Inhibition of retinoblastoma protein degradation by interaction with the serpin PAI-2 via a novel consensus motif [ 2004 - 2006 ]

Research Grant

Researchers: Prof Andreas Suhrbier (Principal investigator) ,  Toni Antalis

Brief description Plasminogen activator inhibitor-2 (PAI-2) has previously been shown to inhibit the activity of enzymes outside the cell that are involved in blood clotting and cell migration. We have discovered that this activity is probably not the major role of PAI-2. PAI-2 also has a function inside cells that protect and increases the activity of an important tumour suppressor protein called the retinoblastoma tumour suppressor protein (Rb). Rb is involved in many cellular functions such as, cell death, cell differentiation, cell growth, and most importantly prevention of cancer development. Rb is attacked and destroyed by several viruses which causes cells to become cancerous. This grant seeks to fully understand how PAI-2 protects and interacts with Rb. We have already found a new site on Rb to which PAI-2 binds. This site is also used by other proteins in the cell as well as disease causing virus proteins. Examples of these proteins are BRCA1, a protein involved in breast cancer development, and EBNA6, a protein from Epstein Barr virus that causes glandular fever and tumours. We have also found, and seek to explore further, how PAI-2 reverses the activities of the cervical cancer causing proteins of the human papilloma virus. Although at an early stage, these studies may lead to the development of new therapeutic drugs based on PAI-2 for the treatment of various types cancers or warts caused by HPV. Analysing the activity of PAI-2 inside cells will have implications for understanding much of the confusing scientific literature on PAI-2 and will provide a better comprehension of the role of PAI-2 in inflammation, cell differentiation, wound healing and cancer. For example it has long been known that the presence of PAI-2 in cancerous tumours is linked with a better prognosis, an activity that can now be understood in terms of the PAI-2 interaction with Rb. This new understanding may lead to the development of PAI-2 based prognostic assays for cancer.

Funding Amount $AUD 463,500.00

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant