A novel mechanism of tumor suppression by destabilizing AU-rich growth factor mRNA

Abstract

The occurrence of pathologically stable mRNAs of protooncogenes, growth factors and cyclins has been proposed to contribute to experimental and human oncogenesis. In normal resting cells, mRNAs containing an AU-rich element (ARE) in their 3 0 untranslated region are subjected to rapid degradation. Tristetraprolin (TTP) is an RNA-binding zinc-finger protein that promotes decay of ARE-containing mRNAs. Here we report that TTP acts as a potent tumor suppressor in a v-H-ras-dependent mast cell tumor model, where tumors express abnormally stable interleukin-3 (IL-3) mRNA as part of an oncogenic autocrine loop. Premalignant v-H-ras cells were transfected with TTP and injected into syngeneic mice. TTP expression delayed tumor progression by 4 weeks, and late appearing tumors escaped suppression by loss of TTP. When transfected into a fully established tumor line, TTP reduced cloning efficiency in vitro and growth of the inoculated cells in vivo. Transgenic TTP interfered with the autocrine loop by enhancing the degradation of IL-3 mRNA with concomitant reduction of IL-3 secretion. Our data establish the ARE as an antioncogenic target in a model situation, underline the importance of mRNA stabilization in oncogenesis and show for the first time that tumor suppression can be achieved by interfering with mRNA turnover.

Destabilization of vascular endothelial growth factor mRNA by the zinc-finger protein TIS11b

“…Very recently, it has been reported that TTP acts as a potent tumour suppressor when overexpressed in a v-H-ras-dependent mast cell tumour model (Stoecklin et al, 2003). Our results would suggest that this effect could result from decreased VEGF mRNA levels and decreased angiogenesis.…”

Luteinization of porcine preovulatory follicles leads to systematic changes in follicular gene expression

“…The remaining members of the class have known tumor suppressor activities as well but do so through different mechanisms. Tristetraprolin (ZFP36L2) destabilizes growth factor mRNA and increases mRNA turnover (Stoecklin et al 2003) and microseminal protein b, MSMB or PSP94; one of the most highly expressed genes in porcine corpus luteum from our previous work; Jiang et al 2004) is an inhibitor of vascular endothelial growth factor (VEGF) signaling (Lamy et al 2005). Janus kinase 1 can have proliferative or antiproliferative properties depending on the nature the activating ligand (Verma et al 2003).…”

Characterization of the Interaction between Neuronal RNA-binding Protein HuD and AU-rich RNA

“…Such inhibitors might be of clinical importance in situations in which improper mRNA stabilization leads to overexpression of labile mRNAs, such as tumor necrosis factor ␣ overexpression in inflammatory disease (1,5) and proto-oncogene overexpression in cancer cells inappropriately expressing Hu proteins (34,35,47,68). Recent experiments in which TTP was overexpressed demonstrate that the modulation of mRNA decay can be used to suppress oncogenesis (67). This observation emphasizes the importance of understanding the interactions of proteins with the AREs of labile mRNAs, not only at a functional level but at the detailed mechanistic level, as well.…”