Coordinator : A. Telerman (Partner 9)
Starting date: January 2013
Recent data from the partner laboratories (P.P. Di Fiore, J-C Marine and Telerman, partner 10) show a reciprocal repression between p53 and TCTP (Amson et al., 2012), in which p53 represses at the transcriptional level TCTP and TCTP promotes the MDM2-mediated proteasomal degradation of p53. Previous results (M. Vidal, J-C Marine and Telerman) indicate that p53 promotes the secretion of TCTP by the non-classical protein secretion pathway of which the exosomes (Amzallag et al., 2004; Lespagnol et al., 2008b; Passer et al., 2003). The secretion of p53 is mediated by a direct transcriptional target namely TSAP6. All together these results indicate that there is a strong antagonism between p53 and TCTP.
In this project we aim at investigating the mechanisms by which the p53-TSAP6 axis promotes the secretion of TCTP. Obviously "chasing out" of the cell TCTP is necessary for p53, otherwise TCTP promotes its degradation. For the purpose of this work we generated several animal models to investigate these processes properly:
1. TSAP6 knockout mice (TSAP6 KO)
2. TCTP heterozygous knockout mice (TCTP +/- KO)
3. TCTP conditional knockout mice (TCTP cKO)
In these animal models we suggest to investigate:
1. How the p53-TSAP6 pathway regulates protein and RNA secretion and more specifically the secretion of TCTP. This will provide with a comprehensive view of the secretome regulated by the p53-TSAP6-TCTP axis.
2. How p53-TSAP6 mechanistically are regulating this secretion process.
3. How the secretion of proteins by the p53-TSAP6-TCTP axis influences tumor formation and reversion
4. Finally we will investigate the clinical relevance of TCTP secretion by measuring its levels in the sera of a large cohort of breast cancer patients.
The long term goal of the present project is therefore to develop drugs targeting TCTP (Amson et al 2012) and to co-develop a bioassay assessing TCTP status in cancer patients.
The clinical perspective is to propose a TCTP inhibitor in patients defined by TCTP expression.