The RNA-binding protein, HuR, associates with the HuR mRNA, but the consequences 
of this interaction are unknown. Here, we use human diploid fibroblasts (HDFs) 
and cervical carcinoma cells to study this regulatory paradigm. Ectopic 
overexpression of HuR potently enhanced the translation and cytoplasmic levels 
of endogenous HuR, but did not affect HuR mRNA levels. Inhibition of CRM1 
function by Lemptomycin B or by knockdown of CRM1 greatly diminished the 
cytoplasmic levels of endogenous HuR mRNA and hence blocked the induction of 
endogenous HuR by exogenous HuR. Further studies showed that HuR interacted with 
the 3'-untranslated region (UTR) of HuR and that overexpression of HuR increased 
the cytoplasmic levels of a chimeric luciferase-HuR 3'-UTR reporter transcript, 
as well as luciferase activity; conversely, HuR knockdown reduced both 
parameters. Moreover, the loss of HuR in senescent, late-passage HDFs was 
accompanied by a reduced cytoplasmic presence of endogenous HuR mRNA, ectopic 
Luc-HuR-3'UTR reporter transcript, and luciferase activity relative to what was 
observed in young, early-passage cells. Our results reveal a positive feedback 
mechanism for the regulation of HuR, which may play an important role in the 
regulation of HuR during replicative senescence.