{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:52:10Z","timestamp":1787003530745,"version":"build-2736575974"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,7,11]],"date-time":"2017-07-11T00:00:00Z","timestamp":1499731200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,7,11]],"date-time":"2017-07-11T00:00:00Z","timestamp":1499731200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Normal cell cycle progression and proliferation of palatal mesenchymal cells are important for palatal development. As targets of miR-17-92, E2F transcription factors family has been suggested to induce the transcription of miR-17-92 in several cell types. In the present study, we sought to investigate whether this negative feedback loop exists in mouse PMCs and what the function of this negative feedback loop would be in palatal mesenchymal cells. Using GeneMANIA, we revealed that the most important function of experimentally verified targets of miR-17-92 is cell cycle regulation. E2F1 and E2F3, but not E2F2, were extensively expressed in mouse palate. Over-expression of E2F1 significantly increased the expression of all the members of miR-17-92. After increased by E2F1, miR-17 and miR-20a may negatively target E2F1, and thereby prevent the cells from excessive proliferation. We suggest that the negative feedback loop between E2F1 and miR-17-92 may contribute to palatal development by regulating the proliferation and cell cycle of palatal mesenchymal cells.<\/jats:p>","DOI":"10.1038\/s41598-017-05479-7","type":"journal-article","created":{"date-parts":[[2017,7,5]],"date-time":"2017-07-05T10:15:48Z","timestamp":1499249748000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["An E2F1\/MiR-17-92 Negative Feedback Loop mediates proliferation of Mouse Palatal Mesenchymal Cells"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9150-6549","authenticated-orcid":false,"given":"Ling","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoxin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiquan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,7,11]]},"reference":[{"key":"5479_CR1","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1177\/0022034508327868","volume":"88","author":"L Meng","year":"2009","unstructured":"Meng, L., Bian, Z., Torensma, R. & Von den Hoff, J. W. Biological mechanisms in palatogenesis and cleft palate. J Dent Res \n                           88, 22\u201333, doi:10.1177\/0022034508327868 (2009).","journal-title":"J Dent Res"},{"key":"5479_CR2","doi-asserted-by":"publisher","first-page":"e898","DOI":"10.1038\/cddis.2013.424","volume":"4","author":"X Hu","year":"2013","unstructured":"Hu, X., Gao, J., Liao, Y., Tang, S. & Lu, F. Retinoic acid alters the proliferation and survival of the epithelium and mesenchyme and suppresses Wnt\/beta-catenin signaling in developing cleft palate. Cell Death Dis \n                           4, e898, doi:10.1038\/cddis.2013.424 (2013).","journal-title":"Cell Death Dis"},{"key":"5479_CR3","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1177\/0960327110387238","volume":"30","author":"VC Dhulipala","year":"2011","unstructured":"Dhulipala, V. C., Maddali, K. K., Ray, B. K., Welshons, W. V. & Reddy, C. S. Role of p21 and cyclin E in normal and secalonic acid D-inhibited proliferation of human embryonic palatal mesenchymal cells. Hum Exp Toxicol \n                           30, 1222\u20131232, doi:10.1177\/0960327110387238 (2011).","journal-title":"Hum Exp Toxicol"},{"key":"5479_CR4","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cels.2016.01.001","volume":"2","author":"AR Barr","year":"2016","unstructured":"Barr, A. R., Heldt, F. S., Zhang, T., Bakal, C. & Novak, B. A Dynamical Framework for the All-or-None G1\/S Transition. Cell Syst \n                           2, 27\u201337, doi:10.1016\/j.cels.2016.01.001 (2016).","journal-title":"Cell Syst"},{"key":"5479_CR5","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1101\/gad.13.12.1501","volume":"13","author":"CJ Sherr","year":"1999","unstructured":"Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev \n                           13, 1501\u20131512 (1999).","journal-title":"Genes Dev"},{"key":"5479_CR6","doi-asserted-by":"publisher","first-page":"333","DOI":"10.4161\/cc.2.4.428","volume":"2","author":"I Matsumura","year":"2003","unstructured":"Matsumura, I., Tanaka, H. & Kanakura, Y. E2F1 and c-Myc in cell growth and death. Cell Cycle \n                           2, 333\u2013338 (2003).","journal-title":"Cell Cycle"},{"key":"5479_CR7","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1111\/imr.12054","volume":"253","author":"V Olive","year":"2013","unstructured":"Olive, V., Li, Q. & He, L. mir-17-92: a polycistronic oncomir with pleiotropic functions. Immunological reviews \n                           253, 158\u2013166, doi:10.1111\/imr.12054 (2013).","journal-title":"Immunological reviews"},{"key":"5479_CR8","doi-asserted-by":"publisher","first-page":"1603","DOI":"10.1038\/cdd.2013.125","volume":"20","author":"E Mogilyansky","year":"2013","unstructured":"Mogilyansky, E. & Rigoutsos, I. The miR-17\/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell death and differentiation \n                           20, 1603\u20131614, doi:10.1038\/cdd.2013.125 (2013).","journal-title":"Cell death and differentiation"},{"key":"5479_CR9","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1016\/j.cell.2008.02.019","volume":"132","author":"A Ventura","year":"2008","unstructured":"Ventura, A. et al. