These results suggest that IBP may negatively regulate p53 activation through AKT in MCF 7 cells. IBP regulates the sensitivity to cisplatin partly through inhibitor Navitoclax AKT/p53 pathway Since IBP over expression in turn negatively regulates p53 expression, We further investigated whether IBP regulates Inhibitors,Modulators,Libraries the sensitivity to cisplatin in p53 dependent manner. In stable MCF 7/IBP RNAi cells, we inhibited p53 expres sion by p53 targeting RNAi lentiviral infection, then cells were exposed to cisplatin, and cell growth was measured. Inhibition of p53 could decrease cisplatin sensitivity in IBP knockdown MCF 7 cells. Moreover, we established stable Inhibitors,Modulators,Libraries IBP knockdown HCT116 p53 cells, and measured cisplatin induced cell growth suppression in these cells by using CCK 8. As shown in Figure 8B, IBP knockdown also increased cisplatin sensitivity of HCT116 p53 cells.

Furthermore, in IBP over expressing MCF 7 cells, AKT inhibitors Inhibitors,Modulators,Libraries Ly294002 could attenuate cisplatin resistance and increase cisplatin induced apoptosis. These results suggest that IBP may impair cisplatin chemosensitivity in breast cancer cells partly through AKT/p53 pathway. Discussion IBP is a newly discovered protein aberrantly expressed in breast cancer cells. We found that IBP promotes the proliferation and migration of breast cancer cells and its expression is negatively correlated with p53 levels. Previous studies have shown the role of Lck in IBP acti vation in T lymphoma cells. However, little is known about the regulation of IBP expression, particu larly in breast cancer.

Because previous studies have shown that the activity of Rac1 is inversely regulated by functional p53, we investigated whether p53 could regulate IBP in Inhibitors,Modulators,Libraries breast Inhibitors,Modulators,Libraries cancer cells. Here we have identified IBP as a novel p53 target gene. The inhibition of IBP expression corre sponded with increased p53 expression, and the induc tion of IBP was related to p53. p53 could bind to IBP promoter in MCF 7 cells. The present results clearly in dicate that inactivation of wild type p53 at least partially explains the aberrant IBP expression in breast cancer. It was previously reported that p53 could transactivate genes from a noncanonical sellectchem consensus 1/2 site or 3/4 sites that contain a 1/4 site that is adjacent to a 1/2 site or a 1/4 site and is separated from a 1/2 site by a 5 nt spacer. We have shown for the first time that IBP promoter region possesses a noncanonical repressing p53 binding site. We identified that IBP promoter con tains a perfect p53 half site, which contains a CATG core motif. It is known that the C and G positions are essential for the function of the p53 binding site, and the presence of an AT as the WW dinucleotide is associated with the high activity of a half site.