The overall goal of this Program is to investigate the role of the Unfolded Protein Response (UPR) signaling pathway in tumor homeostasis and tumor progression. Rapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as tumor volume expands beyond the established vascularity of the tissue. The UPR functions as a sensor of the availability of key cellular nutrients, such as glucose and oxygen that are criticall important for tumor growth and progression. The UPR and specifically the PERK kinase, has recently been shown to facilitate oncogene-mediated tumor progression, suggesting that the UPR may also respond to bioenergetic challenges triggered by aberrant oncogene-dependent signaling. The overall hypothesis being interrogated by this Program Project is that the UPR and more specifically, the PERK kinase, functions as a sensor of tumor ceil autonomous and non-autonomous bioenergetic stress; the ensuing activation of PERK catalytic function promotes tumor cell adaptation to this stress and thereby facilitates tumor progression. To test this hypothesis, three synergistic projects have been developed. Project 1 will evaluate mechanisms whereby a micro-RNA balances PERK-dependent pro-survival and pro-apoptotic functions. Key preliminary data suggest that miR-211 is a novel regulator of the pro-apoptotic factor, CHOP, and functions to temporally regulate CHOP expression. Project 2 will interrogate the function of PERK as a first response regulator of c- Myc-dependent bioenergetic and proteotoxic stress. Through its capacity to temper protein translation, PERK moderates cellular response to c-Myc thereby ensuring that bioenergetic capacity matches oncogenic demand resulting in tumor growth rather than apoptosis. Project 3 will test the hypothesis that tumor cells activate the UPR, and, perhaps, more broadly the Integrated Stress Response (ISR) due to oncogene activation or oxygen and/or nutritional deficit, and thereby acquire the ability to escape the anti proliferative and pro-apoptotic effects of Type 1 interferons, IFN?/. Through the synergistic functions of this Program, we will ascertain how PERK balances growth with apoptosis (Projects 1 and 2), how PERK responds to environmental challenge (Projects 1 and 3) and how tumor cells utilize PERK and the UPR to adapt to oncogene-triggered bioenergetic stress (Projects 1-2-3). All three projects will make extensive use of scientific Core B (Cell/Tissue Morphology Core) and have already established a working, highly collaborative relationship. It is our supposition that findings stemming from work proposed herein will provide a foundation for the design of novel anti-cancer treatment strategies targeting this pathway.