HuR Maintains a Replicative Life Span by Repressing the ARF Tumor Suppressor

p19ARF plays an essential role in the senescence of mouse cells, and its expression is lost by methylation or deletion of theARF locus; otherwise, p53 is inactivated to bypass senescence.ARF expression is tightly regulated, but little is known about its posttranscriptional regulation. Here, we show that an RNA-binding protein, HuR (human antigen R), repressesARF mRNA translation, thereby maintaining the replicative life span of mouse embryonic fibroblasts (MEFs). Loss of HuR results in premature senescence, with concomitant increases in p19ARF but not p16Ink4a levels, and this senescence is not observed inARF -null MEFs that retain an intactInk4a locus. HuR depletion does not alterARF transcription or stability but enhances ribosome association withARF mRNA. Under these conditions,ARF mRNA accumulates in nucleoli, where it associates with nucleolin. Furthermore, adipose-specific deletion of theHuR gene results in increased p19ARF expression in aged animals, which is accompanied by decreased insulin sensitivity. Together, our findings demonstrate that p19ARF is also regulated at the translational level, and this translational regulation restrains the cellular life span and tissue functionsin vivo .