The triplet flanking sequences in the p53 binding site of IBP promoter also differ from the canonical p53 binding site motif. However, whether the triplet flanking sequences in the half p53 binding site or the 1/4 site that is adja cent to a 1/2 site modulate the p53 response element behaviour in IBP promoter, needs further investigation. In addition, it has been selleck bio shown that p53 mutants can also transactivate gene expression at noncanonical sites. Noncanonical sequences may exhibit responsive ness to p53 in combination with other transcription fac tors, such as the estrogen receptor. In this study, although the role of the p53 mutants or the possible cofac tors in IBP transcription in breast cancer remains to be determined, further experiments will elucidate the mech anism of aberrant IBP expression in breast cancer cells.

So far little information is available concerning the func tion of IBP, especially in breast cancer. IBP is a Inhibitors,Modulators,Libraries GEF related to the Rho GTPases. Recent study showed a new function for GEFs Inhibitors,Modulators,Libraries in the modulation of cell death after genotoxic stress. It is also reported that Cdc42 activity down stream of IBP might regulate mammalian genomic stability. In the present study, we have shown that IBP is decreased upon exposure to DNA damaging agents in a p53 dependent manner. It is known that the status of p53 is associated with resistance to DNA damaging therapies. p53 mutations are common in breast cancer cells and p53 inactivation is an important cause for cisplatin re sistance. p53 pathway plays an important role in DNA damage mediated apoptotic signals.

Here we further demonstrated that IBP regulated cisplatin mediated apop tosis in MCF 7 cells. IBP over expression increased cis platin resistance in MCF 7 cells. The response to DNA damaging agent and the mechanisms Inhibitors,Modulators,Libraries of Inhibitors,Modulators,Libraries cisplatin resistance are complex and multifactorial. It is likely that IBP is one of the mediators for a p53 dependent cisplatin response in breast cancer cells. Mechanisms that Inhibitors,Modulators,Libraries inhibit the propaga tion of DNA damage signalling to the apoptotic machinery are complex. We found that IBP over expression in MCF 7 cells suppressed the basal protein expression of p53 and p21, attenuated p53 phosphorylation, changed the ratio be tween Bax and Bcl 2, and activated AKT. It is known that in chemoresistant cells cisplatin induced p53 phosphoryl ation is attenuated, particularly on Ser15 and http://www.selleckchem.com/products/Tubacin.html Ser20, and the phosphorylation of Ser15 and Ser20 plays an important role in the transduction of p53 mediated apoptosis. These results indicate that IBP plays a role in increased cis platin resistance in at least three aspects the loss of p53 function, over expression of antiapoptotic Bcl 2, and acti vation of the PI3K/AKT pathway.