Transforming Growth Factor β1 (TGF-β1) Suppresses Growth of B-cell Lymphoma Cells by p14ARF-dependent Regulation of Mutant p53

摘要

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 p14ARF and mutant p53, leading to growth arrest. Experimental overexpression of E2F-1 increased p14ARF level and blocked TGF-β1-induced down-regulation of p14ARF. Overexpression of p14ARF blocked the down-regulation of mutant p53 and prevented growth arrest. p14ARF also attenuated TGF-β1-induced p21Cip1/WAF1 induction, which was reversible by p53 siRNA, indicating the involvement of mutant p53 in controlling the TGF-β1-induced expression of p21Cip1/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, p14ARF is present in a trimer consisting of mutant p53-Mdm2-p14ARF and in a dimer consisting of Mdm2-p14ARF. Because it is known that Mdm2 can degrade p53, it is possible that, in its trimeric form, p14ARF is able to stabilize mutant p53 by inhibiting Mdm2. In its dimeric form, p14ARF 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 p14ARF. This work suggests that the high levels of p14ARF often found in tumor cells could be a potential therapeutic target.