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Transforming growth factor β1 (TGF-β1) suppresses growth of B-cell lymphoma cells by p14(ARF)-dependent regulation of mutant p53.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2012 Jun 29; Vol. 287 (27), pp. 23184-95. Date of Electronic Publication: 2012 May 23. - Publication Year :
- 2012
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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.
- Subjects :
- Antineoplastic Agents pharmacology
Cell Division physiology
Cyclin-Dependent Kinase Inhibitor p21 genetics
Down-Regulation drug effects
Down-Regulation physiology
Drug Design
Gene Expression Regulation, Neoplastic drug effects
Gene Expression Regulation, Neoplastic physiology
Humans
Lymphoma, B-Cell genetics
Lymphoma, B-Cell pathology
Promoter Regions, Genetic physiology
RNA, Messenger metabolism
RNA, Small Interfering genetics
Smad2 Protein metabolism
Tumor Cells, Cultured
Tumor Suppressor Protein p14ARF genetics
Tumor Suppressor Protein p53 metabolism
Cell Division drug effects
Lymphoma, B-Cell drug therapy
Transforming Growth Factor beta1 pharmacology
Tumor Suppressor Protein p14ARF metabolism
Tumor Suppressor Protein p53 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 287
- Issue :
- 27
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22621932
- Full Text :
- https://doi.org/10.1074/jbc.M112.351411