{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:57:05Z","timestamp":1791215825677,"version":"4.1.0"},"reference-count":60,"publisher":"American Society of Hematology","issue":"9","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>MDM2 protein is thought to exhibit tumorigenic activity by binding to the p53 tumor-suppressor protein and inhibiting its function. Alternatively, MDM2 may have oncogenic roles other than those resulting from p53 interactions. Here we report that MDM2 can induce expression of the p65 subunit of NF-\u03baB, which is an anti-apoptotic factor expressed in certain neoplastic cells in response to chemotherapy. Initially, we noted that the overexpression of MDM2 protein in leukemic bone marrow cells of patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), and an ALL cell line (EU-4) transfected with theMDM2 gene was associated with elevated expression of p65 and in vitro resistance to doxorubicin (Adriamycin). By cotransfection of the MDM2 gene and p65-promoter-reporter constructs into EU-4 cells, we found that transient and high-level MDM2 expression induced p65 promoter activity. In the presence of wild-type (wt) p53, MDM2 increased p65 promoter activity by reversing p53-mediated suppression of p65. In the absence of p53, MDM2 directly increased p65 promoter activity. Deletion and mutation analysis of the p65 promoter indicated that the region between nt \u2212575 and \u2212178, which contains the first and second Sp1-binding sites, was required for activation by MDM2. Further studies using chromatin immunoprecipitation (CHIP) and electrophoretic mobility shift assay (EMSA) showed that MDM2 was able to directly bind to the Sp1 site of the p65 promoter. Our findings suggest that by inducing p65 expression, MDM2 has a p53-independent role in tumorigenesis, which may further elucidate the association between MDM2 overexpression and resistant disease in childhood ALL.<\/jats:p>","DOI":"10.1182\/blood.v99.9.3367","type":"journal-article","created":{"date-parts":[[2002,10,11]],"date-time":"2002-10-11T18:33:52Z","timestamp":1034361232000},"page":"3367-3375","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":96,"title":["MDM2 induces NF-\u03baB\/p65 expression transcriptionally through Sp1-binding sites: a novel, p53-independent role of MDM2 in doxorubicin resistance in acute lymphoblastic leukemia"],"prefix":"10.1182","volume":"99","author":[{"given":"Lubing","family":"Gu","sequence":"first","affiliation":[{"name":"From the Division of Pediatric Hematology\/Oncology\/BMT, Emory University School of Medicine, Atlanta, GA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry W.","family":"Findley","sequence":"additional","affiliation":[{"name":"From the Division of Pediatric Hematology\/Oncology\/BMT, Emory University School of Medicine, Atlanta, GA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muxiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"From the Division of Pediatric Hematology\/Oncology\/BMT, Emory University School of Medicine, Atlanta, GA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2020021221170158400_B1","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1016\/0092-8674(92)90644-R","article-title":"The MDM-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.","volume":"69","author":"Momand","year":"1992","journal-title":"Cell."},{"key":"2020021221170158400_B2","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/nm0896-912","article-title":"Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer.","volume":"2","author":"Sigalas","year":"1996","journal-title":"Nat Med."},{"key":"2020021221170158400_B3","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1101\/gad.11.6.714","article-title":"Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53.","volume":"11","author":"Lundgren","year":"1997","journal-title":"Genes Dev."},{"key":"2020021221170158400_B4","doi-asserted-by":"crossref","first-page":"4107","DOI":"10.1128\/MCB.13.7.4107","article-title":"Mapping of the p53 and mdm2 interaction domains.","volume":"13","author":"Chen","year":"1993","journal-title":"Mol 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RNA expression leads to malignant transformation.","volume":"9","author":"Beauparlant","year":"1994","journal-title":"Oncogene."},{"key":"2020021221170158400_B9","doi-asserted-by":"crossref","first-page":"24113","DOI":"10.1074\/jbc.272.39.24113","article-title":"Oncogenic Ha-Ras\u2013induced signaling activates NF\u03baB transcriptional activity, which is required for cellular transformation.","volume":"272","author":"Finco","year":"1997","journal-title":"J Biol Chem."},{"key":"2020021221170158400_B10","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1006\/scbi.1997.0062","article-title":"Rel\/NF-\u03baB transcription factors and the control of apoptosis.","volume":"8","author":"Sonenshein","year":"1997","journal-title":"Cancer Biol."},{"key":"2020021221170158400_B11","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1126\/science.3140380","article-title":"I\u03ba\u03b2: a specific inhibitor of the NF\u03baB transcription factor.","volume":"242","author":"Baeuerle","year":"1988","journal-title":"Science."},{"key":"2020021221170158400_B12","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0092-8674(00)81318-5","article-title":"NF\u03baB: ten years after.","volume":"87","author":"Baeuerle","year":"1996","journal-title":"Cell."},{"key":"2020021221170158400_B13","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1172\/JCI119848","article-title":"Aberrant nuclear factor-kappaB\/Rel expression and the pathogenesis of breast cancer.","volume":"100","author":"Sovak","year":"1997","journal-title":"J Clin Invest."},{"key":"2020021221170158400_B14","first-page":"119","article-title":"The nuclear factor-kappa B Rel A transcription factor is constitutively activated in human pancreatic adenocarcinoma cells.","volume":"1","author":"Wang","year":"1999","journal-title":"Clin Cancer Res."