St Vincent's Institute

• Research units

• Structural Biology
• Protein Chemistry and Metabolism
• Molecular Cardiology
• Immunology and Diabetes
• Bone Cell Biology and Disease
• Stem Cell Regulation
  • Research Themes
  • Honours and PhD Projects
  • Staff
• Haematology and Leukaemia
• Molecular Genetics
• Cell Cycle and Cancer
• Cytoskeleton and Cancer
• Pharmacogenomics
• Invasion and Metastasis
• NRL
• Genome Stability

Targeting different HoxA1 isoforms for cancer therapeutics

Project Type

PhD

Summary

Homeobox (Hox) genes contain play critical roles in the embryonic development of numerous organs and have important roles in the regulation of haemopoiesis in the adult. Deregulated expression of a number of Hox genes have been shown to cause cancer. The most 3’ HoxA form, HoxA1, has two alternatively spliced mRNAs that create distinct proteins. The full-length HoxA1 isoform contains the homeodomain, which binds to DNA to activate transcription. The other isoform is a truncated HoxA1 isoform that lacks the homeodoman (named hereafter HoxA1-T). HoxA1-T does not bind to DNA, however has been shown to interact with the full-length HoxA1. The function of and biological effects of HoxA1 and especially HoxA1-T remain largely unknown.

Our data suggest that both full-length HoxA1 and HoxA1-T have important roles in haemopoiesis, and that aberrant expression of full-length HoxA1 can cause a blood cell disease called myelodysplastic syndrome. Interestingly, HoxA1 overexpression has also been associated with aggressive breast cancer. Hence if we can determine how to inhibit HoxA1 function, we might be able to treat patients with these diseases more successfully.

The Parker lab is internationally acclaimed in the field of structural biology and recently determined the 3-D structure of the GM-CSF receptor, which has opened up exciting new avenues in leukaemia treatment. The aims of this interdisciplinary PhD project are to determine the 3-D structure of each of the different HoxA1 forms, which we anticipate will eventually lead to the design of small molecules to therapeutically target the HoxA1 and HoxA1-T isoforms. A high resolution crystal structure of the related HoxA9 bound to Pbx1 and DNA has been determined previously (Genes & Dev. 17: 2060-2072, 2003). This work suggests possible strategies to crystallise a similar HoxA1-Pbx1-DNA complex and a HoxA1-Pbx1-DNA-HoxA1-T complex. This project will involve protein expression, purification, complex formation using chromatography, biophysical analyses of the resultant complexes (Dynamic light scattering, circular dichroism, analytic ultracentrifugation, Biacore), protein crystallisation, crystal structure determination and preliminary structure-based drug design. Cell biology techniques will also be employed to explore further the roles of HoxA1 and HoxA1-T in haemopoiesis to provide complementary biological studies to the protein chemistry techniques employed. Finally, kinase profiling studies will be performed to find additional ways of targeting the HoxA1 pathway for therapeutics.

Prof Michael Parker and A/Prof Louise Purton