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell \n                           132, 875\u2013886, doi:10.1016\/j.cell.2008.02.019 (2008).","journal-title":"Cell"},{"key":"5479_CR10","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1002\/bdra.20684","volume":"88","author":"P Mukhopadhyay","year":"2010","unstructured":"Mukhopadhyay, P. et al. Developmental microRNA expression profiling of murine embryonic orofacial tissue. Birth Defects Res A Clin Mol Teratol \n                           88, 511\u2013534, doi:10.1002\/bdra.20684 (2010).","journal-title":"Birth Defects Res A Clin Mol Teratol"},{"key":"5479_CR11","doi-asserted-by":"publisher","first-page":"3699","DOI":"10.1093\/nar\/gkt070","volume":"41","author":"T Palm","year":"2013","unstructured":"Palm, T. et al. A systemic transcriptome analysis reveals the regulation of neural stem cell maintenance by an E2F1-miRNA feedback loop. Nucleic Acids Res \n                           41, 3699\u20133712, doi:10.1093\/nar\/gkt070 (2013).","journal-title":"Nucleic Acids Res"},{"key":"5479_CR12","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1074\/jbc.M608939200","volume":"282","author":"Y Sylvestre","year":"2007","unstructured":"Sylvestre, Y. et al. An E2F\/miR-20a autoregulatory feedback loop. J Biol Chem \n                           282, 2135\u20132143, doi:10.1074\/jbc.M608939200 (2007).","journal-title":"J Biol Chem"},{"key":"5479_CR13","doi-asserted-by":"publisher","first-page":"D163","DOI":"10.1093\/nar\/gkq1107","volume":"39","author":"SD Hsu","year":"2011","unstructured":"Hsu, S. D. et al. miRTarBase: a database curates experimentally validated microRNA-target interactions. Nucleic Acids Res \n                           39, D163\u2013169 (2011).","journal-title":"Nucleic Acids Res"},{"key":"5479_CR14","doi-asserted-by":"publisher","first-page":"W214","DOI":"10.1093\/nar\/gkq537","volume":"38","author":"D Warde-Farley","year":"2010","unstructured":"Warde-Farley, D. et al. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res \n                           38, W214\u2013220 (2010).","journal-title":"Nucleic Acids Res"},{"key":"5479_CR15","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1242\/dev.073288","volume":"139","author":"P Kaldis","year":"2012","unstructured":"Kaldis, P. & Richardson, H. E. When cell cycle meets development. Development \n                           139, 225\u2013230 (2012).","journal-title":"Development"},{"key":"5479_CR16","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1007\/s00251-010-0505-5","volume":"63","author":"HG Xu","year":"2011","unstructured":"Xu, H. G. et al. Direct repression of the human IRF-3 promoter by E2F1. Immunogenetics \n                           63, 189\u2013196, doi:10.1007\/s00251-010-0505-5 (2011).","journal-title":"Immunogenetics"},{"key":"5479_CR17","doi-asserted-by":"publisher","first-page":"e1003785","DOI":"10.1371\/journal.pgen.1003785","volume":"9","author":"J Wang","year":"2013","unstructured":"Wang, J. et al. MicroRNA-17-92, a direct Ap-2alpha transcriptional target, modulates T-box factor activity in orofacial clefting. PLoS Genet \n                           9, e1003785, doi:10.1371\/journal.pgen.1003785 (2013).","journal-title":"PLoS Genet"},{"key":"5479_CR18","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1002\/jcb.23457","volume":"113","author":"L Li","year":"2012","unstructured":"Li, L., Shi, J. Y., Zhu, G. Q. & Shi, B. MiR-17-92 cluster regulates cell proliferation and collagen synthesis by targeting TGFB pathway in mouse palatal mesenchymal cells. J Cell Biochem \n                           113, 1235\u20131244, doi:10.1002\/jcb.23457 (2012).","journal-title":"J Cell Biochem"},{"key":"5479_CR19","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1039\/c0ib00145g","volume":"3","author":"M Cloutier","year":"2011","unstructured":"Cloutier, M. & Wang, E. Dynamic modeling and analysis of cancer cellular network motifs. Integrative biology: quantitative biosciences from nano to macro \n                           3, 724\u2013732, doi:10.1039\/c0ib00145g (2011).","journal-title":"Integrative biology: quantitative biosciences from nano to macro"},{"key":"5479_CR20","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.gpb.2017.02.002","volume":"15","author":"SR