{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T13:53:19Z","timestamp":1753883599366,"version":"3.41.2"},"reference-count":36,"publisher":"The Endocrine Society","issue":"6","license":[{"start":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"VA Merit"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Instructive signals that delineate the formation of thyroid follicles by thyrotropin (TSH) in stem cells are complex. Here, we have examined the role of protein kinase C (PKC) by using a unique G\u03b1q\/11 biased small molecule (MSq1) to develop thyroid progenitor cells. Mouse embryonic stem cells (mESCs) were differentiated into anterior endoderm cells and treated with either TSH or MSq1 in the presence or absence of PKC inhibitors. The transcriptional and translational response of key thyroid markers\u2014sodium iodide symporter (NIS), thyroglobulin (TG), and thyrotropin receptor (TSHR) as well as potential signaling molecules\u2014were then analyzed.<\/jats:p>\n               <jats:p>The data confirmed that MSq1 is a potent G\u03b1q\/11 activator with a major increase in G\u03b1q\/11 signaling when compared to TSH. MSq1 activation resulted in an increase in thyroid-specific genes, demonstrating that enhanced PKC signaling was able to induce their expression. The specificity of the PKC signals over the protein kinase A (PKA) pathway in regulating thyroid gene expression was shown by using a specific PKC enzyme inhibitor. The data revealed that TG and NIS expression were suppressed in the presence of the PKC inhibition but, in contrast, were not influenced by PKA inhibition. This indicated that PKC activation was the dominant pathway in the inductive process for thyroid hormone production. Furthermore, by examining PKC isoforms we found that PKC\u03be was the predominant form in the ES cells that mediated the effects. Since PKC\u03be can lead to activation of transforming growth factor-\u03b2\u2013activated kinase (pTAK1), and its downstream effector nuclear factor \u03baB (NF\u03baB) complex, this demonstrated the involvement of the TAK1\/NF\u03baB pathway in thyroid speciation.<\/jats:p>","DOI":"10.1210\/endocr\/bqad067","type":"journal-article","created":{"date-parts":[[2023,4,30]],"date-time":"2023-04-30T14:59:42Z","timestamp":1682866782000},"source":"Crossref","is-referenced-by-count":0,"title":["Thyroid Stem Cell Speciation\u2014a Major Role for PKC"],"prefix":"10.1210","volume":"164","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4226-3728","authenticated-orcid":false,"given":"Rauf","family":"Latif","sequence":"first","affiliation":[{"name":"Thyroid Research Unit, Icahn School of Medicine at Mount Sinai , New York, NY 10029 , USA"},{"name":"James J. Peters VA Medical Center , New York, NY 10468 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2982-5212","authenticated-orcid":false,"given":"Syed A","family":"Morshed","sequence":"additional","affiliation":[{"name":"Thyroid Research Unit, Icahn School of Medicine at Mount Sinai , New York, NY 10029 , USA"},{"name":"James J. Peters VA Medical Center , New York, NY 10468 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin","family":"McCann","sequence":"additional","affiliation":[{"name":"Thyroid Research Unit, Icahn School of Medicine at Mount Sinai , New York, NY 10029 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3909-2750","authenticated-orcid":false,"given":"Terry F","family":"Davies","sequence":"additional","affiliation":[{"name":"Thyroid Research Unit, Icahn School of Medicine at Mount Sinai , New York, NY 10029 , USA"},{"name":"James J. Peters VA Medical Center , New York, NY 10468 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2023,4,30]]},"reference":[{"issue":"7422","key":"2023060218070514800_bqad067-B1","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1038\/nature11525","article-title":"Generation of functional thyroid from embryonic stem cells","volume":"491","author":"Antonica","year":"2012","journal-title":"Nature"},{"issue":"5","key":"2023060218070514800_bqad067-B2","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.stem.2015.09.004","article-title":"Regeneration of thyroid function by transplantation of differentiated pluripotent stem cells","volume":"17","author":"Kurmann","year":"2015","journal-title":"Cell Stem Cell"},{"issue":"4","key":"2023060218070514800_bqad067-B3","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1089\/thy.2012.0644","article-title":"Thyroid follicle formation and thyroglobulin expression in multipotent endodermal stem cells","volume":"23","author":"Ma","year":"2013","journal-title":"Thyroid"},{"issue":"8","key":"2023060218070514800_bqad067-B4","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1242\/dev.033951","article-title":"Activin\/Nodal signalling maintains pluripotency by controlling Nanog expression","volume":"136","author":"Vallier","year":"2009","journal-title":"Development"},{"issue":"2","key":"2023060218070514800_bqad067-B5","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1089\/thy.2016.0264","article-title":"TAZ induction