Coordinate regulation of mRNA decay networks by GU-rich elements and CELF1

Department of Microbiology, Center for Infectious Diseases and Microbiology Translational Research, University of Minnesota, Minneapolis, MN, USA.
Current opinion in genetics & development (Impact Factor: 7.57). 04/2011; 21(4):444-51. DOI: 10.1016/j.gde.2011.03.002
Source: PubMed


The GU-rich element (GRE) was identified as a conserved sequence enriched in the 3' UTR of human transcripts that exhibited rapid mRNA turnover. In mammalian cells, binding to GREs by the protein CELF1 coordinates mRNA decay of networks of transcripts involved in cell growth, migration, and apoptosis. Depending on the context, GREs and CELF1 also regulate pre-mRNA splicing and translation. GREs are highly conserved throughout evolution and play important roles in the development of organisms ranging from worms to man. In humans, abnormal GRE-mediated regulation contributes to disease states and cancer. Thus, GREs and CELF proteins serve critical functions in gene expression regulation and define an important evolutionarily conserved posttranscriptional regulatory network.

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    • "Many genes are subjected to post-transcriptional regulation via control of the rate of mRNA turnover for transcripts bearing destabilizing cis-elements [12]. Among the very few regulatory factors identified thus far, CELF1 regulates post-transcriptional gene expression by facilitating alternative splicing, translation [13], and mRNA degradation, and it functions by binding directly to RNA [14]. Rattenbacher et al. identified the CELF1 gene and its target proteins as a critical posttranscriptional regulatory network that may play a role in the development of cancer [8]. "
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    ABSTRACT: The RNA-binding protein, CUG-binding protein 1 (CUGBP1), regulates gene expression at the levels of alternative splicing, mRNA degradation, and translation. We used RNA immunoprecipitation followed by microarray analysis to identify the cytoplasmic mRNA targets of CUGBP1 in resting and activated primary human T cells and found that CUGBP1 targets were highly enriched for the presence of GU-rich elements (GREs) in their 3'-untranslated regions. The number of CUGBP1 target transcripts decreased dramatically following T cell activation as a result of activation-dependent phosphorylation of CUGBP1 and decreased ability of CUGBP1 to bind to GRE-containing RNA. A large percentage of CUGBP1 target transcripts exhibited rapid and transient up-regulation, and a smaller percentage exhibited transient down-regulation following T cell activation. Many of the transiently up-regulated CUGBP1 target transcripts encode important regulatory proteins necessary for transition from a quiescent state to a state of cellular activation and proliferation. Overall, our results show that CUGBP1 binding to certain GRE-containing target transcripts decreased following T cell activation through activation-dependent phosphorylation of CUGBP1.
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    ABSTRACT: Discoveries made over the past 20 years highlight the importance of mRNA decay as a means of modulating gene expression and thereby protein production. Up until recently, studies largely focused on identifying cis-acting sequences that serve as mRNA stability or instability elements, the proteins that bind these elements, how the process of translation influences mRNA decay and the ribonucleases that catalyse decay. Now, current studies have begun to elucidate how the decay process is regulated. This Review examines our current understanding of how mammalian cell mRNA decay is controlled by different signalling pathways and lays out a framework for future research.
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