Associate Professor

Dept. of Medicine
Division of Hematology & Oncology

Contact Information:

Office Address: BBRB 765
Phone: 205-975-2409
Websites: School of Medicine Faculty Profile


University of Alabama
BS, Biochemistry, 1982

University of Alabama
PhD, 1986

Research Description:

Translation initiation is generally accomplished via ribosomal scanning from the beginning (5'-end) of the mRNA, and for many genes this a relatively efficient process which is not subject to specific regulatory controls. However, the genes most critical to the control of cellular proliferation and survival (e.g. protooncogenes, growth factor receptors, and apoptotic regulators) are associated with very long, highly structured 5'-untranslated leader sequences which present significant obstacles to 40S ribosomal scanning and translation initiation. These complex 5'-UTRs serve essentially as "RNA promoters", with structural features and regulatory protein binding sites which provide the opportunity for specific regulation of gene expression at the translational level. Such features include upstream open reading frames (uORFs), which derail the scanning ribosome, and internal ribosomal entry sites (IRESs), which recruit the 40S ribosomal subunit into the vicinity of the authentic translation initiation codon. Importantly, these do not appear to be static structural features, rather they are regulated through dynamic interactions with sequence-specific RNA-binding proteins. Roughly 8% of all human genes encode RNA-binding proteins, yet we are just beginning to profile the spectrum of RNA-binding proteins and their functions in regulating gene expression. In fact, we are just now beginning to realize that these RNA-binding translation-regulatory proteins are capable of a degree of sequence specificity rivaling that of the much more thoroughly studied DNA-binding transcription factors, whose roles in gene expression and in tumorigenesis have been well-established over the past 20 years. Our research has focused on two genes, the protooncogene c-myc and the potent anti-apoptotic factor IGF1R, both of which are directly implicated in human breast cancer pathogenesis, and both of which are regulated at the translational level. In particular, we are investigating the IGF1R IRES, the c-myc uORF, and the RNA-binding proteins interacting with each of these complex 5'-untranslated sequences. We hypothesized that the dynamic, competitive interactions between these RNA-binding proteins and the IGF1R and c-myc 5'-UTRs may determine the functional state of the mRNA (whether it is actively translated, temporarily repressed, or permanently sequestered to facilitate the induction of apoptosis; molecular triage), and have accumulated data which support this hypothesis. Perhaps most importantly, our data indicate that pathological alterations in the activities of these RNA-binding translation-regulatory proteins may be responsible for dysregulation of gene expression in human breast cancer cells, and may contribute significantly to the molecular pathogenesis of this disease. Ultimately, this work is intended to establish gene-specific translational control mechanisms as targets for development of molecular therapeutic interventions.


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