{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T06:34:26Z","timestamp":1775975666805,"version":"3.50.1"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2005,1,20]],"date-time":"2005-01-20T00:00:00Z","timestamp":1106179200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2005,1,20]],"date-time":"2005-01-20T00:00:00Z","timestamp":1106179200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Cancer"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Background<\/jats:title>\n                        <jats:p>Insulin-like growth factor binding protein (IGFBP)-3 functions as a carrier of insulin-like growth factors (IGFs) in circulation and a mediator of the growth suppression signal in cells. There are two reported p53 regulatory regions in the <jats:italic>IGFBP3<\/jats:italic> gene; one upstream of the promoter and one intronic. We previously reported a hot spot of promoter hypermethylation of IGFBP-3 in human hepatocellular carcinomas and derivative cell lines. As the hot spot locates at the putative upstream p53 consensus sequences, these p53 consensus sequences are really functional is a question to be answered.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>In this study, we examined the p53 consensus sequences upstream of the IGFBP-3 promoter for the p53 induced expression of IGFBP-3. Deletion, mutagenesis, and methylation constructs of IGFBP-3 promoter were assessed in the human hepatoblastoma cell line HepG2 for promoter activity.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>Deletions and mutations of these sequences completely abolished the expression of IGFBP-3 in the presence of p53 overexpression. <jats:italic>In vitro<\/jats:italic> methylation of these p53 consensus sequences also suppressed IGFBP-3 expression. In contrast, the expression of IGFBP-3 was not affected in the absence of p53 overexpression. Further, we observed by electrophoresis mobility shift assay that p53 binding to the promoter region was diminished when methylated.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusion<\/jats:title>\n                        <jats:p>From these observations, we conclude that four out of eleven p53 consensus sequences upstream of the IGFBP-3 promoter are essential for the p53 induced expression of IGFBP-3, and hypermethylation of these sequences selectively suppresses p53 induced IGFBP-3 expression in HepG2 cells.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/1471-2407-5-9","type":"journal-article","created":{"date-parts":[[2005,1,20]],"date-time":"2005-01-20T20:28:04Z","timestamp":1106252884000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation"],"prefix":"10.1186","volume":"5","author":[{"given":"Tadashi","family":"Hanafusa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiyuki","family":"Shinji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidenori","family":"Shiraha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Nouso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiaki","family":"Iwasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eichiro","family":"Yumoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiro","family":"Ono","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norio","family":"Koide","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2005,1,20]]},"reference":[{"key":"197_CR1","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/S1359-6101(96)00053-6","volume":"8","author":"DR Clemmons","year":"1997","unstructured":"Clemmons DR: Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev. 1997, 8: 45-62. 10.1016\/S1359-6101(96)00053-6.","journal-title":"Cytokine Growth Factor Rev"},{"key":"197_CR2","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1677\/joe.0.1750033","volume":"175","author":"KW Lee","year":"2002","unstructured":"Lee KW, Cohen P: Nuclear effects: unexpected intracellular actions of insulin-like growth factor binding protein-3. J Endocrinol. 2002, 175: 33-40. 