{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T21:25:28Z","timestamp":1782854728916,"version":"3.54.5"},"reference-count":56,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T00:00:00Z","timestamp":1652313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["1403\/14"],"award-info":[{"award-number":["1403\/14"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Normal growth and development in mammals are tightly controlled by numerous genetic factors and metabolic conditions. The growth hormone (GH)-insulin-like growth factor-1 (IGF1) hormonal axis is a key player in the regulation of these processes. Dysregulation of the GH-IGF1 endocrine system is linked to a number of pathologies, ranging from growth deficits to cancer. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor (GHR) gene, leading to GH resistance and short stature as well as a number of metabolic abnormalities. Of major clinical relevance, epidemiological studies have shown that LS patients do not develop cancer. While the mechanisms associated with cancer protection in LS have not yet been elucidated, genomic analyses have identified a series of metabolic genes that are over-represented in LS patients. We hypothesized that these genes might constitute novel targets for IGF1 action. With a fold-change of 11.09, UDP-glucuronosyltransferase 2B15 (UGT2B15) was the top up-regulated gene in LS. The UGT2B15 gene codes for an enzyme that converts xenobiotic substances into lipophilic compounds and thereby facilitates their clearance from the body. We investigated the regulation of UGT2B15 gene expression by IGF1 and insulin. Both hormones inhibited UGT2B15 mRNA levels in endometrial and breast cancer cell lines. Regulation of UGT2B15 protein levels by IGF1\/insulin, however, was more complex and not always correlated with mRNA levels. Furthermore, UGT2B15 expression was dependent on p53 status. Thus, UGT2B15 mRNA levels were higher in cell lines expressing a wild-type p53 compared to cells containing a mutated p53. Animal studies confirmed an inverse correlation between UGT2B15 and p53 levels. In summary, increased UGT2B15 levels in LS might confer upon patient\u2019s protection from genotoxic damage.<\/jats:p>","DOI":"10.3390\/cells11101627","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T21:46:53Z","timestamp":1652392013000},"page":"1627","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of UDP-Glucuronosyltransferase 2B15 (UGT2B15) as a Target for IGF1 and Insulin Action"],"prefix":"10.3390","volume":"11","author":[{"given":"Rive","family":"Sarfstein","sequence":"first","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik","family":"Nagaraj","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6364-9307","authenticated-orcid":false,"given":"Shivang","family":"Parikh","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmit","family":"Levy","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zvi","family":"Laron","sequence":"additional","affiliation":[{"name":"Endocrinology and Diabetes Research Unit, Schneider Children\u2019s Medical Center, Petah Tikva 49292, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1522-1362","authenticated-orcid":false,"given":"Dafna","family":"Benayahu","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0154-1290","authenticated-orcid":false,"given":"Haim","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,12]]},"reference":[{"key":"ref_1","first-page":"825","article-title":"A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro","volume":"49","author":"Salmon","year":"1957","journal-title":"J. Lab. Clin. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/ncpendmet0427","article-title":"Mechanisms of disease: Metabolic effects of growth hormone and insulin-like growth factor-1","volume":"3","author":"LeRoith","year":"2007","journal-title":"Nat. Clin. Pract. Endocrinol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1056\/NEJMp038156","article-title":"Insulin-like growth factors and the basis of growth","volume":"349","author":"Rosenfeld","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"T115","DOI":"10.1530\/JME-17-0298","article-title":"Insulin-like growth factors: Actions on the skeleton","volume":"61","author":"Yakar","year":"2018","journal-title":"J. Mol. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1016\/j.cmet.2016.05.014","article-title":"The somatotropic axis in human aging: Framework for the current state of knowledge and future research","volume":"23","author":"Milman","year":"2016","journal-title":"Cell Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3889","DOI":"10.1073\/pnas.89.9.3889","article-title":"Ras proteins are essential and selective for the action of insulin-like growth factor 1 late in the G1 phase of the cell cycle in BALB\/c murine fibroblasts","volume":"89","author":"Lu","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","first-page":"47","article-title":"Cell cycle and growth control","volume":"3","author":"Baserga","year":"1993","journal-title":"Crit. Rev. Eukaryot. Gene Expr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"159","DOI":"10.3389\/fonc.2016.00159","article-title":"Insulin-like growth factor 1 signaling axis meets p53 genome protection pathways","volume":"6","author":"Werner","year":"2016","journal-title":"Front. