[Frontiers in Bioscience 16, 2307-2325, June 1, 2011]

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

Beth E. Zucconi1, Gerald M. Wilson11

1Department of Biochemistry and Molecular Biology and Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, 108 N. Greene St., Baltimore, MD 21201

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Functions of AUF1 in post-transcriptional control of gene expression
3.1. Substrate selectivity of AUF1
3.2. Structural considerations and consequences of AUF1 binding
3.3. The AUF1 interactome and mechanics of ARE-directed mRNA decay
4. Positive and negative contributions of AUF1 to neoplasia
4.1. Insights from AUF1 target mRNAs
4.2. Anti-tumorigenic roles of AUF1 in regulation of the cell cycle and apoptosis
4.3. AUF1 regulates expression of factors contributing to pre-cancerous chronic inflammation
4.4. Pro-tumorigenic roles of AUF1: over-expression induces malignancy
5. Functional and regulatory distinctions among AUF1 isoforms
6. Subcellular localization of AUF1
6.1. AUF1 translocation mechanisms
6.2. AUF1 relocalization in malignant cells
6.3. Cellular regulation of AUF1 localization
7. AUF1 modifications
7.1. Identified AUF1 phosphorylation events
7.2. Hyperphosphorylation of AUF1
7.3. AUF1 modifications induced by isomerization
8. Summary and further questions
9. Acknowledgements
10. References

1. 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.