Modulation of neoplastic gene regulatory pathways by the RNA-binding factor AUF1

Abstract

The mRNA-binding protein AUF1 regulates the expression of many key players in cancer including proto-oncogenes, regulators of apoptosis and the cell cycle, and pro-inflammatory cytokines, principally by directing the decay kinetics of their encoded mRNAs. Most studies support an mRNA-destabilizing role for AUF1, although other findings suggest additional functions for this factor. In this review, we explore how changes in AUF1 isoform distribution, subcellular localization, and post-translational protein modifications can influence the metabolism of targeted mRNAs. However, several lines of evidence also support a role for AUF1 in the initiation and/or development of cancer. Many AUF1-targeted transcripts encode products that control pro- and anti-oncogenic processes. Also, overexpression of AUF1 enhances tumorigenesis in murine models, and AUF1 levels are enhanced in some tumors. Finally, signaling cascades that modulate AUF1 function are deregulated in some cancerous tissues. Together, these features suggest that AUF1 may play a prominent role in regulating the expression of many genes that can contribute to tumorigenic phenotypes, and that this post-transcriptional regulatory control point may be subverted by diverse mechanisms in neoplasia.

Figure 1

Schematic of AUF1 isoforms generated by alternative splicing. Both p42 ^AUF1 and p45^AUF1 contain the 49 amino acid region encoded by exon 7 (green) while p40 ^AUF1 and p45 ^AUF1 contain the 19 amino acid region encoded by exon 2 (yellow). All isoforms contain two RRMs (RNA recognition motifs) each composed of characteristic RNP-2 and RNP-1 boxes respectively (red) followed by a Gln-rich domain. The isoform names are listed at left and number of amino acids at right.