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

Abstract

p19^ARF plays an essential role in the senescence of mouse cells, and its expression is lost by methylation or deletion of the ARF 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), represses ARF mRNA translation, thereby maintaining the replicative life span of mouse embryonic fibroblasts (MEFs). Loss of HuR results in premature senescence, with concomitant increases in p19^ARF but not p16^Ink4a levels, and this senescence is not observed in ARF-null MEFs that retain an intact Ink4a locus. HuR depletion does not alter ARF transcription or stability but enhances ribosome association with ARF mRNA. Under these conditions, ARF mRNA accumulates in nucleoli, where it associates with nucleolin. Furthermore, adipose-specific deletion of the HuR gene results in increased p19^ARF expression in aged animals, which is accompanied by decreased insulin sensitivity. Together, our findings demonstrate that p19^ARF is also regulated at the translational level, and this translational regulation restrains the cellular life span and tissue functions in vivo.

This article is related to:

Forget Transcription: Translation Is Where the Action Is

ACKNOWLEDGMENTS

We thank Leo Tsuda for providing the GFP-L10 construct, Takashi Funatsu for providing MS2-EGFP-NLS cDNA, and Noboru Motoyama for his valuable discussion and technical support.

This work was supported by grants from the Japanese Ministry of Education, Culture, Science, and Technology (grant 22790879) and the Japan Health Foundation.

We declare that we have no conflict of interest.