directs differentiation of thyroid follicular cells from human embryonic stem cells","volume":"27","author":"Ma","year":"2017","journal-title":"Thyroid"},{"issue":"24","key":"2023060218070514800_bqad067-B6","doi-asserted-by":"crossref","first-page":"15776","DOI":"10.1073\/pnas.242322099","article-title":"Defining thyrotropin-dependent and -independent steps of thyroid hormone synthesis by using thyrotropin receptor-null mice","volume":"99","author":"Marians","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"2023060218070514800_bqad067-B7","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/cge.13627","article-title":"Molecular defects in thyroid dysgenesis","volume":"97","author":"Mio","year":"2020","journal-title":"Clin Genet"},{"issue":"24","key":"2023060218070514800_bqad067-B8","doi-asserted-by":"crossref","first-page":"15462","DOI":"10.1073\/pnas.242328999","article-title":"Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland","volume":"99","author":"Postiglione","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"2023060218070514800_bqad067-B9","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1210\/jcem-66-5-968","article-title":"Autonomous growth, but not autonomous function, in embryonic human thyroids: a clue to understanding autonomous goiter growth?","volume":"66","author":"Peter","year":"1988","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2023060218070514800_bqad067-B10","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1073\/pnas.93.1.116","article-title":"The human thyrotropin receptor: a heptahelical receptor capable of stimulating members of all four G protein families","volume":"93","author":"Laugwitz","year":"1996","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"2023060218070514800_bqad067-B11","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0009745","article-title":"Principles and determinants of G-protein coupling by the rhodopsin-like thyrotropin receptor","volume":"5","author":"Kleinau","year":"2010","journal-title":"PLoS One"},{"issue":"1","key":"2023060218070514800_bqad067-B12","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1210\/en.2008-0878","article-title":"Characterization of thyrotropin receptor antibody-induced signaling cascades","volume":"150","author":"Morshed","year":"2009","journal-title":"Endocrinology"},{"issue":"9","key":"2023060218070514800_bqad067-B13","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1172\/JCI30380","article-title":"Thyrocyte-specific Gq\/G11 deficiency impairs thyroid function and prevents goiter development","volume":"117","author":"Kero","year":"2007","journal-title":"J Clin Invest"},{"issue":"1","key":"2023060218070514800_bqad067-B14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1210\/en.2013-2079","article-title":"Allosteric modulators hit the TSH receptor","volume":"155","author":"Davies","year":"2014","journal-title":"Endocrinology"},{"issue":"2","key":"2023060218070514800_bqad067-B15","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.ando.2011.03.002","article-title":"Small molecule TSHR agonists and antagonists","volume":"72","author":"Neumann","year":"2011","journal-title":"Ann Endocrinol (Paris)"},{"key":"2023060218070514800_bqad067-B16","doi-asserted-by":"crossref","first-page":"372","DOI":"10.3389\/fendo.2020.00372","article-title":"A Gq biased small molecule active at the TSH receptor","volume":"11","author":"Latif","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"4","key":"2023060218070514800_bqad067-B17","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1002\/stem.605","article-title":"Self-renewal versus lineage commitment of embryonic stem cells: protein kinase C signaling shifts the balance","volume":"29","author":"Dutta","year":"2011","journal-title":"Stem Cells"},{"issue":"8","key":"2023060218070514800_bqad067-B18","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/ni1097","article-title":"Protein kinase C and beyond","volume":"5","author":"Spitaler","year":"2004","journal-title":"Nat Immunol"},{"issue":"12","key":"2023060218070514800_bqad067-B19","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1242\/dev.145615","article-title":"Development of the thyroid gland","volume":"144","author":"Nilsson","year":"2017","journal-title":"Development"},{"key":"2023060218070514800_bqad067-B20","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3389\/fendo.2016.00003","article-title":"The \u201cTSH Receptor Glo Assay\u201d\u2014a high-throughput detection system for thyroid stimulation","volume":"7","author":"Latif","year":"2016","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2023060218070514800_bqad067-B21","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal Biochem"},{"key":"2023060218070514800_bqad067-B22","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3389\/fendo.2015.00056","article-title":"Thyroid cell differentiation from murine induced pluripotent stem cells","volume":"6","author":"Ma","year":"2015","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"1","key":"2023060218070514800_bqad067-B23","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41572-020-0184-y","article-title":"Graves\u2019 