The c-fos proto-oncogene provides a good system to study the processes underlying messenger RNA degradation. After growth factor stimulation of susceptible cells, the c-fos transcription rate transiently increases from a low basal level by as much as 50-fold¹, producing a large amount of exceedingly unstable c-fos mRNA that is rapidly degraded^1–3. Here, we investigate the c-fos mRNA degradation process, and find that: (1) ongoing translation of the c-fos mRNA itself is required for its degradation; (2) after synthesis, the mRNA poly(A) tail is rapidly removed, in a translation-dependent manner, leading to accumulation of apparently de-adenylated RNA; (3) deletion or replacement of an AU-rich sequence at the mRNA 3′ end significantly stabilizes the mRNA; (4) deletion of the 3′ AU-rich sequences dramatically slows the poly(A) shortening rate. These results suggest that the 3′ AU-rich sequences act to destabilize the mRNA by directing rapid removal of the mRNA poly(A) tract.