{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:09:54Z","timestamp":1791346194479,"version":"4.3.1"},"reference-count":80,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T00:00:00Z","timestamp":1612137600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB) transcription factor is a key regulator of cell survival, proliferation, and gene expression. Although activation of NF-\u03baB signaling in thyroid follicular cells after thyrotropin (TSH) receptor (TSHR) engagement has been reported, the downstream signaling leading to NF-\u03baB activation remains unexplored. Here, we sought to elucidate the mechanisms that regulate NF-\u03baB signaling activation in response to TSH stimulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Fisher rat-derived thyroid cell lines and primary cultures of NF-\u03baB essential modulator (NEMO)-deficient mice thyrocytes were used as models. Signaling pathways leading to the activation of NF-\u03baB were investigated by using chemical inhibitors and phospho-specific antibodies. Luciferase reporter gene assays and site-directed mutagenesis were used to monitor NF-\u03baB-dependent gene transcriptional activity and the expression of thyroid differentiation markers was assessed by reverse transcription quantitative polymerase chain reaction and Western blot, respectively. Chromatin immunoprecipitation (ChIP) was carried out to investigate NF-\u03baB subunit p65 DNA binding, and small interfering RNA (siRNA)-mediated gene knockdown approaches were used for studying gene function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Using thyroid cell lines, we observed that TSH treatment leads to protein kinase C (PKC)-mediated canonical NF-\u03baB p65 subunit nuclear expression. Moreover, TSH stimulation phosphorylated the kinase TAK-1, and its knockdown abolished TSH-induced NF-\u03baB transcriptional activity. TSH induced the transcriptional activity of the NF-\u03baB subunit p65 in a protein kinase A (PKA)-dependent phosphorylation at Ser-276. In addition, p65 phosphorylation at Ser-276 induced acetyl transferase p300 recruitment, leading to its acetylation on Lys-310 and thereby enhancing its transcriptional activity. Evaluation of the role played by NF-\u03baB in thyroid physiology demonstrated that the canonical NF-\u03baB inhibitor BAY 11-7082 reduced TSH-induced expression of thyroid differentiation markers. The involvement of NF-\u03baB signaling in thyroid physiology was confirmed by assessing the TSH-induced gene expression in primary cultures of NEMO-deficient mice thyrocytes. ChIP and the knockdown experiments revealed that p65 is a nuclear effector of TSH actions, inducing the transcripcional expression of thyroid differentiation markers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Taken together, our results point to NF-\u03baB being a pivotal mediator in the TSH-induced thyroid follicular cell differentiation, a relevant finding with potential physiological and pathophysiological implications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2020.0208","type":"journal-article","created":{"date-parts":[[2020,9,16]],"date-time":"2020-09-16T05:43:27Z","timestamp":1600235007000},"page":"299-314","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":12,"title":["The Transcription Factor NF-\u03baB Mediates Thyrotropin-Stimulated Expression of Thyroid Differentiation Markers"],"prefix":"10.1177","volume":"31","author":[{"given":"Romina Celeste","family":"Geysels","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, C\u00f3rdoba, Argentina."},{"name":"Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda\u2014Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CIBICI-CONICET), C\u00f3rdoba, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Peyret","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, C\u00f3rdoba, Argentina."},{"name":"Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda\u2014Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CIBICI-CONICET), C\u00f3rdoba, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariano","family":"Mart\u00edn","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, C\u00f3rdoba, Argentina."},{"name":"Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda\u2014Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CIBICI-CONICET), C\u00f3rdoba, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magal\u00ed","family":"Nazar","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, C\u00f3rdoba, Argentina."},{"name":"Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda\u2014Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CIBICI-CONICET), C\u00f3rdoba, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Reale","sequence":"additional","affiliation":[{"name":"Biogem Consortium, Ariano Irpino, Italy."},{"name":"Dipartimento di Scienze e Tecnologie, Universit\u00e0 degli Studi del Sannio, Benevento, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Eduardo","family":"Bernal Barquero","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, C\u00f3rdoba, Argentina."},{"name":"Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda\u2014Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CIBICI-CONICET), C\u00f3rdoba, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Miranda","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina."},{"name":"Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales\u2014Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (IQUIBICEN-CONICET), Buenos Aires, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo Adri\u00e1n","family":"Mart\u00ed","sequence":"additional","affiliation":[{"name":"Departamento de Qu\u00edmica Biol\u00f3gica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina."},{"name":"Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales\u2014Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (IQUIBICEN-CONICET), Buenos Aires, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Vito","sequence":"additional","affiliation":[{"name":"Biogem Consortium, Ariano Irpino, Italy."},{"name":"Dipartimento di Scienze e Tecnologie, Universit\u00e0 degli Studi del Sannio, Benevento, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Mar\u00eda","family":"Masini-Repiso","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, C\u00f3rdoba, Argentina."},{"name":"Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda\u2014Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CIBICI-CONICET), C\u00f3rdoba, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Pablo","family":"Nicola","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, C\u00f3rdoba, Argentina."},{"name":"Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda\u2014Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas (CIBICI-CONICET), C\u00f3rdoba, Argentina."