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| CODE |
HEALTH-IT-LCP-7 |
| TITLE |
Role of Sgk1 in the regulation of cell proliferation, survival and differentiation. Sgk1 in cancer development. |
| PROGRAMME / THEME |
Health |
| FUNDING SCHEME |
CP-IP Collaborative project (large scale integrating) |
| DEADLINE |
31/12/2008 |
| ORGANISATION TYPE |
University |
| PROJECT DESCRIPTION |
Serum and glucocorticoid regulated kinase 1 (Sgk1) is a serine threonine kinase that is approximately 45-55% homologous to protein kinase B (Akt/PKB) and is activated by serum, steroids, insulin, vasopressin and interleukin2 at the transcriptional and post-translational level.
Traditionally the kinase has been described to be involved in the hormonal regulation of sodium absorption in the kidney principal cells.
Several lines of recent evidence suggest that Sgk1 is important in transducing growth factor and steroid dependent survival signals and may have a role in the development of resistance to chemotherapy. The interleukin-2 is a cytokine that is essential for lymphocytic survival and function. Ectopic expression of the IL-2 receptor in epithelial tissues has been reported previously, although the functional significance of this expression is still being investigated. We provided novel structural and functional information on the expression of the IL-2 receptor in kidney cancer cells and in other normal and neoplastic human epithelial tissues. In A-498 kidney cancer cells, we showed that IL-2 binding to its own receptor triggers a signal transduction pathway leading to the inhibition of proliferation and apoptosis. We found that the inhibition of proliferation is associated with Erk1/2 dephosphorylation, whereas the survival signals appear to be mediated by Sgk1 activation. Interleukins 2, through Sgk1, protects kidney cancer cells by doxorubicin induced apoptosis.
We also produced and characterized stably transfected Hela cell lines expressing wild type and dominant negative Sgk1. Sgk1 is essential for Hela cell survival, cell cycle progression and epithelial to mesenchimal transition. Moreover Sgk1 promotes the cell survival and the clonogenic potential, by binding to p53 and activating MDM2 dependent p53 ubiquitination. The results, obtained in stably transfected Hela cells, were confirmed by the analysis of various cancer lines characterized by different expression of p53 and are strengthened by the phenotypic characterization of an original mouse model expressing the dominant negative mutant of Sgk1 under the control of a Tet regulated promoter, driven by the liver specific expression of the transactivator.
Since the transcription of Sgk1 is activated by p53, we propose a finely tuned feed-back model where Sgk1 down-regulates the expression of p53 by enhancing its mono and poly-ubiquitination.
We are now interested in the production in small molecules interfering with the ability of Sgk1 to regulate the expression on p53 . These molecules might find an application in the treatment of human cancers. Moreover we are interested in looking for mechanisms that might deregulate the expression on Sgk1 in human tumors, including the expression of micro RNA or alternative spliced variants.
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| PARTNER SOUGHT |
We are intersted in partnership with other public or private research facilities that may share our interest in the role of Sgk1 in cancer development. We are also interested in the collaboration with private industries interested in drug research and development, that may be intrested in the production of small molecules interfering with the function of Sgk1 . |
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