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1126\/science.279.5350.563","article-title":"Plasma insulin-like growth factor-I and prostate cancer risk: A prospective study","volume":"279","author":"Chan","year":"1998","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1016\/S0140-6736(97)10384-1","article-title":"Circulating concentrations of insulin-like growth factor-I and risk of breast cancer","volume":"351","author":"Hankinson","year":"1998","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"111003","DOI":"10.1016\/j.mce.2020.111003","article-title":"Role of the GH-IGF1 system in progression of cancer","volume":"518","author":"Werner","year":"2020","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1016\/S0140-6736(04)16044-3","article-title":"Insulin-like growth factor-I, IGF binding protein-3, and cancer risk: Systematic review and meta-regression analysis","volume":"363","author":"Renehan","year":"2004","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nrc3215","article-title":"The insulin and insulin-like growth factor receptor family in neoplasia: An update","volume":"12","author":"Pollak","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4235","DOI":"10.1210\/jc.2006-1641","article-title":"Controversy in clinical endocrinology: Problems with reclassification of insulin-like growth factor I production and action disorders","volume":"91","author":"Cohen","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.tem.2008.03.003","article-title":"IGF signaling defects as causes of growth failure and IUGR","volume":"19","author":"Klammt","year":"2008","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4210","DOI":"10.1210\/jc.2008-0509","article-title":"Consensus statement on the diagnosis and treatment of children with idiopathic short stature: A summary of the Growth Hormone Research Society, The Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology Workshop","volume":"93","author":"Cohen","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1056\/NEJM199610313351805","article-title":"Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene","volume":"335","author":"Woods","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_18","first-page":"39","article-title":"Genetic mutations in the GH\/IGF axis","volume":"16","year":"2018","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1159\/000341739","article-title":"Spectrum of insulin-like growth factor deficiency","volume":"23","author":"Wit","year":"2012","journal-title":"Endocr. Dev."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Laron, Z., and Kopchik, J.J. (2011). Laron Syndrome-From Man to Mouse, Springer.","DOI":"10.1007\/978-3-642-11183-9"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1210\/jc.2003-031033","article-title":"Extensive personal experience. Laron syndrome (primary growth hormone resistance or insensitivity): The personal experience 1958\u20132003","volume":"89","author":"Laron","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.mrrev.2016.08.002","article-title":"IGF-I deficiency, longevity and cancer protection of patients with Laron syndrome","volume":"772","author":"Laron","year":"2017","journal-title":"Mutat. Res. Rev. Mutat. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1056\/NEJM198910123211501","article-title":"Laron dwarfism and mutations of the growth hormone-receptor gene","volume":"321","author":"Amselem","year":"1989","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8083","DOI":"10.1073\/pnas.86.20.8083","article-title":"Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism","volume":"86","author":"Godowski","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.ghir.2006.10.007","article-title":"Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: A preliminary report","volume":"17","author":"Shevah","year":"2007","journal-title":"Growth Horm. IGF Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1530\/EJE-10-0859","article-title":"Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies","volume":"164","author":"Steuerman","year":"2011","journal-title":"Eur. J. Endocrinol."},{"key":"ref_27","first-page":"70ra13","article-title":"Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans","volume":"3","author":"Balasubramanian","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_28","first-page":"6","article-title":"Fifty years on: New lessons from Laron syndrome","volume":"19","author":"Werner","year":"2017","journal-title":"Isr. Med. Assoc. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1530\/ERC-16-0054","article-title":"Identification of signaling pathways associated with cancer protection in Laron syndrome","volume":"23","author":"Rotem","year":"2016","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Werner, H., Lapkina-Gendler, L., Achlaug, L., Nagaraj, K., Somri, L., Yaron-Saminsky, D., Pasmanik-Chor, M., Sarfstein, R., Laron, Z., and Yakar, S. (2019). Genome-Wide Profiling of Laron Syndrome Patients Identifies Novel Cancer Protection Pathways. Cells, 8.","DOI":"10.3390\/cells8060596"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Werner, H., Sarfstein, R., Nagaraj, K., and Laron, Z. (2020). Laron syndrome research paves the way for new insights in oncological investigation. Cells, 9.","DOI":"10.3390\/cells9112446"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"33466","DOI":"10.1074\/jbc.M703370200","article-title":"UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 enzymes are major determinants of the androgen response in prostate cancer LNCaP cells","volume":"282","author":"Chouinard","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.tem.2003.10.005","article-title":"Inactivation of androgens by UDP-glucuronosyltransferase enzymes in humans","volume":"14","author":"Pelletier","year":"2003","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Grant, D.J., Chen, Z., Howard, L.E., Wiggins, E., De Hoedt, A., Vidal, A.C., Carney, S.T., Squires, J., Magyar, C.E., and Huang, J. (2017). UDP-glucuronosyltransferases and biochemical recurrence in prostate cancer progression. