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Experimental Oncology

Alan Underhill

Associate Chair, Graduate Studies,
Associate Professor and Mary Johnston Chair in Melanoma Research

Experimental Oncology
Department of Oncology
University of Alberta
Cross Cancer Institute
11560 University Avenue
Edmonton, Alberta T6G 1Z2

Tel: 780.432.8903
alan.underhill@ualberta.ca

Profile

Research Interests
The Underhill laboratory is interested in deciphering how master regulators of melanocyte development contribute to melanoma pathogenesis. In addition, we are also examining how histone modifications regulate the balance between cell proliferation and differentiation, and how this is overridden in cancer.

Project 1: Melanocyte transcription factors in melanoma
Malignant melanoma is one of the few cancers that continue to show an increase in incidence. The Underhill laboratory’s research focuses on the transcription factor PAX3, which is co-opted in malignant melanoma where it contributes to tumor proliferation and survival. This same factor is required during embryonic development to specify and expand the melanocyte lineage and people with only one functional copy of PAX3 are characterized by pigmentary deficiencies. As a transcription factor, PAX3 regulates the expression of other genes and this is an essential facet of its role in melanoma. Nevertheless, the identity of these genes is largely unknown. A key goal of our research program is the identification of PAX3 target genes in melanoma, which will provide a molecular picture of a key gene network in melanoma pathogenesis.

Project 2: Epigenetic control in cell differentiation and cancer
An essential component in the management and functional output of eukaryotic genomes is that their DNA is assembled into chromatin via the formation of nucleosomes, which comprise 147 bp of DNA wrapped nearly twice around an octamer of the core histone proteins H2A, H2B, H3, and H4 in equal stoichiometry. In addition to providing a means to compact the genome so that it fits within the nuclear confines, chromatin serves diverse roles in facilitating expression, repression and long-term silencing, replication, recombination, repair of damaged DNA, and mitosis. Over and above the regulatory information embedded in the genome, these different processes require a broad range of epigenetic controls that include chemical modification of DNA and histones, histone variants, linker histones and other chromatin architectural proteins, as well as the RNAi machinery. Within this scheme, our laboratory is examining how the methylation of lysine 20 on histone H4 modulates cell differentiation and how this process becomes aberrant in cancer.

We currently make extensive use of biochemical, genetic, molecular, cell-imaging, and computational approaches towards these ends. Research in the Underhill laboratory is supported by grants from the CIHR and ACRI, and Dr. Underhill holds the Mary Johnston Chair in Melanoma Research.

Publications

Corry GN, Hendzel MJ, and Underhill DA (2008) Subnuclear localization and mobility are key indicators of PAX3 dysfunction in Waardenburg syndrome. Hum Molec Genet. 17:1825-1837. *Featured on issue cover.
 
Duggan BL, Cabilio NR, Dickie P, Witmer J, Goping IS, Underhill DA, and Bleackley RC (2008) A novel lineage-specific hypersensitive site is essential for position independent granzyme B expression in transgenic mice. Biochem Biophys Res Commun. 368:357-363.
 
Berry FB, Lines MA, Oas JM, Footz T, Underhill DA, Gage PJ, and Walter MA (2006) Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dosage in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Hum Molec Genet. 15:905-919. *Selected as RECOMMENDED by Faculty of 1000.
 
McManus K, Biron VL, Heit R, Underhill DA, and Hendzel MJ. (2006) Histone H3 lysine 9 trimethylation is dynamic during mitosis and functions in chromosome congression and segregation. J Biol Chem. 281:8888-8897. *Selected as MUST READ in Faculty of 1000.
 
Goping IS, Sawchuk T, Underhill DA, and Bleackley RC (2006) Identification of ?-tubulin as a granzyme B-substrate during CTL-mediated apoptosis. J Cell Sci. 119:858-865.
 
Corry GN and Underhill DA (2005) Pax3 target gene recognition occurs through distinct modes that are differentially affected by disease-associated mutations. Pigment Cell Res. 18:427-438.
Reviews:

Heit R, Underhill DA, Chan C, and Hendzel MJ (2006) Epigenetic regulation of centromere formation and kinetochore function. Biochem Cell Biol. 84:617-630.
 
Corry GN and Underhill DA (2005) Subnuclear compartmentalization of sequence-specific transcription factors and regulation of eukaryotic gene expression. Biochem Cell Biol. 83:535-547.
 
Publication updates:

Corry GN, Raghuram N, Missiaen KK, Hu N, Hendzel MJ, and Underhill DA. (2010) The PAX3 paired domain and homeodomain function as a single binding module in vivo to regulate subnuclear localization and mobility by a mechanism that requires base-specific recognition. Journal of Molecular Biology (doi:10.1016/j.jmb.2010.07.016).
 
Craik AC, Veldhoen RA, Czernic M, Buckland TW, Kyselytzia K, Ghosh S, Lai R, Damaraju S, Underhill DA, Mackey J, and Goping IS. (2010) The BH3-only protein Bad confers breast cancer sensitivity to taxanes through a non-apoptotic mechanism. Oncogene (doi:10.1038/onc.2010.272).