{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:21:33Z","timestamp":1781104893331,"version":"3.54.1"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"9","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,4,24]]},"abstract":"<jats:p>\n                    DNA methylation of tumor suppressor genes is a common feature of\n human cancer. The cyclin-dependent kinase inhibitor gene\n                    <jats:italic>p16\/Ink4A<\/jats:italic>\n                    is hypermethylated in a wide range of\n malignant tissues and the\n                    <jats:italic>p14\/ARF<\/jats:italic>\n                    gene located 20 kb\n upstream on chromosome 9p21 is also methylated in carcinomas.\n                    <jats:italic>p14\/ARF<\/jats:italic>\n                    (ARF, alternative reading frame) does not\n inhibit the activities of cyclins or cyclin-dependent kinase complexes;\n however, the importance of the two gene products in the etiology of\n cancer resides in their involvement in two major cell cycle regulatory\n pathways: p53 and the retinoblastoma protein, Rb, respectively.\n Distinct first exons driven from separate promoters are spliced onto\n the common exons 2 and 3 and the resulting proteins are translated in\n different reading frames. Both genes are expressed in normal cells but\n can be alternatively or coordinately silenced when their CpG islands\n are hypermethylated. Herein, we examined the presence of methyl-CpG\n binding proteins associated with aberrantly methylated promoters, the\n distribution of acetylated histones H3 and H4 by chromatin\n immunoprecipitation assays, and the effect of chemical treatment with\n 5-aza-2\u2032-deoxycytidine (5aza-dC) and trichostatin A on gene induction\n in colon cell lines by quantitative reverse transcriptase\u2013PCR. We\n observed that the methyl-CpG binding protein MBD2 is targeted to\n methylated regulatory regions and excludes the acetylated histones H3\n and H4, resulting in a localized inactive chromatin configuration. When\n methylated, the genes can be induced by 5aza-dC but the combined action\n of 5aza-dC and trichostatin A results in robust gene expression. Thus,\n methyl-CpG binding proteins and histone deacetylases appear to\n cooperate\n                    <jats:italic>in vivo<\/jats:italic>\n                    , with a dominant effect of DNA\n methylation toward histone acetylation, and repress expression of tumor\n suppressor genes hypermethylated in cancers.\n                  <\/jats:p>","DOI":"10.1073\/pnas.101617298","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:44:19Z","timestamp":1027680259000},"page":"4990-4995","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":153,"title":["Selective association of the methyl-CpG binding protein MBD2 with the silent\n                    <i>p14\/p16<\/i>\n                    locus in human neoplasia"],"prefix":"10.1073","volume":"98","author":[{"given":"Fr\u00e9d\u00e9rique","family":"Magdinier","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Embryology, National Institute of Child\r Health and Human Development, National Institutes of Health, Building\r 18T, Room 106, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan P.","family":"Wolffe","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Embryology, National Institute of Child\r Health and Human Development, National Institutes of Health, Building\r 18T, Room 106, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,4,17]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5293.1672"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90385-2"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8153634"},{"key":"e_1_3_3_4_2","first-page":"2988","volume":"55","author":"Stone S","year":"1995","unstructured":"S Stone, P Jiang, P Dayananth, S V Tavtigian, H Katcher, D Parry, G Peters, A Kamb Cancer Res 55, 2988\u20132994 (1995).","journal-title":"Cancer Res"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-419X(98)00017-1"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/368753a0"},{"key":"e_1_3_3_7_2","first-page":"21","volume":"11","author":"Duro D","year":"1995","unstructured":"D Duro, O Bernard, V Della Valle, R Berger, C J Larsen Oncogene 11, 21\u201329 (1995).","journal-title":"Oncogene"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V91.3.1016"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.4.1793"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.22.12754"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.11.6457"},{"key":"e_1_3_3_12_2","first-page":"129","volume":"60","author":"Esteller M","year":"2000","unstructured":"M Esteller, S Tortola, M Toyota, G Capella, M A Peinado, S B Baylin, J G Herman Cancer Res 60, 129\u2013133 (2000).","journal-title":"Cancer Res"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/5047"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/8807"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81532-9"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202248"},{"key":"e_1_3_3_17_2","first-page":"188","volume":"71","author":"Dante R","year":"1994","unstructured":"R Dante, S Ribieras, S Baldassini, V Martin, O Benzerara, C Bouteille, A Bremond, L Frappart, M C Rio, Y Lasne Lab Invest 71, 188\u2013192 (1994).","journal-title":"Lab Invest"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203414"},{"key":"e_1_3_3_19_2","first-page":"591","volume":"58","author":"Myohanen S K","year":"1998","unstructured":"S K Myohanen, S B Baylin, J G Herman Cancer Res 58, 591\u2013593 (1998).","journal-title":"Cancer Res"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(97)01181-5"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5439.481"},{"key":"e_1_3_3_22_2","first-page":"1245","volume":"58","author":"Gonzalgo M L","year":"1998","unstructured":"M L Gonzalgo, T Hayashida, C M Bender, M M Pao, Y C Tsai, F A Gonzales, H D Nguyen, T T Nguyen, P A Jones Cancer Res 58, 1245\u20131252 (1998).","journal-title":"Cancer Res"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(87)90689-9"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/321209a0"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-230X(08)60702-2"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.12.6870"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0960-9822(93)90340-T"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90430-3"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90610-O"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81887-5"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.11.6538"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/561"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/30764"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/12664"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/12659"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.15.1924"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(98)01636-9"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/71750"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/77023"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/77124"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.14.5107-5118.2000"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.99-0817com"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.101617298","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T20:11:25Z","timestamp":1649794285000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.101617298"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,4,17]]},"references-count":42,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2001,4,24]]}},"alternative-id":["10.1073\/pnas.101617298"],"URL":"https:\/\/doi.org\/10.1073\/pnas.101617298","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,4,17]]},"assertion":[{"value":"2000-12-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2001-04-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}