Dr. Leslie A. Krushel
The University of Texas MD Anderson Cancer Center
Department of Biochemistry and Molecular Biology
- Protein synthesis
- Alzheimer's Disease
- Aurora kinases
- Learning and memory
- Amyloid precursor protein
We are interested in RNA biology. Our goals are to understand the basic and fundamental mechanisms of protein synthesis and determine how these mechanisms contribute to both normal and disease states, in particular, Alzheimer's Disease and cancer. The major mechanism to regulate protein synthesis is at the step of initiation. Initiating translation of a messenger RNA requires recruiting the ribosome to the mRNA and positioning it at the initiator codon (AUG). The major mechanism for these processes is called the cap/scanning model whereby the cap-binding protein binds the very 5' end of the mRNA (the m7G cap structure) and recruits the translational machinery including the 40S ribosome. The ribosome, in turn, migrates or scans along the 5' leader (or untranslated region) until it encounters an AUG in a proper context. An alternative and less well understood mechanism is the recruitment of the ribosome by the 5' leader. These regions downstream of the cap structure are called internal ribosomal entry sites (IRESes). IRESes have been best studied in a subset of viruses including poliovirus and Hepatitis C. To date, only a small percentage of eukaryotic mRNAs have been shown to contain an IRES and the mechanism and function of these eukaryotic IRESes is not well understood. It is proposed that conditions that inhibit or down-regulate cap-dependent translation maintain or up-regulate IRES-dependent translation. These same conditions contribute to Alzheimer's Disease and cancer. Indeed, our lab has identified IRESes in mRNAs that code for proteins that are essential for the etiology of Alzheimer's Disease (Amyloid Precursor protein and Tau protein) as well as contribute to carcinogenesis (Aurora A Kinase). We are presently identifying cis IRES elements (RNA sequences and RNA structure required for IRES activity), as well as trans IRES elements (proteins that bind the IRES and recruit the translational machinery). In addition, we are examining the regulation (or misregulation) of the above IRESes in part by identifying intracellular signaling pathways that potentially lead to the post-translational modification of specific RNA-binding proteins. Finally, we are examining the in vivo relevance of IRES-dependent translation through the study of neuronal protein synthesis in culture as well as the creation of transgenic animals.
Projects/Techniques: Essentially we cover a wide array of molecular, cellular, and biochemical techniques to identify RNA sequences and RNA structure, novel proteins, levels of protein synthesis, post-translational modification of proteins, regulation of protein synthesis in-vitro, ex-vivo and in-vivo, intracellular pathways that regulate IRES activity, etc. Students will be trained in the techniques appropriate to the projects in which they are interested.
Beaudoin ME, Poirel VJ, Krushel LA. Regulating amyloid precursor protein synthesis through an internal ribosomal entry site. Nucleic Acids Res 36(21):6835-47, 12/2008. e-Pub 10/2008. PMCID: PMC2588504.
Dobson T, Kube E, Timmerman S, Krushel LA. Identifying intrensic and extrinsic determinants that regulate internal initiation of translation mediated by the FMR1 5' leader. BMC Mol Biol 9:89, 2008. PMCID: PMC2576346.
Timmerman SL, Pfingsten JS, Kieft JS, Krushel LA. The 5' leader of the mRNA encoding the mouse neurotrophin receptor TrkB contains two internal ribosomal entry sites that are differentially regulated. PLoS One 3(9):e3242, 2008. PMCID: PMC2531235.
Veo BL, Krushel LA. Translation initiation of the human tau mRNA through an internal ribosomal entry site. J Alzheimers Dis 16(2):271-5, 2/2009.