BAG3 Mediated Down-regulation in Expression of p66shc has Ramifications on Cellular Proliferation, Apoptosis and Metastasis.

ABSTRACT

Redundancy of cancer cells towards ROS-mediated apoptosis despite expressing proline-rich p66shc abundantly needs to be investigated properly. P66shc, an adapter protein, is indispensable both for initiating ROS-mediated apoptosis and subsequent ROS generation through Rac-1 activation. P66shc gets phosphorylated at Ser-36 that triggers its translocation to the mitochondria and subsequent release of Cytochrome c in response to oxidative stress. It also aids in Rac-1 dependent NADPH oxidase activation, leading to the generation of cytosolic ROS that can perform diverse functions depending on its concentration. This study has identified the multi-faceted anti-apoptotic protein BAG3 as an interacting partner of p66shc. BAG3 utilizes its WW domain to bind to the proline-rich motifs of p66shc. BAG3, through its WW domain, antagonizes p66shc mediated apoptosis, by inhibiting both the expression and phosphorylation of p66shc under normal and oxidative stress conditions. This results in significant protection against ROS-mediated apoptosis. BAG3-mediated reduction in p66shc expression increases cell proliferation and metastasis. The increase in cell proliferation is attributed to the impact of BAG3 on Rac-1 activation and ROS production under normal conditions. This study has unraveled an interactor of p66shc that enhances pro-survival role while simultaneously suppressing its apoptotic role.