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3463-6"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"388","DOI":"10.3389\/fphar.2016.00388","article-title":"Structure and protein-protein interactions of human UDP-glucuronosyltransferases","volume":"7","author":"Fujiwara","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.biocel.2013.02.019","article-title":"The UDP-glucuronosyltransferases: Their role in drug metabolism and detoxification","volume":"45","author":"Rowland","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1006\/jmbi.1999.3374","article-title":"Isolation and characterization of the human UGT2B15 gene, localized within a cluster of UGT2B genes and pseudogenes on chromosome 4","volume":"295","author":"Turgeon","year":"2000","journal-title":"J. Mol. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1210\/endo.142.2.7958","article-title":"Relative enzymatic activity, protein stability, and tissue distribution of human steroid-metabolizing UGT2B subfamily members","volume":"142","author":"Turgeon","year":"2001","journal-title":"Endocrinology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"109579","DOI":"10.1016\/j.celrep.2021.109579","article-title":"Skin exposure to UVB light induces a skin-brain-gonad axis and sexual behavior","volume":"36","author":"Parikh","year":"2021","journal-title":"Cell Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1073\/pnas.1715930115","article-title":"Identification of thioredoxin-interacting protein (TXNIP) as a downstream target for IGF1 action","volume":"115","author":"Nagaraj","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ejca.2020.09.034","article-title":"Identification of nephronectin as a new target for IGF1 action","volume":"141","author":"Sarfstein","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Shibel, R., Sarfstein, R., Nagaraj, K., Lapkina-Gendler, L., Laron, Z., Dixit, M., Yakar, S., and Werner, H. (2021). The olfactory receptor gene product, OR5H2, modulates endometrial cancer cells proliferation via interaction with the IGF1 signaling pathway. Cells, 10.","DOI":"10.3390\/cells10061483"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4437","DOI":"10.18632\/oncotarget.27055","article-title":"Identification of ZYG11A as a candidate IGF1-dependent proto-oncogene in endometrial cancer","volume":"10","author":"Achlaug","year":"2019","journal-title":"Oncotarget"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1016\/j.ejca.2011.09.014","article-title":"p53 regulates insulin-like growth factor-I receptor gene expression in uterine serous carcinoma and predicts responsiveness to an insulin-like growth factor-I receptor-directed targeted therapy","volume":"48","author":"Bentov","year":"2012","journal-title":"Eur. J. Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1038\/sj.bjc.6605335","article-title":"Mutant p53 mediates survival of breast cancer cells","volume":"101","author":"Lim","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nrg3185","article-title":"Insights into the regulation of protein abundance from proteomic and transcriptomic analyses","volume":"13","author":"Vogel","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1080\/15384047.2015.1026480","article-title":"Human UDP-Glucuronosyltransferases: Effects of altered expression in breast and pancreatic cancer cell lines","volume":"16","author":"Dates","year":"2015","journal-title":"Cancer Biol. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5881","DOI":"10.1158\/0008-5472.CAN-15-3372","article-title":"Androgen and estrogen receptors in breast cancer coregulate human UDP-glucuronosyltransferases 2B15 and 2B17","volume":"76","author":"Hu","year":"2016","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1002\/pros.20749","article-title":"Androgen receptor mediates the expression of UDP-glucuronosyltransferase 2 B15 and B17 genes","volume":"68","author":"Bao","year":"2008","journal-title":"Prostate"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"E428","DOI":"10.1210\/jc.2011-2064","article-title":"Differential expression of the androgen-conjugating UGT2B15 and UGT2B17 enzymes in prostate tumor cells during cancer progression","volume":"97","author":"Fazli","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Vidal, A.C., Tucker, C., Schildkraut, J.M., Richardson, R.M., McPhail, M., Freedland, S.J., Hoyo, C., and Grant, D.J. (2013). Novel associations of UDP-glucuronosyltransferase 2B gene variants with prostate cancer risk in a multiethnic study. BMC Cancer, 13.","DOI":"10.1186\/1471-2407-13-556"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jsbmb.2015.09.021","article-title":"Epigenetic regulation of steroid inactivating UDP-glucuronosyltransferases by microRNAs in prostate cancer","volume":"155","author":"Margaillan","year":"2016","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1124\/jpet.115.226118","article-title":"Regulation of human UGT2B15 and UGT2B17 by miR-376c in prostate cancer cell lines","volume":"354","author":"Wijayakumara","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1080\/15592294.2020.1795601","article-title":"Expression of UDP Glucuronosyltransferases 2B15 and 2B17 is associated with methylation status in prostate cancer cells","volume":"16","author":"Carney","year":"2021","journal-title":"Epigenetics"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Hu, D.G., Marri, S., Mackenzie, P.I., Hulin, J.A., McKinnon, R.A., and Meech, R. (2021). The expression profiles and deregulation of UDP-glycosyltransferase (UGT) genes in human cancers and their association with clinical outcomes. Cancers, 13.","DOI":"10.3390\/cancers13174491"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/10\/1627\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:09:56Z","timestamp":1760137796000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/10\/1627"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,12]]},"references-count":56,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["cells11101627"],"URL":"https:\/\/doi.org\/10.3390\/cells11101627","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,12]]}}}