{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T03:02:20Z","timestamp":1773802940051,"version":"3.50.1"},"reference-count":18,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2014,6,27]],"date-time":"2014-06-27T00:00:00Z","timestamp":1403827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Proliferating thyroid cells are more sensitive to UV-C radiations than quiescent cells. The effect is mediated by nuclear phosphatidylcholine and sphingomyelin metabolism. It was demonstrated that proton beams arrest cell growth and stimulate apoptosis but until now there have been no indications in the literature about their possible mechanism of action. Here we studied the effect of protons on FRTL-5 cells in culture. We showed that proton beams stimulate slightly nuclear neutral sphingomyelinase activity and inhibit nuclear sphingomyelin-synthase activity in quiescent cells whereas stimulate strongly nuclear neutral sphingomyelinase activity and do not change nuclear sphingomyelin-synthase activity in proliferating cells. The study of neutral sphingomyelinase\/sphingomyelin-synthase ratio, a marker of functional state of the cells, indicated that proton beams induce FRTL-5 cells in a proapoptotic state if the cells are quiescent and in an initial apoptotic state if the cells are proliferating. The changes of cell life are accompanied by a decrease of nuclear sphingomyelin and increase of bax protein.<\/jats:p>","DOI":"10.3390\/ijms150711555","type":"journal-article","created":{"date-parts":[[2014,6,27]],"date-time":"2014-06-27T11:23:16Z","timestamp":1403868196000},"page":"11555-11565","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Critical Role for the Protons in FRTL-5 Thyroid Cells:  Nuclear Sphingomyelinase Induced-Damage"],"prefix":"10.3390","volume":"15","author":[{"given":"Elisabetta","family":"Albi","sequence":"first","affiliation":[{"name":"Laboratory of Nuclear Lipid BioPathology, Research Center of Biochemical-Specialized Analyses, Perugia 06100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppina","family":"Perrella","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Udine, Udine 33100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Lazzarini","sequence":"additional","affiliation":[{"name":"Laboratory of Nuclear Lipid BioPathology, Research Center of Biochemical-Specialized Analyses, Perugia 06100, Italy"},{"name":"Department of Clinical and Biological Sciences, University of Udine, Udine 33100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0588-1658","authenticated-orcid":false,"given":"Samuela","family":"Cataldi","sequence":"additional","affiliation":[{"name":"Laboratory of Nuclear Lipid BioPathology, Research Center of Biochemical-Specialized Analyses, Perugia 06100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Remo","family":"Lazzarini","sequence":"additional","affiliation":[{"name":"Laboratory of Nuclear Lipid BioPathology, Research Center of Biochemical-Specialized Analyses, Perugia 06100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Floridi","sequence":"additional","affiliation":[{"name":"Laboratory of Nuclear Lipid BioPathology, Research Center of Biochemical-Specialized Analyses, Perugia 06100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Ambesi-Impiombato","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Udine, Udine 33100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Curcio","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Udine, Udine 33100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2014,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/0027-5107(80)90178-5","article-title":"On the mechanics of chromosomal aberrations: A study with single and multiple spatially-associated protons","volume":"69","author":"Geard","year":"1980","journal-title":"Mutat. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102","DOI":"10.2307\/3579723","article-title":"Induction of chromosome aberrations in human cells by charged particles","volume":"48","author":"Wu","year":"1997","journal-title":"Radiat. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1080\/095530097143734","article-title":"Substructure in the cell survival response at low radiation dose: Effect of different subpopulations","volume":"71","author":"Skarsgard","year":"1997","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_4","first-page":"135","article-title":"The late effects of proton irradiation on cell growth, cell cycle arrest and apoptosis in a human melanoma cell line","volume":"20","author":"Nikolic","year":"2001","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1667\/0033-7587(2002)158[0475:ROTFCT]2.0.CO;2","article-title":"Response of thyroid follicular cells to gamma irradiation compared to proton irradiation: II. The role of connexin 32","volume":"158","author":"Green","year":"2002","journal-title":"Radiat. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.abb.2008.07.018","article-title":"The nuclear ceramide\/diacylglycerol balance depends on the physiological state of thyroid cells and changes during UV-C radiation-induced apoptosis","volume":"478","author":"Albi","year":"2008","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3455","DOI":"10.1073\/pnas.77.6.3455","article-title":"Culture of hormone-dependent functional epithelial cells from rat thyroids","volume":"77","author":"Parks","year":"1980","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","first-page":"527","article-title":"Cell cycle synchronization of FRTL5 cells. A physiological model system","volume":"17","author":"Monaco","year":"1998","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1089\/ast.2010.0461","article-title":"Thyroid cell growth: Sphingomyelin metabolism as non-invasive marker for cell damage acquired during spaceflight","volume":"10","author":"Albi","year":"2010","journal-title":"Astrobiology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e98250","DOI":"10.1371\/journal.pone.0098250","article-title":"A firmer understanding of the effect of hypergravity on thyroid tissue: Cholesterol and thyrotropin receptor","volume":"27","author":"Albi","year":"2014","journal-title":"PLoS One"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5289","DOI":"10.1091\/mbc.e08-05-0517","article-title":"Lipid microdomains in cell nucleus","volume":"19","author":"Cascianelli","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"ref_12","first-page":"325","article-title":"Effect of phospholipids on the activity of DNA polymerase I from E. coli.","volume":"24","author":"Novello","year":"1975","journal-title":"Ital. J. Biochem."},{"key":"ref_13","first-page":"211","article-title":"Sphingomyelin: A small-big molecule in the nucleus","volume":"661","author":"Albi","year":"2006","journal-title":"Recent Res. Dev. Biophys. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1194\/jlr.R800009-JLR200","article-title":"Nuclear sphingolipids: Metabolism and signaling","volume":"49","author":"Ledeen","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6529","DOI":"10.3390\/ijms14046529","article-title":"Nuclear lipid microdomain as place of interaction between sphingomyelin and DNA during Liver regeneration","volume":"14","author":"Albi","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_16","unstructured":"Barnes, D.W.H., Esnouf, M.P., and Stocken, L.A. (1957). Some experiments in favour of the cellular hypothesis for the speen curative factor. Adv. Radiobiol., 211\u2013213."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1194\/jlr.D700041-JLR200","article-title":"Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics","volume":"49","author":"Matyash","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1007\/s00216-011-5154-5","article-title":"Quantification of plasma phospholipids by ultra performance liquid chromatography tandem mass spectrometry","volume":"401","author":"Rabagny","year":"2011","journal-title":"Anal. Bioanal. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/7\/11555\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:13:04Z","timestamp":1760217184000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/7\/11555"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,27]]},"references-count":18,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2014,7]]}},"alternative-id":["ijms150711555"],"URL":"https:\/\/doi.org\/10.3390\/ijms150711555","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,6,27]]}}}