},{"key":"2020021221170158400_B15","doi-asserted-by":"crossref","first-page":"14008","DOI":"10.1074\/jbc.273.22.14008","article-title":"Constitutive activation of NF\u03baB causes resistance to apoptosis in human cutaneous T cell lymphoma HuT-78 cells.","volume":"273","author":"Giri","year":"1998","journal-title":"J Biol Chem."},{"key":"2020021221170158400_B16","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1126\/science.274.5288.782","article-title":"An essential role for NF-\u03baB in preventing TNF-\u03b1\u2013induced cell death.","volume":"274","author":"Beg","year":"1996","journal-title":"Science."},{"key":"2020021221170158400_B17","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1126\/science.274.5288.784","article-title":"TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of 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histone deacetylase to repress transcription.","volume":"92","author":"Luo","year":"1998","journal-title":"Cell."},{"key":"2020021221170158400_B37","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/sj.leu.2401619","article-title":"Incidence and prognostic significance of MDM2 oncoprotein overexpression in relapsed childhood acute lymphoblastic leukemia.","volume":"14","author":"Zhou","year":"2000","journal-title":"Leukemia."},{"key":"2020021221170158400_B38","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1126\/science.281.5383.1680","article-title":"NF\u03baB antiapoptosis: induction of TRAF1 and TRAF2 and cIAP1 and c-IAP2 to suppress caspase-8 activation.","volume":"281","author":"Wang","year":"1998","journal-title":"Science."},{"key":"2020021221170158400_B39","doi-asserted-by":"crossref","first-page":"10057","DOI":"10.1073\/pnas.94.19.10057","article-title":"Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-\u03baB control.","volume":"94","author":"Chu","year":"1997","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021221170158400_B40","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1084\/jem.188.1.211","article-title":"Nuclear factor (NF)-\u03baB-regulated X-chromosome\u2013linked iap gene expression protects endothelial cells from tumor necrosis factor \u03b1-induced apoptosis.","volume":"188","author":"Stehlik","year":"1998","journal-title":"J Exp Med."},{"key":"2020021221170158400_B41","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1210\/endo.142.2.7957","article-title":"Nuclear factor-\u03baB\u2013mediated X-linked inhibitor of apoptosis protein expression prevents rat granulosa cells from tumor necrosis factor \u03b1-induced apoptosis.","volume":"142","author":"Xiao","year":"2001","journal-title":"Endocrinology."},{"key":"2020021221170158400_B42","first-page":"4531","article-title":"p53-mediated repression of nuclear factor-\u03baB RelA via the transcriptional integrator p300.","volume":"58","author":"Ravi","year":"1998","journal-title":"Cancer Res."},{"key":"2020021221170158400_B43","doi-asserted-by":"crossref","first-page":"3485","DOI":"10.1128\/MCB.19.5.3485","article-title":"Transcriptional cross talk between NF-\u03baB and p53.","volume":"19","author":"Webster","year":"1999","journal-title":"Mol Cell Biol."},{"key":"2020021221170158400_B44","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1074\/jbc.274.4.1879","article-title":"CREB-binding protein is a nuclear integrator of nuclear factor-\u03baB and p53 signaling.","volume":"274","author":"Wadgaonkar","year":"1999","journal-title":"J Biol Chem."},{"key":"2020021221170158400_B45","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1182\/blood.V87.3.1155.bloodjournal8731155","article-title":"High incidence of potential p53 inactivation in poor outcome childhood acute lymphoblastic leukemia at diagnosis.","volume":"87","author":"Marks","year":"1996","journal-title":"Blood."},{"key":"2020021221170158400_B46","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1200\/JCO.1997.15.3.1158","article-title":"Altered expression of p53 and mdm-2 proteins at diagnosis is associated with early treatment failure in childhood acute lymphoblastic leukemia.","volume":"15","author":"Marks","year":"1997","journal-title":"J Clin Oncol."},{"key":"2020021221170158400_B47","doi-asserted-by":"crossref","first-page":"9979","DOI":"10.1073\/pnas.88.22.9979","article-title":"Wild-type p53 can down-modulate the activity of various promoters.","volume":"88","author":"Ginsberg","year":"1991","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021221170158400_B48","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1073\/pnas.88.5.1958","article-title":"Growth suppression induced by wild-type p53 protein is accompanied by selective down-regulation of proliferating-cell nuclear antigen expression.","volume":"88","author":"Mercer","year":"1991","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021221170158400_B49","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1128\/MCB.15.1.227","article-title":"Two domains of p53 interact with the TATA-binding protein, and the adenovirus 13S E1A protein disrupts the association, relieving p53-mediated transcriptional repression.","volume":"15","author":"Horikoshi","year":"1995","journal-title":"Mol Cell Biol."},{"key":"2020021221170158400_B50","first-page":"935","article-title":"p53 represses Sp1 DNA binding and HIV-LTR directed transcription.","volume":"43","author":"Bargonetti","year":"1997","journal-title":"Cell Mol Biol."},{"key":"2020021221170158400_B51","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1101\/gad.4.4.659","article-title":"SV40 stimulates expression of the trans-acting factor Sp1 at the mRNA levels.","volume":"4","author":"Saffer","year":"1990","journal-title":"Genes 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