by":"crossref","first-page":"4150","DOI":"10.1128\/MCB.25.10.4150-4165.2005","article-title":"Glucocorticoid receptor (GR)-associated SMRT binding to C\/EBP\u03b2 TAD and Nrf2 Neh4\/5: role of SMRT recruited to GR in GSTA2 gene repression.","volume":"25","author":"Ki","year":"2005","journal-title":"Mol Cell Biol"},{"key":"2020071613272379800_R13","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1073\/pnas.0606476104","article-title":"Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer.","volume":"104","author":"Ferna\u0301ndez-Majada","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613272379800_R14","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.tibs.2007.05.002","article-title":"Modification in reverse: the SUMO proteases.","volume":"32","author":"Mukhopadhyay","year":"2007","journal-title":"Trends Biochem Sci"},{"key":"2020071613272379800_R15","doi-asserted-by":"crossref","first-page":"3409","DOI":"10.1002\/pmic.200800646","article-title":"Systematic study of protein sumoylation: development of a site-specific predictor of SUMOsp 2.0.","volume":"9","author":"Ren","year":"2009","journal-title":"Proteomics"},{"key":"2020071613272379800_R16","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1471-2105-9-8","article-title":"A novel method for high accuracy sumoylation site prediction from protein sequences.","volume":"9","author":"Xu","year":"2008","journal-title":"BMC Bioinformatics"},{"key":"2020071613272379800_R17","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1073\/pnas.0503698102","article-title":"PDSM, a motif for phosphorylation-dependent SUMO modification.","volume":"103","author":"Hietakangas","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613272379800_R18","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/nmeth1006","article-title":"Ubc9 fusion-directed SUMOylation (UFDS): a method to analyze function of protein SUMOylation.","volume":"4","author":"Jakobs","year":"2007","journal-title":"Nat Methods"},{"key":"2020071613272379800_R19","doi-asserted-by":"crossref","first-page":"e109","DOI":"10.1093\/nar\/gkm617","article-title":"Ubc9 fusion-directed SUMOylation identifies constitutive and inducible SUMOylation","volume":"35","author":"Jakobs","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"2020071613272379800_R20","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1046\/j.1365-2265.2001.01323.x","article-title":"Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance.","volume":"55","author":"Ruiz","year":"2001","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071613272379800_R21","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1210\/jc.2004-1920","article-title":"A novel point mutation in the ligand-binding domain (LBD) of the human glucocorticoid receptor (hGR) causing generalized glucocorticoid resistance: the importance of the C terminus of hGR LBD in conferring transactivational activity.","volume":"90","author":"Charmandari","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613272379800_R22","first-page":"296","article-title":"Cushing\u2019s disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation.","volume":"108","author":"Karl","year":"1996","journal-title":"Proc Assoc Am Physicians"},{"key":"2020071613272379800_R23","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1196\/annals.1321.014","article-title":"Familial\/sporadic glucocorticoid resistance: clinical phenotype and molecular mechanisms.","volume":"1024","author":"Charmandari","year":"2004","journal-title":"Ann NY Acad Sci"},{"key":"2020071613272379800_R24","first-page":"124","article-title":"Nelson\u2019s syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene.","volume":"81","author":"Karl","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613272379800_R25","first-page":"1088","article-title":"Expression of glucocorticoid receptor gene isoforms in corticotropin-secreting tumors.","volume":"82","author":"Dahia","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613272379800_R26","first-page":"1193","article-title":"Glucocorticoid receptor structure and function in an adrenocorticotropin-secreting small cell lung cancer.","volume":"9","author":"Gaitan","year":"1995","journal-title":"Mol Endocrinol"},{"key":"2020071613272379800_R27","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1101\/gad.1444606","article-title":"Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease.","volume":"20","author":"Bilodeau","year":"2006","journal-title":"Genes Dev"},{"key":"2020071613272379800_R28","first-page":"101","article-title":"Corepressors and nuclear hormone receptor function.","volume":"254","author":"Ordentlich","year":"2001","journal-title":"Curr Top Microbiol Immunol"},{"key":"2020071613272379800_R29","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1146\/annurev.physiol.66.032802.155556","article-title":"The role of corepressors in transcriptional regulation by nuclear hormone receptors.","volume":"66","author":"Privalsky","year":"2004","journal-title":"Annu Rev Physiol"},{"key":"2020071613272379800_R30","doi-asserted-by":"crossref","first-page":"37341","DOI":"10.1074\/jbc.M706978200","article-title":"Induction of the SUMO-specific protease 1 transcription by the androgen receptor in prostate cancer cells.","volume":"282","author":"Bawa-Khalfe","year":"2007","journal-title":"J Biol Chem"},{"key":"2020071613272379800_R31","doi-asserted-by":"crossref","first-page":"3723","DOI":"10.1016\/j.febslet.2008.09.057","article-title":"Modulation of transcriptional corepressor activity of prospero-related homeobox protein (Prox1) by SUMO modification.","volume":"582","author":"Shan","year":"2008","journal-title":"FEBS Lett"},{"key":"2020071613272379800_R32","doi-asserted-by":"crossref","first-page":"3519","DOI":"10.1073\/pnas.96.7.3519","article-title":"SMRTe, a silencing mediator for retinoid and thyroid hormone receptors-extended isoform that is more related to the nuclear receptor corepressor.","volume":"96","author":"Park","year":"1999","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613272379800_R33","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1073\/pnas.96.6.2639","article-title":"Unique forms of human and mouse nuclear receptor corepressor SMRT.","volume":"96","author":"Ordentlich","year":"1999","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613272379800_R34","doi-asserted-by":"crossref","first-page":"4226","DOI":"10.1182\/blood-2003-10-3583","article-title":"Expression of SMRT\u03b2 promotes ligand-induced activation of mutated and wild-type retinoid receptors.","volume":"104","author":"Co\u0302te\u0301","year":"2004","journal-title":"Blood"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/151\/8\/3697\/9011164\/endo3697.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/151\/8\/3697\/9011164\/endo3697.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T23:51:18Z","timestamp":1594943478000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/151\/8\/3697\/2456885"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,6,16]]},"references-count":34,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2010,8,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2010-0335","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,6,16]]}}}