McGee","year":"2017","unstructured":"McGee, S. R., Tibiche, C., Trifiro, M. & Wang, E. Network Analysis Reveals A Signaling Regulatory Loop in the PIK3CA-mutated Breast Cancer Predicting Survival Outcome. Genomics, proteomics & bioinformatics \n                           15, 121\u2013129, doi:10.1016\/j.gpb.2017.02.002 (2017).","journal-title":"Genomics, proteomics & bioinformatics"},{"key":"5479_CR21","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1039\/b905382d","volume":"5","author":"C Fu","year":"2009","unstructured":"Fu, C., Li, J. & Wang, E. Signaling network analysis of ubiquitin-mediated proteins suggests correlations between the 26S proteasome and tumor progression. Molecular bioSystems \n                           5, 1809\u20131816, doi:10.1039\/b905382d (2009).","journal-title":"Molecular bioSystems"},{"key":"5479_CR22","doi-asserted-by":"publisher","first-page":"e03475","DOI":"10.7554\/eLife.03475","volume":"3","author":"C Bertoli","year":"2014","unstructured":"Bertoli, C. & de Bruin, R. A. Turning cell cycle entry on its head. Elife \n                           3, e03475, doi:10.7554\/eLife.03475 (2014).","journal-title":"Elife"},{"key":"5479_CR23","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1002\/dvdy.24225","volume":"244","author":"CR Hill","year":"2015","unstructured":"Hill, C. R., Jacobs, B. H., Brown, C. B., Barnett, J. V. & Goudy, S. L. Type III transforming growth factor beta receptor regulates vascular and osteoblast development during palatogenesis. Dev Dyn \n                           244, 122\u2013133, doi:10.1002\/dvdy.24225 (2015).","journal-title":"Dev Dyn"},{"key":"5479_CR24","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1016\/j.biocel.2010.03.004","volume":"42","author":"V Olive","year":"2010","unstructured":"Olive, V., Jiang, I. & He, L. mir-17-92, a cluster of miRNAs in the midst of the cancer network. Int J Biochem Cell Biol \n                           42, 1348\u20131354, doi:10.1016\/j.biocel.2010.03.004 (2010).","journal-title":"Int J Biochem Cell Biol"},{"key":"5479_CR25","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1038\/cdd.2013.24","volume":"20","author":"D Chen","year":"2013","unstructured":"Chen, D., Chen, Y., Forrest, D. & Bremner, R. E2f2 induces cone photoreceptor apoptosis independent of E2f1 and E2f3. Cell death and differentiation \n                           20, 931\u2013940, doi:10.1038\/cdd.2013.24 (2013).","journal-title":"Cell death and differentiation"},{"key":"5479_CR26","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1096\/fj.02-0515com","volume":"17","author":"Y Zhu","year":"2003","unstructured":"Zhu, Y., Jin, K., Mao, X. O. & Greenberg, D. A. Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression. Faseb j \n                           17, 186\u2013193, doi:10.1096\/fj.02-0515com (2003).","journal-title":"Faseb j"},{"key":"5479_CR27","doi-asserted-by":"publisher","first-page":"4732","DOI":"10.1158\/1078-0432.CCR-10-1408","volume":"16","author":"GQ Zhu","year":"2010","unstructured":"Zhu, G. Q. et al. Hypoxia inducible factor 1alpha and hypoxia inducible factor 2alpha play distinct and functionally overlapping roles in oral squamous cell carcinoma. Clin Cancer Res \n                           16, 4732\u20134741, doi:10.1158\/1078-0432.ccr-10-1408 (2010).","journal-title":"Clin Cancer Res"},{"key":"5479_CR28","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1093\/nar\/gki200","volume":"33","author":"AM Cheng","year":"2005","unstructured":"Cheng, A. M., Byrom, M. W., Shelton, J. & Ford, L. P. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res \n                           33, 1290\u20131297, doi:10.1093\/nar\/gki200 (2005).","journal-title":"Nucleic Acids Res"},{"key":"5479_CR29","doi-asserted-by":"publisher","first-page":"3069","DOI":"10.1002\/jcb.24184","volume":"113","author":"X Zhu","year":"2012","unstructured":"Zhu, X., Ozturk, F., Liu, C., Oakley, G. G. & Nawshad, A. Transforming growth factor-beta activates c-Myc to promote palatal growth. J Cell Biochem \n                           113, 3069\u20133085, doi:10.1002\/jcb.24184 (2012).","journal-title":"J Cell Biochem"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05479-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05479-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05479-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T01:37:45Z","timestamp":1671759465000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05479-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,11]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["5479"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-05479-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,11]]},"assertion":[{"value":"16 March 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 May 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 July 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"5148"}}