disease","volume":"6","author":"Davies","year":"2020","journal-title":"Nat Rev Dis Primers"},{"issue":"Pt 5","key":"2023060218070514800_bqad067-B24","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1042\/BST0351018","article-title":"Functional PKC in vivo analysis using deficient mouse models","volume":"35","author":"Leitges","year":"2007","journal-title":"Biochem Soc Trans"},{"issue":"2","key":"2023060218070514800_bqad067-B25","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1089\/thy.2020.0208","article-title":"The transcription factor NF-\u03baB mediates thyrotropin-stimulated expression of thyroid differentiation markers","volume":"31","author":"Geysels","year":"2021","journal-title":"Thyroid"},{"key":"2023060218070514800_bqad067-B26","first-page":"423","article-title":"Protein kinase C signaling and cell cycle regulation","volume":"3","author":"Black","year":"2012","journal-title":"Front Immunol"},{"issue":"9","key":"2023060218070514800_bqad067-B27","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.1210\/jc.2011-1047","article-title":"Clinical review: the emerging cell biology of thyroid stem cells","volume":"96","author":"Davies","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2023060218070514800_bqad067-B28","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.mce.2016.11.012","article-title":"Regenerative therapy for hypothyroidism: mechanisms and possibilities","volume":"445","author":"Hollenberg","year":"2017","journal-title":"Mol Cell Endocrinol"},{"issue":"8","key":"2023060218070514800_bqad067-B29","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1089\/thy.2020.0930","article-title":"The transient human thyroid progenitor cell: examining the thyroid continuum from stem cell to follicular cell","volume":"31","author":"Davies","year":"2021","journal-title":"Thyroid"},{"issue":"4","key":"2023060218070514800_bqad067-B30","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1089\/thy.2014.0537","article-title":"Human embryonic stem cells form functional thyroid follicles","volume":"25","author":"Ma","year":"2015","journal-title":"Thyroid"},{"issue":"2","key":"2023060218070514800_bqad067-B31","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/0006-291X(80)90329-0","article-title":"Acute effect of thyrotropin on phosphatidylinositol degradation and transient accumulation of diacylglycerol in isolated thyroid follicles","volume":"97","author":"Igarashi","year":"1980","journal-title":"Biochem Biophys Res Commun"},{"issue":"4","key":"2023060218070514800_bqad067-B32","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1111\/imm.12510","article-title":"Protein kinase C in the immune system: from signalling to chromatin regulation","volume":"146","author":"Lim","year":"2015","journal-title":"Immunology"},{"issue":"1","key":"2023060218070514800_bqad067-B33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1089\/thy.1996.6.53","article-title":"Regulation of protein kinase C isoforms in FRTL-5 thyroid cells by TSH and phorbol ester","volume":"6","author":"Matowe","year":"1996","journal-title":"Thyroid"},{"issue":"12","key":"2023060218070514800_bqad067-B34","doi-asserted-by":"crossref","first-page":"4919","DOI":"10.1210\/en.2012-2234","article-title":"Thyroid and bone: macrophage-derived TSH-\u03b2 splice variant increases murine osteoblastogenesis","volume":"154","author":"Baliram","year":"2013","journal-title":"Endocrinology"},{"issue":"10","key":"2023060218070514800_bqad067-B35","doi-asserted-by":"crossref","first-page":"3737","DOI":"10.1172\/JCI63948","article-title":"Hyperthyroid-associated osteoporosis is exacerbated by the loss of TSH signaling","volume":"122","author":"Baliram","year":"2012","journal-title":"J Clin Invest"},{"key":"2023060218070514800_bqad067-B36","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2021.657195","article-title":"Single-cell trajectory inference guided enhancement of thyroid maturation in vitro using TGF-Beta inhibition","volume":"12","author":"Romitti","year":"2021","journal-title":"Front Endocrinol (Lausanne)"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/endo\/advance-article-pdf\/doi\/10.1210\/endocr\/bqad067\/50148632\/bqad067.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/164\/6\/bqad067\/50513811\/bqad067.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/164\/6\/bqad067\/50513811\/bqad067.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,3]],"date-time":"2023-06-03T04:30:51Z","timestamp":1685766651000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/doi\/10.1210\/endocr\/bqad067\/7147332"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,17]]},"references-count":36,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,4,17]]}},"URL":"https:\/\/doi.org\/10.1210\/endocr\/bqad067","relation":{},"ISSN":["1945-7170"],"issn-type":[{"type":"electronic","value":"1945-7170"}],"subject":[],"published-other":{"date-parts":[[2023,6]]},"published":{"date-parts":[[2023,4,17]]},"article-number":"bqad067"}}