Critical Contribution of RAL GTPases to Growth and Survival of Breast Cancer Cells
Annual summary rept. 5 Mar 2004-4 Mar 2007
TEXAS UNIV AT DALLAS SOUTHWESTERN MEDICAL CENTER
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The monomeric Ral GTPases, RalA and RalB have been recognized as core components of the regulatory framework supporting tumorigenic transformation. Specifically, RalA is required to maintain anchorage independent proliferation while RalB is required to suppress apoptotic checkpoint activation. Here, we have defined the mechanistic contribution of RalB to cancer cell survival. We find that in normal human epithelia, a RalBSec5TBK1 signal transduction cascade connects viral surveillance receptors to activation of host defense gene expression. We find that this pathway is aberrantly engaged by oncogene activation in tumors with the consequence of deflecting programmed cell death pathways that would normally engage in response to oncogene-induced stress. The obligate chronic activation of TBK1 kinase in breast cancer cells coupled with the absence of toxicity upon TBK1 inactivation in normal breast epithelia suggests this protein represents a facile therapeutic target.
- Medicine and Medical Research