Mechanisms coordinating ELAV/Hu mRNA regulons
Section snippets
ELAV/Hu proteins bind A/G-UUU rich RNA sequences while stabilizing and/or activating translation of targeted mRNAs
The highly conserved ELAV/Hu family of RBPs consists of four family members, including three that are predominantly cytoplasmic and neuron-specific (HuB/Hel-N1, HuC and HuD) and one that is expressed primarily in the nucleus of all human cells (HuA/HuR) (reviewed in [11, 12, 13, 14]). Each Hu protein consists of three RNA recognition motifs (RRMs) and a flexible hinge/linker region between RRM2 and RRM3 [11]. Using several assays including UV crosslinking procedures, our lab discovered that HuB
ELAV/Hu proteins cooperatively form multimeric “ribonucleosomes”
An early observation regarding the functions of ELAV/Hu RBPs was that they bind to A/G-U rich sequences and form multimeric (or oligomeric) RNPs when binding to RNA targets [15, 31]. For example, a uniform array of progressively shifted HuB–RNA complexes was observed using gel mobility shifts suggesting that multiple protein molecules bind to a targeted mRNA in a concentration-dependent manner [15]. Similar findings were subsequently reported for HuD using an in vivo chemical crosslinking
The troika of coordinated gene expression
Gene expression is coordinated by three known mechanisms: (i) DNA operons/regulons, (ii) promoter-based transcription initiation, and (iii) RNA operons/regulons [4, 9••, 39, 40, 41]. In bacteria, DNA operons represent genes that function together and are physically grouped on the chromosome, but also by transcription factors that function at each promoter site. Eukaryotes also use promoter-based gene coordination, but they do not generally have traditional DNA operons. Genes that function
Transcriptomic and ribonomic analysis of gene expression
One of the inherent problems with simple transcriptomic methods such as RNA-seq is that they only detect the net accumulation of each type of mRNA. In fact, such “steady state” or accumulated levels depend not only on rates of RNA synthesis but also on rates of decay. Recent methods, such as 4-thiouridine pulsing [48], allow these two competing processes to be discriminated because newly synthesized mRNA can be separated from “old” partially decayed mRNA. These and other ribonomic methods have
Mechanistic models of ELAV/Hu effects on miRNPs and implications in oncogenesis
As noted above, early indications that over expression of ELAV proteins HuB and HuR stabilize ARE-containing mRNAs helped explain how synthesis of the encoded target proteins increases [16, 17, 21, 22, 23, 24, 25, 65]. There have been many attempts to address how HuR may affect mRNA functions through interactions with microRNAs. One of the first proposed mechanistic explanations for increased translation of a HuR mRNA target was discovered using the cationic amino acid transporter 1 (CAT1)
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
References (81)
- et al.
Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP
Cell
(2010) - et al.
HuR and mRNA stability
Cell Mol Life Sci
(2001) - et al.
Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs
EMBO J
(1998) - et al.
RNA-binding protein HuR enhances p53 translation after ultraviolet light irradiation
Proc Natl Acad Sci USA
(2003) MicroRNAs: genomics, biogenesis, mechanism, and function
Cell
(2004)- et al.
Complex formation of the neuron-specific ELAV-like Hu RNA-binding proteins
Nucleic Acids Res
(2002) - et al.
Set of novel, conserved proteins fold pre-messenger RNA into ribonucleosomes
Proteins
(1986) - et al.
A systems view of mRNP biology
Genes Dev
(2004) Life without transcriptional control? From fly to man and back again
EMBO J
(2002)- et al.
Posttranscriptional control and the role of RNA-binding proteins in gene regulation in trypanosomatid protozoan parasites
Wiley Interdiscip Rev RNA
(2010)