10.1677\/joe.0.1750033.","journal-title":"J Endocrinol"},{"key":"197_CR3","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1038\/377646a0","volume":"377","author":"L Buckbinder","year":"1995","unstructured":"Buckbinder L, Talbott R, Velasco-Miguel S, Takenaka I, Faha B, Seizinger BR, Kley N: Induction of the growth inhibitor IGF-binding protein 3 by p53. Nature. 1995, 377: 646-649. 10.1038\/377646a0.","journal-title":"Nature"},{"key":"197_CR4","first-page":"1545","volume":"56","author":"ZS Gucev","year":"1996","unstructured":"Gucev ZS, Oh Y, Kelley KM, Rosenfeld RG: Insulin-like growth factor binding protein 3 mediates retinoic acid- and transforming growth factor beta2-induced growth inhibition in human breast cancer cells. Cancer Res. 1996, 56: 1545-1550.","journal-title":"Cancer Res"},{"key":"197_CR5","doi-asserted-by":"publisher","first-page":"12181","DOI":"10.1074\/jbc.272.18.12181","volume":"272","author":"R Rajah","year":"1997","unstructured":"Rajah R, Valentinis B, Cohen P: Insulin-like growth factor (IGF)-binding protein-3 induces apoptosis and mediates the effects of transforming growth factor-beta1 on programmed cell death through a p53- and IGF-independent mechanism. J Biol Chem. 1997, 272: 12181-12188. 10.1074\/jbc.272.18.12181.","journal-title":"J Biol Chem"},{"key":"197_CR6","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1210\/en.137.1.296","volume":"137","author":"V Besset","year":"1996","unstructured":"Besset V, Le Magueresse-Battistoni B, Collette J, Benahmed M: Tumor necrosis factor alpha stimulates insulin-like growth factor binding protein 3 expression in cultured porcine Sertoli cells. Endocrinology. 1996, 137: 296-303. 10.1210\/en.137.1.296.","journal-title":"Endocrinology"},{"key":"197_CR7","doi-asserted-by":"publisher","first-page":"10489","DOI":"10.1074\/jbc.M109604200","volume":"277","author":"J Hong","year":"2002","unstructured":"Hong J, Zhang G, Dong F, Rechler MM: Insulin-like Growth Factor (IGF)-binding Protein-3 Mutants That Do Not Bind IGF-I or IGF-II Stimulate Apoptosis in Human Prostate Cancer Cells. J Biol Chem. 2002, 277: 10489-10497. 10.1074\/jbc.M109604200.","journal-title":"J Biol Chem"},{"key":"197_CR8","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1002\/hep.510290414","volume":"29","author":"DG Kim","year":"1999","unstructured":"Kim DG, Lee DY, Cho BH, You KR, Kim MY, Ahn DS: Down-regulation of insulin-like growth factor binding proteins and growth modulation in hepatoma cells by retinoic acid. Hepatology. 1999, 29: 1091-1098. 10.1002\/hep.510290414.","journal-title":"Hepatology"},{"key":"197_CR9","first-page":"115","volume":"13","author":"H Huynh","year":"2002","unstructured":"Huynh H, Chow PK, Ooi LL, Soo KC: A possible role for insulin-like growth factor-binding protein-3 autocrine\/paracrine loops in controlling hepatocellular carcinoma cell proliferation. Cell Growth Differ. 2002, 13: 115-122.","journal-title":"Cell Growth Differ"},{"key":"197_CR10","doi-asserted-by":"crossref","first-page":"G447","DOI":"10.1152\/ajpgi.2000.278.3.G447","volume":"278","author":"EM Zimmermann","year":"2000","unstructured":"Zimmermann EM, Li L, Hoyt EC, Pucilowska JB, Lichtman S, Lund PK: Cell-specific localization of insulin-like growth factor binding protein mRNAs in rat liver. Am J Physiol Gastrointest Liver Physiol. 2000, 278: G447-57.","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"197_CR11","first-page":"4802","volume":"58","author":"T Zou","year":"1998","unstructured":"Zou T, Fleisher AS, Kong D, Yin J, Souza RF, Wang S, Smolinski KN, Abraham JM, Meltzer SJ: Sequence alterations of insulin-like growth factor binding protein 3 in neoplastic and normal gastrointestinal tissues. Cancer Res. 1998, 58: 4802-4804.","journal-title":"Cancer Res"},{"key":"197_CR12","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S0304-3835(01)00736-4","volume":"176","author":"T Hanafusa","year":"2002","unstructured":"Hanafusa T, Yumoto Y, Nouso K, Nakatsukasa H, Onishi T, Fujikawa T, Taniyama M, Nakamura S, Uemura M, Takuma Y, Yumoto E, Higashi T, Tsuji T: Reduced expression of insulin-like growth factor binding protein-3 and its promoter hypermethylation in human hepatocellular carcinoma. Cancer Lett. 2002, 176: 149-158. 