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* Department of Experimental Pathology and Oncology, University of Florence, Florence, Italy;
¶ Institute of Mutagenesis and Differentiation, CNR, Pisa, Italy; and
§ Department of Pharmacology, University of Milan, Milan, Italy
3Correspondence: Sergio Capaccioli, Department of Experimental Pathology and Oncology, University of Florence, Viale G.B. Morgagni 50, 50134 Florence, Italy. E-mail: sergio{at}cesit1.unifi.it; or Angelo Nicolin, Department of Pharmacology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy. E-mail: angelo.nicolin{at}unimi.it
The control of mRNA stability is becoming recognized as a crucial point of gene expression regulation. A common element responsible for mRNA decay modulation is the adenine- and uracil-rich element that is found in the 3' untranslated region of numerous mRNAs subjected to fast expression changes in response to various stimuli. Previously we identified a post-transcriptional regulation level for the antiapoptotic bcl-2 gene, which could be involved 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 chordates examined, but even between chordates and the nematode Caenorhabditis elegans (ced-9 gene). As for other well-established destabilizing AREs, the insertion of the bcl-2 ARE downstream from stable ß-globin mRNA causes an enhanced decay of the ß-globin transcript, which proves its functional role. This possibility is corroborated by the fact that the pathway leading to the modulating activity of bcl-2 ARE is influenced by PKC, since the addition of DAG and TPA markedly attenuated the bcl-2 ARE destabilizing potential. Conversely, it is noteworthy that when C2-ceramide is added to the culture medium as the apoptotic agent, the ß-globin transcript harboring the bcl-2 ARE undergoes a dramatic increase in decay. This observation clearly indicates that the destabilizing function of bcl-2 ARE is enhanced by apoptotic stimuli and suggests that this element could be involved in a post-transcriptional mechanism of bcl-2 down-regulation during apoptosis. The half-life of the mRNA of bcl-2 in Jurkat cells is prolonged by PKC stimulation and shortened by C2-ceramide addition, strongly supporting the view that bcl-2 mRNA stability plays a physiological role in modulating bcl-2 expression, particularly in its down-regulation during apoptosis. Thus, this element becomes a new candidate for mediating those bcl-2 gene expression changes—from apoptosis-associated down-regulation to tumor-associated overexpression—observed thus far that profoundly influence single cell fate and tissue homeostasis. Schiavone, N., Rosini, P., Quattrone, A., Donnini, M., Lapucci, A., Citti, L., Bevilacqua, A., Nicolin, A., Capaccioli, S. 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.
Key Words: bcl-2 regulation • RNA decay • RNA half-life • gene regulation
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