Among the hundreds of protein kinases known to date, protein kinase CK2 has been shown to act as an essential component for cell survival. Compelling evidence strongly supports that CK2 is involved in the regulation of cell proliferation. CK2 activity is increased in tumour cells and its catalytic subunit may act as an oncogene, as suggested by a recent observation in transgenic mice. However understanding of its cellular functions at the molecular level remains elusive.
The present project aims at an understanding of CK2 functions related to proliferation in normal and cancer cells, with a concerted approach combining complementary expertise's, with the major objectives as follows :
1. Understand the structural and functional organisation of CK2 that governs its activity, its regulation and its specificity. This conducted using is complementary approaches, including a set of kinase mutants and should result in the development of new possibilities to manipulate CK2 functions in living cells.
2. Identify the CK2 subunit genes and develop methods to probe their activity in living cells and to manipulate the expression of the kinase or its subunits in cancer cells.
3. Unravel the cellular proteins which are targets of CK2 in vivo, by using the double hybrid system in yeast. Comparative patterns of CK2 target proteins in normal, cancer cells and human tumours should sheet light on the specific behaviour of CK2 in transformed cells and its possible role in oncogenesis.
4. Understand the role of CK2 in the regulation of specific cell functions related to growth control and cancer (I) organisation of the cytoskeleton and neurite formation; (II) regulation of topoisomeraseII and of topo-II dependent resistance to anticancer agents; (III) cell response to the growth factor FGF-2 and rRNA synthesis regulation; (IV) role in the regulation of the p53 protein functions as a cell cycle suppressor and a cell apoptosis inducer in response to anticancer agents.
5. Examine the status of CK2 (gene expression, molecular organisation and activity) in cancer cells and in frequent human tumours in Europe (i.e. colorectal and breast cancers). In this context, the kinase may emerge as a potential prognostic parameter of value in patient management as well as a potential target for drug therapy.
The present project represents a long waited opportunity for the partners to associate their interest and potential in a concerted task force. This common endeavour should shed light on the implication of an ubiquitous although still mysterious protein kinase in basic regulation processes related to cell growth and neoplasia and may suggest related new strategies in cancer therapy.