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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‐2gene, which could be involved in t(14;18) lymphoma‐associated bcl‐2overexpression. Here we demonstrate that bcl‐2mRNA 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 Caeno‐rhabditis elegans (ced‐9gene). As for other well‐established destabilizing AREs, the insertion of the bcl‐2ARE downstream from stable β‐globin mRNA causes an enhanced decay of the β‐globin transcript, which proves its functional role. This possibility is corroborated by the fact that the pathway leading to the modulating activity of bcl‐2ARE is influenced by PKC, since the addition of DAG and TPA markedly attenuated the bcl‐2ARE destabilizing potential. Conversely, it is noteworthy that when C2‐ceramide is added to the culture medium as the apoptotic agent, the β‐globin transcript harboring the bcl‐2ARE undergoes a dramatic increase in decay. This observation clearly indicates that the destabilizing function of bcl‐2ARE is enhanced by apoptotic stimuli and suggests that this element could be involved in a post‐transcriptional mechanism of bcl‐2down‐regulation during apoptosis. The half‐life of the mRNA of bcl‐2in Jurkat cells is prolonged by PKC stimulation and shortened by C2‐ceramide addition, strongly supporting the view that bcl‐2mRNA stability plays a physiological role in modulating bcl‐2expression, particularly in its down‐regulation during apoptosis. Thus, this element becomes a new candidate for mediating those bcl‐2gene expression changes— from apoptosis‐associated down‐regulation to tumor‐associated overexpression—observed thus far that profoundly influence single cell fate and tissue ho‐meostasis. 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. FASEB J.14, 174–184(2000)