THIS IS A SHANNON AWARD PROVIDING PARTIAL SUPPORT FOR THE RESEARCH PROJECTS THAT FALL SHORT OF THE ASSIGNED INSTITUTE'S FUNDING RANGE BUT ARE IN THE MARGIN OF EXCELLENCE. THE SHANNON AWARD IS INTENDED TO PROVIDE SUPPORT TO TEST THE FEASIBILITY OF THE APPROACH; DEVELOP FURTHER TESTS AND REFINE RESEARCH TECHNIQUES; PERFORM SECONDARY ANALYSIS OF AVAILABLE DATA SETS; OR CONDUCT DISCRETE PROJECTS THAT CAN DEMONSTRATE THE PI'S RESEARCH CAPABILITIES OR LEAD ADDITIONAL WEIGHT TO AN ALREADY MERITORIOUS APPLICATION. THE APPLICATION BELOW IS TAKEN FROM THE ORIGINAL DOCUMENT SUBMITTED BY THE PRINCIPAL INVESTIGATOR. Cell growth and differentiation is tightly regulated by a signaling pathway known as the MAP kinase cascade. This cascade is activated in the majority of human cancers, through the action of specific oncogenes and culminates in the phosphorylation of the MAP kinases (also called ERKs). The proto-oncogene ras (p21) is the most commonly activated oncogene in human tumors and turns on MAP kinases through the stimulation of upstream components of this cascade. Recently a second parallel signaling pathway called the stress-activated protein kinase cascade has been identified. This pathway is activated by a variety of extracellular stresses including radiation and chemotherapeutic agents and like the MAP kinase cascade is also activated by the proto-oncogene ras. We propose that the stress-activated protein kinase cascade triggers apoptosis (programmed cell death) and that this pathway is inactivated by a novel family of MAP kinase phosphatases (MKPs) that are rapidly induced during mitogenesis. We will demonstrate the actions of MKPs on JNKs using biochemical techniques following their expression in transformed cell lines. We propose that the pathophysiological response to JNK activation (programmed cell death) can be blocked through dephosphorylation by MKPs. We will examine the induction of apoptosis in MKP overexpressing cells to demonstrate MKPs ability to block apoptoic responses. The inhibition of MKPs should activate latent stress-activated pathways and induce apoptosis in tumor cells. These studies will establish that MKPs are potential targets for novel phosphatase inhibitors that, by inactivating MKPs, will potentiate the apoptoic action of other anti- cancer treatments.