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2021,2,12]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2012-1072"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.242322099"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.242328999"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.9.5882"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.15.3.1162"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2007-0093"},{"key":"e_1_3_5_8_2","first-page":"1587","article-title":"Protein kinase-C activation during thyrotropin-stimulated proliferation of rat FRTL-5 thyroid cells","volume":"130","author":"Fujimoto J","year":"1992","unstructured":"Fujimoto J, , Brenner-Gati L. 1992. Protein kinase-C activation during thyrotropin-stimulated proliferation of rat FRTL-5 thyroid cells. Endocrinology, 130:1587\u20131592.","journal-title":"Endocrinology"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30380"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00071"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00471"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2008-0878"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2011.0480"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2007-0459"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2012-1567"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2010-0102"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-1192"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.711697"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.12.2.576"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.16.2.0774"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.142.1.7918"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2003.11.026"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2008-0353"},{"key":"e_1_3_5_24_2","first-page":"1931","article-title":"Identification and characterization of a 3\u2032,5\u2032-cyclic adenosine monophosphate-responsive element in the human corticotropin-releasing hormone gene promoter","volume":"6","author":"Spengler D","year":"1992","unstructured":"Spengler D, , Rupprecht R, , Van LP, , Holsboer F. 1992. Identification and characterization of a 3\u2032,5\u2032-cyclic adenosine monophosphate-responsive element in the human corticotropin-releasing hormone gene promoter. Mol Endocrinol, 6:1931\u20131941.","journal-title":"Mol Endocrinol"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.071241"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(89)92727-7"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5412.309"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.183.3.1013"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.115.6.1295"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2006.08.003"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni985"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.8.1839"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2016.02.006"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2015.11.020"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1607231113"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-1824"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2019.0046"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-00718"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01980"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2018-00603"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M000916200"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.11.5568"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2016.08.036"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2010.05.004"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2008.12.003"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2005-0493"},{"key":"e_1_3_5_47_2","first-page":"2577","article-title":"Somatic and germline mutations of the TSH receptor gene in thyroid diseases","volume":"80","author":"Van Sande J","year":"1995","unstructured":"Van Sande J, , Parma J, , Tonacchera M, , Swillens S, , Dumont J, , Vassart G. 1995. Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J Clin Endocrinol Metab, 80:2577\u20132585.","journal-title":"J Clin Endocrinol Metab"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601622"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11525"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells5010012"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2004-0020"},{"key":"e_1_3_5_52_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.14.9.0516"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1720163"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2013-1377"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.1677\/joe.1.06486"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.19.11453"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3540573"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2004-1178"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2009.08.018"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1677\/JOE-07-0452"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2007-1588"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00771-2"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.140.4.6619"},{"key":"e_1_3_5_64_2","first-page":"14449","article-title":"The role of TAK1 expression in thyroid cancer","volume":"8","author":"Lin P","year":"2015","unstructured":"Lin P, , Niu W, , Peng C, , Zhang Z, , Niu J. 2015. The role of TAK1 expression in thyroid cancer. Int J Clin Exp Pathol, 8:14449\u201314456.","journal-title":"Int J Clin Exp Pathol"},{"key":"e_1_3_5_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2014.02.015"},{"key":"e_1_3_5_66_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0075100"},{"key":"e_1_3_5_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-34427-2"},{"key":"e_1_3_5_68_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.073783"},{"key":"e_1_3_5_69_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M003043200"},{"key":"e_1_3_5_70_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2004-0426"},{"key":"e_1_3_5_71_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0228794"},{"key":"e_1_3_5_72_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-1735"},{"key":"e_1_3_5_73_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2016-1609"},{"key":"e_1_3_5_74_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.142"},{"key":"e_1_3_5_75_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2012.0237"},{"key":"e_1_3_5_76_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-0400"},{"key":"e_1_3_5_77_2","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-17-0433"},{"key":"e_1_3_5_78_2","first-page":"287","article-title":"Association of NF-kappaB polymorphisms with clinical outcome of non-medullary thyroid carcinoma","volume":"24","author":"Plantinga TS","year":"2017","unstructured":"Plantinga TS, , Petrulea MS, , Oosting M, , Joosten LAB, , Piciu D, , Smit JW, , Netea-Maier RT, , Georgescu CE. 2017. Association of NF-kappaB polymorphisms with clinical outcome of non-medullary thyroid carcinoma. Endocr Relat Cancer, 24:287\u2013298.","journal-title":"Endocr Relat Cancer"},{"key":"e_1_3_5_79_2","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-11-0076"},{"key":"e_1_3_5_80_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2007.0357"},{"key":"e_1_3_5_81_2","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-17-0182"}],"container-title":["Thyroid\u00ae"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/thy.2020.0208","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/thy.2020.0208","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/thy.2020.0208","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T22:07:26Z","timestamp":1777586846000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/thy.2020.0208"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2]]},"references-count":80,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,2]]}},"alternative-id":["10.1089\/thy.2020.0208"],"URL":"https:\/\/doi.org\/10.1089\/thy.2020.0208","relation":{},"ISSN":["1050-7256","1557-9077"],"issn-type":[{"value":"1050-7256","type":"print"},{"value":"1557-9077","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2]]}}}