A conserved AU-rich element in the 3 ' untranslated region of bcl-2 mRNA is endowed with a destabilizing function that is involved in bcl-2 down-regulation during apoptosis

The control of mRNA stability is becoming recognized as a crucial point of gene expression regulation. A common element responsible for mRNA decay mod ulation is the adenine- and uracil-rich element that is found in the 3' unt ranslated region of numerous mRNAs subjected to fast expression changes in response to various stimuli. Previously we identified a post-transcriptiona l regulation level for the antiapoptotic bcl-2 gene, which could be involve d in t(14;18) lymphoma-associated bcl-2 overexpression. Here we demonstrate that bcl-2 mRNA is endowed with an adenine- and uracil-rich element (ARE) characterized by high evolutionary conservation not only among all chordate s examined, but even between chordates and the nematode Caenorhabditis eleg ans (ced-9 gene). As for other well-established destabilizing AREs, the ins ertion of the bcl-2 ARE downstream from stable beta-globin mRNA causes an e nhanced decay of the beta-globin transcript, which proves its functional ro le. This possibility is corroborated by the fact that the pathway leading t o the modulating activity of bcl-2 ARE is influenced by PKC, since the addi tion of DAG and TPA markedly attenuated the bcl-2 ARE destabilizing potenti al. Conversely, it is noteworthy that when C-2-ceramide is added to the cul ture medium as the apoptotic agent, the beta-globin transcript harboring th e bcl-2 ARE undergoes a dramatic increase in decay. This observation clearl y indicates that the destabilizing function of bcl-2 ARE is enhanced by apo ptotic stimuli and suggests that this element could be involved in a post-t ranscriptional mechanism of bcl-2 down-regulation during apoptosis. The hal f-life of the mRNA of bcl-2 in Jurkat cells is prolonged by PKC stimulation and shortened by C-2-ceramide addition, strongly supporting the view that bcl-2 mRNA stability plays a physiological role in modulating bcl-2 express ion, particularly in its down-regulation during apoptosis. Thus, this eleme nt becomes a new candidate for mediating those bcl-2 gene expression change s-from apoptosis-associated down-regulation to tumor-associated overexpress ion-observed thus far that profoundly influence single cell fate and tissue homeostasis. Schiavone, N., Rosini, P., Quattrone, A., Donnini, M., Lapucc i, A., Citti, L., Bevilacqua, A., Nicolin, A., Capaccioli, S. A conserved A U-rich element in the 3' untranslated region of bcl-2 mRNA is endowed with a destabilizing function that is involved in bcl-2 down-regulation during a poptosis.