10.1016\/S0304-3835(01)00736-4.","journal-title":"Cancer Lett"},{"key":"197_CR13","doi-asserted-by":"publisher","first-page":"5527","DOI":"10.1158\/0008-5472.CAN-03-4061","volume":"64","author":"MF Fraga","year":"2004","unstructured":"Fraga MF, Herranz M, Espada J, Ballestar E, Paz MF, Ropero S, Erkek E, Bozdogan O, Peinado H, Niveleau A, Mao JH, Balmain A, Cano A, Esteller M: A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors. Cancer Res. 2004, 64: 5527-5534.","journal-title":"Cancer Res"},{"key":"197_CR14","doi-asserted-by":"publisher","first-page":"6569","DOI":"10.1038\/sj.onc.1207882","volume":"23","author":"YS Chang","year":"2004","unstructured":"Chang YS, Wang L, Suh YA, Mao L, Karpen SJ, Khuri FR, Hong WK, Lee HY: Mechanisms underlying lack of insulin-like growth factor-binding protein-3 expression in non-small-cell lung cancer. Oncogene. 2004, 23: 6569-6580. 10.1038\/sj.onc.1207882.","journal-title":"Oncogene"},{"key":"197_CR15","doi-asserted-by":"publisher","first-page":"3817","DOI":"10.1210\/endo.142.9.8380","volume":"142","author":"GE Walker","year":"2001","unstructured":"Walker GE, Wilson EM, Powell D, Oh Y: Butyrate, a histone deacetylase inhibitor, activates the human IGF binding protein-3 promoter in breast cancer cells: molecular mechanism involves an Sp1\/Sp3 multiprotein complex. Endocrinology. 2001, 142: 3817-3827. 10.1210\/en.142.9.3817.","journal-title":"Endocrinology"},{"key":"197_CR16","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/sj.onc.1200804","volume":"14","author":"JC Bourdon","year":"1997","unstructured":"Bourdon JC, Deguin-Chambon V, Lelong JC, Dessen P, May P, Debuire B, May E: Further characterisation of the p53 responsive element--identification of new candidate genes for trans-activation by p53. Oncogene. 1997, 14: 85-94. 10.1038\/sj.onc.1200804.","journal-title":"Oncogene"},{"key":"197_CR17","doi-asserted-by":"crossref","first-page":"12642","DOI":"10.1016\/S0021-9258(19)38392-9","volume":"265","author":"ML Cubbage","year":"1990","unstructured":"Cubbage ML, Suwanichkul A, Powell DR: Insulin-like growth factor binding protein-3. Organization of the human chromosomal gene and demonstration of promoter activity. J Biol Chem. 1990, 265: 12642-12649.","journal-title":"J Biol Chem"},{"key":"197_CR18","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1093\/jnci\/88.9.601","volume":"88","author":"RL Rocha","year":"1996","unstructured":"Rocha RL, Hilsenbeck SG, Jackson JG, Lee AV, Figueroa JA, Yee D: Correlation of insulin-like growth factor-binding protein-3 messenger RNA with protein expression in primary breast cancer tissues: detection of higher levels in tumors with poor prognostic features. J Natl Cancer Inst. 1996, 88: 601-606.","journal-title":"J Natl Cancer Inst"},{"key":"197_CR19","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/S1535-6108(02)00030-2","volume":"1","author":"D Singh","year":"2002","unstructured":"Singh D, Febbo PG, Ross K, Jackson DG, Manola J, Ladd C, Tamayo P, Renshaw AA, D'Amico AV, Richie JP, Lander ES, Loda M, Kantoff PW, Golub TR, Sellers WR: Gene expression correlates of clinical prostate cancer behavior. Cancer Cell. 2002, 1: 203-209. 10.1016\/S1535-6108(02)00030-2.","journal-title":"Cancer Cell"},{"key":"197_CR20","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1038\/sj.onc.1206153","volume":"22","author":"K Yamazaki","year":"2003","unstructured":"Yamazaki K, Sakamoto M, Ohta T, Kanai Y, Ohki M, Hirohashi S: Overexpression of KIT in chromophobe renal cell carcinoma. Oncogene. 2003, 22: 847-852. 10.1038\/sj.onc.1206153.","journal-title":"Oncogene"},{"key":"197_CR21","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/S0165-4608(03)00300-5","volume":"149","author":"E Kettunen","year":"2004","unstructured":"Kettunen E, Anttila S, Seppanen JK, Karjalainen A, Edgren H, Lindstrom I, Salovaara R, Nissen AM, Salo J, Mattson K, Hollmen J, Knuutila S, Wikman H: Differentially expressed genes in nonsmall cell lung cancer: expression profiling of cancer-related genes in squamous cell lung cancer. Cancer Genet Cytogenet. 