Poster Presentation 30th Lorne Cancer Conference 2018

The role of ZYG11 family members in development and disease (#213)

Charlene Magtoto 1 , Lorey Smith 2 , Lee Miles 3 , Nathan Godde 1 , Iva Nikolic 2 4 , Seb Dworkin 3 , Kaylene Simpson 2 4 , Helena Richardson 1 , Patrick Humbert 1
  1. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
  2. Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia
  3. Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC, Australia
  4. Victorian Centre for Functional Genomics, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia

Early cellular hallmarks of epithelial cancers include the disruption of cell polarity, cell morphology and tissue architecture. Our lab has recently identified ZYG11A as a novel regulator of mammalian epithelial cell morphology1. Although a role for these genes has been described in cell cycle control and HPV16 E7 viral oncoprotein function, little is known about the function ZYG11A and other ZYG11 family members in the regulation of cell polarity and cell morphology2,3.

To investigate the function of ZYG11 family members in epithelial development and cellular organization, I have used a combination of gene expression, live cell imaging, and functional analysis in mammalian epithelial cells as well as generated ZYG11 homologue mutants in Drosophila and zebrafish. Our initial studies provide evidence for divergent functions for individual ZYG11 family members in mammalian cells as well as a fundamental requirement for ZYG11 in Drosophila and zebrafish development.

As ZYG11A has been implicated in protein ubiquitination, I hypothesise that the loss of ZYG11A will deregulate the turnover of a large network of proteins4. Using RNAi screening of candidate biochemical and genetic interactors, I have initially identified key adhesion and polarity proteins as potential targets of ZYG11A regulation. Through the implementation of proximity-dependent biotin labelling, I aim to build a better understanding of the ubiquitination targets and pathways regulated by the ZYG11 family that contribute to the regulation of cell polarity, morphology, and how this may ultimately regulate the initiation and progression of epithelial cancer.

  1. Smith, L. K., Thomas, D. W., Simpson, K. J., & Humbert, P. O. (2016). A Phenotypic High-Content Screening Assay to Identify Regulators of Membrane Protein Localization. Assay Drug Dev Technol, 14(8), 478–488. https://doi.org/10.1089/adt.2016.733
  2. Balachandran, R. S., Heighington, C. S., Starostina, N. G., Anderson, J. W., Owen, D. L., Vasudevan, S., & Kipreos, E. T. (2016). The ubiquitin ligase CRL2 ZYG11 targets cyclin B1 for degradation in a conserved pathway that facilitates mitotic slippage. The Journal of Cell Biology, 215(2), 151–166. https://doi.org/10.1083/jcb.201601083
  3. White, E. A., Sowa, M. E., Tan, M. J. A., Jeudy, S., Hayes, S. D., Santha, S., … Howley, P. M. (2012). Systematic identification of interactions between host cell proteins and E7 oncoproteins from diverse human papillomaviruses. Proceedings of the National Academy of Sciences of the United States of America, 109(5), E260-7. https://doi.org/10.1073/pnas.1116776109
  4. Vasudevan, S., Starostina, N. G., & Kipreos, E. T. (2007). The Caenorhabditis elegans cell-cycle regulator ZYG-11 defines a conserved family of CUL-2 complex components. EMBO Rep, 8. https://doi.org/10.1038/sj.embor.7400895