Additionally, overexpression of IRS 1 attenuates the inhibitory effect of oxidative stress on mTORp70 S6K signaling. These results suggest that overexpression of IRS 1 competes with the together inhibitory signal mediated by oxidative stress on mTOR. Importantly, the oxidative stress mediated induction of autophagy was attenuated by overexpres sion of IRS 1. Taken together, these findings suggest that inhibition of IRS 1PI3KAktmTOR sig naling is another mechanism for oxidative stress induced autophagy. We demonstrated that overexpression of IRS 1 inhibits autophagy in the present study. The previous finding in dicating that knockout of IRS 1 results in increased numbers of autophagosomes in mice cardiomyocytes further supports our data, and suggests that IRS 1 is involved in the regulation of autophagy.

We found that overexpression of IRS 1 increases both ERK and mTOR Inhibitors,Modulators,Libraries p70 S6K activity. Activation Inhibitors,Modulators,Libraries of ERK signaling induces autophagy, activation of mTOR signaling inhibits autophagy, and activation of p70 S6K signaling induces autophagy. Basal autophagy was decreased in cells overexpressing IRS 1 even though ERK and p70 S6K signaling were activated. This might be due to the interaction of com plex intracellular signaling networks in response to dif ferent stimuli, and be explained by the presence of different downstream mTOR signaling pathways. The mTORp70 S6K signaling is involved in cell growth, thus, cells overexpressing IRS 1 grow more rapidly than the control cells do. However, the mTOR unc 51 like kinase signaling negatively regulates autophagy.

In summary, Inhibitors,Modulators,Libraries mTOR is activated by overexpression of IRS 1 in cells, in which autophagy is inhibited. Despite its lack Inhibitors,Modulators,Libraries of intrinsic kinase properties, IRS 1 is thought to be involved in tumorigenesis, it interacts with B catenin, an important regulator of stemprogenitor cell fate, and Inhibitors,Modulators,Libraries levels of B catenin target genes, such as c myc and cyclin D1, are increased in mammary tumors that overexpress IRS 1. IRS 1 directly binds, interacts, and cooperates with numerous oncogene proteins, including JCV T antigen, and simian virus 40 T antigen. Additionally, IRS 1 has an anti apoptotic function that protects cells from apoptotic cell death. In this study, we found that activation of IRS 1 signaling pro motes cell proliferation, probably via concomi tant activation of mTORp70 S6K and ERK signaling.

Both of these pathways are involved in cell growth and Enzastaurin CAS proliferation. Further, IRS 1 protects cells from oxidative stress mediated cell death. These may be the reasons why the expression levels of IRS 1 increase in some types of cancers. Thus, our find ings afford a credible explanation for IRS 1 involvement in the tumor initiation and progression. The proposed relationship between IRS 1, oxidative stress, and regulation of autophagy and cell growth is shown in Figure 9.