Characterization of the Role of Stra6 in Tumor Suppression Mechanisms

Stra6 is a protein that is upregulated in response to retinoids. Interestingly, we have found that Stra6 can induces p53 independently of DNA damage through ROS generation. Stra6 have shown a great induction of p53 protein levels with high stability as well. p53 stabilisation through Stra6 leads to stimulate downstream proapoptotic events such as increase the activation of caspase-3, caspase-9 and PARP cleavage. Stra6 have shown the capability of driving tumour cell to apoptosis after cell sensitized with ATRA and stimulated with DNA damaging agents. However, both Stra6 and p53 were important to achieve maximum percentage of cell death, as this was observed by detecting a positive feedback loop between Stra6 and p53. Pull-down assay of Stra6 protein have shown truncated forms of the Stra6 protein with molecular weights of 25 and 15 kDa. Basically, we have found that the small form of Stra6 with 25 kDa was translocated from cell membrane to cytosol in the absence of DNA damage and it was found to be located within the nucleus in response to DNA damage. Furthermore, this shorter form of Stra6 was capable of generating ROS and enhancing p53 dependent apoptotic cell death via the upregulation mechanism of the downstream cascade of p53 signalling pathway. Additionally, mass spectrometry data have identified some of cytosolic and nuclear proteins as Stra6’s protein binding partners. Remarkably, several of these identified proteins were related to apoptosis, as well were associated in the regulation of important cellular mechanisms. We propose that Stra6 can sensitize tumor cells to DNA damaging agents and function as an apoptotic protein in a p53-dependent manner.