The RNA binding protein HuR regulates the stability of many target mRNAs. Here, 
we report that HuR associated with the 3' untranslated region of the mRNA 
encoding the longevity and stress-response protein SIRT1, stabilized the SIRT1 
mRNA, and increased SIRT1 expression levels. Unexpectedly, oxidative stress 
triggered the dissociation of the [HuR-SIRT1 mRNA] complex, in turn promoting 
SIRT1 mRNA decay, reducing SIRT1 abundance, and lowering cell survival. The cell 
cycle checkpoint kinase Chk2 was activated by H(2)O(2), interacted with HuR, and 
was predicted to phosphorylate HuR at residues S88, S100, and T118. Mutation of 
these residues revealed a complex pattern of HuR binding, with S100 appearing to 
be important for [HuR-SIRT1 mRNA] dissociation after H(2)O(2). Our findings 
demonstrate that HuR regulates SIRT1 expression, underscore functional links 
between the two stress-response proteins, and implicate Chk2 in these processes.