The adenylate uridylate-rich elements (AREs) mediate the rapid turnover of mRNAs encoding proteins that regulate cellular growth and body response to exogenous agents such as microbes, inflammatory and environmental stimuli. However, the full repertoire of ARE-containing mRNAs is unknown. Here, we explore the distribution of AREs in human mRNA sequences. Computational derivation of a 13-bp ARE pattern was performed using multiple expectation maximization for motif elicitations (MEME) and consensus analyses. This pattern was statistically validated for the specificity towards the 3'-untranslated region and not coding region. The computationally derived ARE pattern is the basis of a database which contains non-redundant full-length ARE-mRNAs. The ARE-mRNA database (ARED; http://rc.kfshrc.edu.sa/ared) reveals that ARE-mRNAs encode a wide repertoire of functionally diverse proteins that belong to different biological processes and are important in several disease states. Cluster analysis was performed using the ARE sequences to demonstrate potential relationships between the type and number of ARE motifs, and the functional characteristics of the proteins.

A comprehensive search that utilized a large set of mRNA data from human genome databases and additionally, expressed sequence tag (EST) database characterized this latest update of AU-rich elements (AREs) containing mRNA database (ARED). A large number of ARE-mRNA, as much as 4000, were recovered and include many of ARE alternative forms. This number represents as much as 5–8% of the human genes depending on the entire number of genes. The new ARED does not contain only larger and diverse number of ARE-mRNAs but additional functionality and enhanced search capabilities are given in the database website . These include class and cluster of AREs, source mRNAs, EST evidence, buildup information, retrieval of lists of genes, and integration with current and new NCBI data, such as Entrez ID and Unigene. Gene Ontology analysis shows there are significant differences in functional diversity of ARED when compared with the overall genome. Many of ARE-genes mediate regulatory processes, reactions to outside stimuli, RNA metabolism, and developmental processes particularly those of early and transient responses. The wide interest in mRNA turnover and importance of AREs in health and disease signify the compilation of ARE-genes.

Adenylate/uridylate-rich element (ARE)-mediated mRNA turnover is an important regulatory component of gene expression for innate and specific immunity, in the hematopoietic system, in cellular growth regulation, and for many other cellular processes. This diversity is reflected in the distribution of AREs in the human genome, which we have established as a database of more than 900 ARE-containing genes that may utilize AREs as a means of controlling cellular mRNA levels. The p38 mitogen-activated protein kinase (MAP kinase) pathway has been implicated in regulating the stability of nine ARE-containing transcripts. Here we explored the entire spectrum of ARE-containing genes for p38-dependent regulation of ARE-mediated mRNA turnover with a custom cDNA array containing probes for 950 ARE mRNAs. The human monocytic cell line THP-1 treated with lipopolysaccharide (LPS) was used as a reproducible cellular model system that allowed us to precisely control the conditions of mRNA induction and decay in the absence and presence of the p38 inhibitor SB203580. This approach allowed us to establish an LPS-induced ARE mRNA expression profile in human monocytes and determine the half-lives of 470 AU-rich mRNAs. Most importantly, we identified 42 AU-rich genes, previously unrecognized, that show p38-dependent mRNA stabilization. In addition to a number of cytokines, several interesting novel AU-rich transcripts likely to play a role in macrophage activation by LPS exhibited p38-dependent transcript stabilization, including macrophage-specific colony-stimulating factor 1, carbonic anhydrase 2, Bcl2, Bcl2-like 2, and nuclear factor erythroid 2-like 2. Finally, the identification of the p38-dependent upstream activator MAP kinase kinase 6 as a member of this group identifies a positive feedback loop regulating macrophage signaling via p38 MAP kinase-dependent transcript stabilization.The regulation of mRNA stability is an important factor in modulating gene expression, in particular for transiently expressed genes that require tightly controlled mRNA levels. For different cytokines, growth factors, and proto-oncogenes with short mRNA half-lives, modulating the decay rate involves adenylate/uridylate (AU)-rich elements (AREs), often consisting of one to several copies of the sequence AUUUA located in the 3Ј untranslated region (12). With a bioinformatics approach, we previously identified several hundred ARE-containing genes that were compiled in the ARE mRNA database (ARED) (2). These genes encode a wide variety of proteins, implicating ARE-mediated mRNA decay in a broader spectrum of cellular processes than was previously recognized.The molecular mechanisms by which AREs are used to fine-tune mRNA turnover are thought to involve specific RNA-binding proteins (33,34). trans-Acting factors from different protein families that bind AREs and influence mRNA degradation have been identified. The Hu family proteins HuR and HuB have been shown to bind many different AU-rich messages and stabilize these in several different cell systems ...

Drug targets are rare in organelles; they are more likely to be enzymes, particularly oxidoreductases, transferases or lyases and not ligases; they are involved in binding, signalling and communication; they are secreted; and have long lifetimes, shown by lack of PEST signals and the presence of N-glycosylation. This can be summarized into eight key properties that are desirable in a human drug target, namely: high hydrophobicity, high length, SignalP motif present, no PEST motif, more than two N-glycosylated amino acids, not more than one O-glycosylated Ser, low pI and membrane location. The sequence features were used as inputs to a support vector machine (SVM), allowing the assignment of any sequence to the drug target or non-target classes with an accuracy in the training set of 96%. We identified 668 proteins (23%) in the non-target set that have target-like properties. We suggest that drug discovery programmes would be more likely to succeed if new targets are chosen from this set or their homologues.

The Adenylate Uridylate (AU)-Rich Element Database, ARED-mRNA version 2.0, contains information not present in the previous ARED. This includes additional data entries, new information and links to Unigene, LocusLink, RefSeq records and mouse homologue data. An ARE consensus sequence specific to the 3'UTR is the basis of ARED that demonstrated two important findings: (i) AREs are present in a large, previously unrecognized set of human mRNAs; and (ii) ARE-mRNAs encode proteins of diverse functions which are largely involved in early and transient biological responses. In this update, we have modified the strategy for identifying ARE-mRNA in order to systematically deal with inconsistencies of molecule type and mRNA region in GenBank records. Potential uses for the ARED in functional genomics are also given. The database is accessible via the web, http://rc.kfshrc.edu.sa/ared, with a new querying system that allows searching ARE-mRNAs by any public database identifier or name. The ARED website also contains relevant links to uses for the ARED.