2004, 149: 98-106. 10.1016\/S0165-4608(03)00300-5.","journal-title":"Cancer Genet Cytogenet"},{"key":"197_CR22","doi-asserted-by":"publisher","first-page":"6483","DOI":"10.1128\/MCB.20.17.6483-6495.2000","volume":"20","author":"B Mannhardt","year":"2000","unstructured":"Mannhardt B, Weinzimer SA, Wagner M, Fiedler M, Cohen P, Jansen-Durr P, Zwerschke W: Human papillomavirus type 16 E7 oncoprotein binds and inactivates growth-inhibitory insulin-like growth factor binding protein 3. Mol Cell Biol. 2000, 20: 6483-6495. 10.1128\/MCB.20.17.6483-6495.2000.","journal-title":"Mol Cell Biol"},{"key":"197_CR23","doi-asserted-by":"publisher","first-page":"39146","DOI":"10.1074\/jbc.M006964200","volume":"275","author":"S Fanayan","year":"2000","unstructured":"Fanayan S, Firth SM, Butt AJ, Baxter RC: Growth inhibition by insulin-like growth factor-binding protein-3 in T47D breast cancer cells requires transforming growth factor-beta (TGF-beta ) and the type II TGF-beta receptor. J Biol Chem. 2000, 275: 39146-39151. 10.1074\/jbc.M006964200.","journal-title":"J Biol Chem"},{"key":"197_CR24","doi-asserted-by":"publisher","first-page":"7255","DOI":"10.1074\/jbc.M108038200","volume":"277","author":"S Fanayan","year":"2002","unstructured":"Fanayan S, Firth SM, Baxter RC: Signaling through the Smad pathway by insulin-like growth factor-binding protein-3 in breast cancer cells. Relationship to transforming growth factor-beta 1 signaling. J Biol Chem. 2002, 277: 7255-7261. 10.1074\/jbc.M108038200.","journal-title":"J Biol Chem"},{"key":"197_CR25","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/0092-8674(90)90251-9","volume":"62","author":"M Laiho","year":"1990","unstructured":"Laiho M, DeCaprio JA, Ludlow JW, Livingston DM, Massague J: Growth inhibition by TGF-beta linked to suppression of retinoblastoma protein phosphorylation. Cell. 1990, 62: 175-185. 10.1016\/0092-8674(90)90251-9.","journal-title":"Cell"},{"key":"197_CR26","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1210\/jc.86.3.1274","volume":"86","author":"C Deal","year":"2001","unstructured":"Deal C, Ma J, Wilkin F, Paquette J, Rozen F, Ge B, Hudson T, Stampfer M, Pollak M: Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators. J Clin Endocrinol Metab. 2001, 86: 1274-1280. 10.1210\/jc.86.3.1274.","journal-title":"J Clin Endocrinol Metab"},{"key":"197_CR27","doi-asserted-by":"publisher","first-page":"4961","DOI":"10.1128\/MCB.16.9.4961","volume":"16","author":"P Friedlander","year":"1996","unstructured":"Friedlander P, Haupt Y, Prives C, Oren M: A mutant p53 that discriminates between p53-responsive genes cannot induce apoptosis. Mol Cell Biol. 1996, 16: 4961-4971.","journal-title":"Mol Cell Biol"},{"key":"197_CR28","doi-asserted-by":"publisher","first-page":"4952","DOI":"10.1128\/MCB.16.9.4952","volume":"16","author":"RL Ludwig","year":"1996","unstructured":"Ludwig RL, Bates S, Vousden KH: Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function. Mol Cell Biol. 1996, 16: 4952-4960.","journal-title":"Mol Cell Biol"}],"container-title":["BMC Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2407-5-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/1471-2407-5-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2407-5-9","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2407-5-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T12:29:50Z","timestamp":1728304190000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmccancer.biomedcentral.com\/articles\/10.1186\/1471-2407-5-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,1,20]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2005,12]]}},"alternative-id":["197"],"URL":"https:\/\/doi.org\/10.1186\/1471-2407-5-9","relation":{},"ISSN":["1471-2407"],"issn-type":[{"value":"1471-2407","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,1,20]]},"assertion":[{"value":"26 August 2004","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 January 2005","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 January 2005","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"9"}}