Thus, the effect of N17Rac1 on G2 M phase cells is probably cell type spe cific and or time dependent. In contrast, expression of N17Rac1 in MCF 7 cells abrogates the IR induced acti vation of Rac1, and this, in turn, http://www.selleckchem.com/products/Cisplatin.html is associated with an attenuation of G2 M arrest in irradiated cells Inhibitors,Modulators,Libraries and an increase in the amount of mitotic cells after irradiation. Previous studies from several laboratories, including our own, have suggested an important role for ERK1 2 signaling in the activation of the G2 M checkpoint response after DNA damage. These studies have demonstrated that DNA damage induces ERK1 2 activation and that this is associated with the induction of G2 M arrest. Additional studies demonstrate that inhibition of ERK1 2 abrogates the G2 M checkpoint response after DNA damage, resulting in increased sen sitivity of cells to DNA damaging agents.

Results presented in this report indicate that Rac1 inhi bition after incubation of cells with a specific inhibitor Inhibitors,Modulators,Libraries or transfection with Rac1 specific siRNA abrogates IR induced phosphorylation of MEK1 2 and ERK1 2, as well as the IR induced G2 M checkpoint Inhibitors,Modulators,Libraries activation, suggesting Rac1 as the upstream regulator of IR induced ERK1 2 signaling. A role for p53 in the regulation of the G2 M check point response has been suggested by previous studies, as several of the transcriptional targets of p53 can directly or indirectly inhibit Cdc2 kinase, which include p21Waf1 Cip1, 14 3 3s, and Gadd45.

However, the results of Inhibitors,Modulators,Libraries this report suggest that IR induced G2 M cell cycle arrest as well as the regulation of Rac1 on the IR induced G2 M checkpoint response is apparently inde pendent of p53, as among the four breast cancer cell lines used for the studies, MDA MB 231 and T47D cells express mutant p53, whereas MCF 7 and ZR75 1 express Inhibitors,Modulators,Libraries wild type p53. Consistent with our observation, results from other studies also show that p53 status has no influence on IR induced G2 M cycle arrest. t IR induced G2 M arrest in human breast cancer cells is markedly attenuated by the inhibition of Rac1. Further more, the results in Figure 7 and Additional file 1, Fig ure S4, provide evidence that Rac1 inhibition significantly increases the sensitivity of MCF 7 cells to irradiation, which involves apoptosis induction. These results suggest a strong correlation between the attenua tion of G2 M arrest and the increased radiation sensitiv ity in MCF 7 cells treated with IR in the presence of Rac1 inhibition.

It is possible that the increased radia tion sensitivity is simply a consequence of the attenua tion of IR induced G2 M arrest by Rac1 inhibition. However, it could also be due to a new function of Rac1. Future studies must address this question. In this report, click here we also tested the effect of Rac1 inhibi tion on IR induced G2 M arrest in normal human mam mary epithelial cells.