title: Transforming growth factor β1 (TGF-β1) suppresses growth of B-cell lymphoma cells by p14(ARF)-dependent regulation of mutant p53.
abstract: Previously we reported that TGF-β1-induced growth suppression was associated with a decrease in mutant p53 levels in B-cell lymphoma cells. The goal of the present study was to understand the mechanism involved in TGF-β1-mediated down-regulation of mutant p53. In RL and CA46, two B-cell lymphoma cell lines, TGF-β1 treatment caused down-regulation of E2F-1 transcription factor resulting in the down-regulation of both p14(ARF) and mutant p53, leading to growth arrest. Experimental overexpression of E2F-1 increased p14(ARF) level and blocked TGF-β1-induced down-regulation of p14(ARF). Overexpression of p14(ARF) blocked the down-regulation of mutant p53 and prevented growth arrest. p14(ARF) also attenuated TGF-β1-induced p21(Cip1/WAF1) induction, which was reversible by p53 siRNA, indicating the involvement of mutant p53 in controlling the TGF-β1-induced expression of p21(Cip1/WAF1). The interaction observed between phospho-Smad2 and mutant p53 in the nucleus could be the mechanism responsible for blocking the growth-suppressive effects of TGF-β1. In RL cells, p14(ARF) is present in a trimer consisting of mutant p53-Mdm2-p14(ARF) and in a dimer consisting of Mdm2-p14(ARF). Because it is known that Mdm2 can degrade p53, it is possible that, in its trimeric form, p14(ARF) is able to stabilize mutant p53 by inhibiting Mdm2. In its dimeric form, p14(ARF) may be sequestering Mdm2, limiting its ability to degrade p53. Collectively, these data demonstrate a unique mechanism in which the inhibition of TGF-β1-mediated growth suppression by mutant p53 can be reversed by the down-regulation of its stabilizing protein p14(ARF). This work suggests that the high levels of p14(ARF) often found in tumor cells could be a potential therapeutic target.
authors.affiliation: Lymphocyte Cell Biology Unit, Laboratory of Molecular Biology and Immunology, Intramural Research Program, NIA, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Paritosh
authors.initials: P
authors.lastname: Ghosh
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Farrell
authors.forename: Rachel
authors.initials: R
authors.lastname: Munk
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Rezanka
authors.forename: Carl Y
authors.initials: CY
authors.lastname: Sasaki
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C495901:TP53 protein, human; D053773:Transforming Growth Factor beta1; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53