Molecular Endocrinology

Head: Professor Leon Bach

Enquiries

Leon.Bach@med.monash.edu.au Enquiries from potential B Sc(Hons), B Med Sci, PhD and MD students are especially welcome.

Research Areas

Insulin-like growth factors and cancer

Dr Ping Fu

Structure of the C-terminal domain of IGFBP-6

Insulin-like growth factors (IGF-I and –II) are essential for normal growth. Excessive IGF activity contributes to the growth of many cancer cells, and drug companies are actively exploring IGF inhibitors as potential therapies.

IGF activity is regulated by a family of six IGF binding proteins (IGFBPs). We are studying IGFBP-6, which is a specific inhibitor of IGF-II. In addition, it may have other antitumour properties. We have previously shown that IGFBP-6 inhibits growth of cancer cells and slows tumour growth in animals.

Current projects include:

1. Site-directed mutagenesis to further delineate the actions of IGFBP-6.
2. Genomic and proteomic approaches to understanding the actions of IGFBP-6.
3. Analysis of the effects of IGFBP-6 on the cell biology of cancer cells, including invasion, migration, proliferation and apoptosis.
4. Structural studies of IGF:IGFBP interactions.

SELECTED REFERENCES

Gallicchio MA, Kneen M, Hall C, Scott AM, Bach LA. Overexpression of insulin-like growth factor binding protein-6 inhibits rhabdomyosarcoma growth in vivo. Int J Cancer 94, 645-651, 2001

Leng SL, Leeding KS, Whitehead RH, Bach LA. Insulin-like growth factor (IGF)-binding protein-6 inhibits IGF-II-induced but not basal proliferation and adhesion of LIM 1215 colon cancer cells. Mol Cell Endocrinol 174, 121-127, 2001

Gallicchio MA, van Sinderin M, Bach LA. IGFBP-6 and CCI-779, an ester analog of rapamycin, additively inhibit rhabdomyosarcoma growth. Horm Met Res 35: 822-827, 2003

Headey SJ, Keizer DW, Yao S, Brasier G, Kantharidis P, Bach LA, Norton RS. C-terminal domain of insulin-like growth factor (IGF) binding protein-6: structure and interactions with IGF-II. Mol Endocrinol 18: 2740-2750, 2004

Bach LA, Headey SJ, Norton RS. IGF binding proteins; the pieces are falling into place. Trends Endocrinol Metab 16, 228-234

Development of diabetic complications

Dr Anne McRobert, Dr Marisa Gallicchio

AGEs induce reactive oxygen species formation in proximal tubule cells (left: control, right: AGE)

The prevalence of diabetes mellitus is increasing and 7% of the Australian adult population now have this illness. Blood glucose levels are increased in diabetes, which leads to the formation of glucose-modified proteins (AGEs) and the possibility of life-threatening complications. The focus of the research group is the role of AGEs in the development of diabetic complications, particularly kidney disease.

We have recently identified that the ERM family of proteins (ezrin, radixin and moesin) specifically binds to AGEs in kidneys and we are now studying the role of this interaction in diabetic complications.

Current projects include:

1. Characterisation of the AGE-ERM binding interaction.
2. Analysis of changes in ERM cellular localisation.
3. Analysis of signalling pathways perturbed by AGE-ERM interactions.
4. The role of reactive oxygen species in AGE-induced cell damage.

SELECTED REFERENCES

McRobert EA, Gallicchio MA, Jerums G, Cooper ME, Bach LA. The amino terminal domains of ERM proteins bind advanced glycation endproducts: an interaction that may play a role in the development of diabetic complications. J Biol Chem 278: 25783-25789, 2003

Bach LA, Gallicchio MA, McRobert EA, Tikoo A, Cooper ME. Effects of AGEs on ezrin-dependent functions in LLC-PK1 proximal tubule cells. In: Baynes J, Monnier V, Ames J, Thorpe S (eds) The Maillard Reaction: Chemistry at the Interface of Nutrition, Aging, and Disease, Ann NY Acad Sci 1043: 609-616, 2005.

McRobert EA, Tikoo A, Gallicchio MA, Cooper ME, Bach LA. Localization of the ezrin binding site for glycated proteins. In: Baynes J, Monnier V, Ames J, Thorpe S (eds) The Maillard Reaction: Chemistry at the Interface of Nutrition, Aging, and Disease, Ann NY Acad Sci 1043: 617-624, 2005.

Gallicchio MA, McRobert EA, Tikoo A, Cooper ME, Bach LA. Ezrin overexpression inhibits the effects of advanced glycation endproducts on tubulogenesis and migration. J Am Soc Nephrol 17:414-421, 2006.