title: RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage.
abstract: RNA-binding protein HuR modulates the stability and translational efficiency of messenger RNAs (mRNAs) encoding essential components of the cellular proliferation, growth and survival pathways. Consistent with these functions, HuR levels are often elevated in cancer cells and reduced in senescent and quiescent cells. However, the molecular mechanisms that control HuR expression are poorly understood. Here we show that HuR protein autoregulates its abundance through a negative feedback loop that involves interaction of the nuclear HuR protein with a GU-rich element (GRE) overlapping with the HuR major polyadenylation signal (PAS2). An increase in the cellular HuR protein levels stimulates the expression of long HuR mRNA species containing an AU-rich element (ARE) that destabilizes the mRNAs and thus reduces the protein production output. The PAS2 read-through occurs due to a reduced recruitment of the CstF-64 subunit of the pre-mRNA cleavage stimulation factor in the presence of the GRE-bound HuR. We propose that this mechanism maintains HuR homeostasis in proliferating cells. Since only the nuclear HuR is expected to contribute to the auto-regulation, our model may explain the longstanding observation that the increase in the total HuR expression in cancer cells often correlates with the accumulation of its substantial fraction in the cytoplasm.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, SBS-02n-45, Singapore, 637551, Singapore.
authors.forename: Weijun
authors.initials: W
authors.lastname: Dai
authors.forename: Gen
authors.initials: G
authors.lastname: Zhang
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Makeyev
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D002460:Cell Line; D039241:Cleavage Stimulation Factor; D003593:Cytoplasm / Q000378:metabolism; D051959:ELAV Proteins / Q000235:genetics* / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D051379:Mice; D026723:Polyadenylation; D012322:RNA Precursors / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D000952:Antigens, Polyomavirus Transforming; C474466:CSTF2T protein, human; D039241:Cleavage Stimulation Factor; D051959:ELAV Proteins; D012322:RNA Precursors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins