Understanding the mechanism underlying oncogene addiction is of major importance given their role in driving tumorigenesis. This proposal focuses on a new discovery, whereby we reveal a novel mechanism for oncogene addiction. A genetic N-RAS/Ink4a mouse melanoma model established the oncogenic role of the transcription factor ATF2 in melanoma. This is achieved through its constitutive nuclear localization, where ATF2 is active as a transcription factor and DNA damage response protein. We recently discovered that constitutive nuclear localization of ATF2 impairs a newly identified function for this protein in te cytosol. Following exposure of cells to genotoxic, ATF2 is exported from the nucleus to enable its localization at the mitochondrial outer membrane (MOM), where it impairs MOM potential and augments apoptosis. This process underlies a newly disclosed mechanism by which ATF2 contributes to cell death. Although this mitochondrial function of ATF2 is seen in most cell types, it is attenuated or lost in melanoma. Moreover, the ability of ATF2 to localize to the MOM is controlled by PKC epsilon (PKC?). Melanoma cells express high levels of PKC?, which effectively locks ATF2 in the nucleus and prevents its export and function at the mitochondria. These observations form the basis for our hypothesis that PKC? control of ATF2 nuclear export constitutes a novel paradigm for oncogene addiction in melanoma, and therefore offers unique opportunities for studying unrecognized pathways underlying melanoma development &progression, which can be exploited for development of innovative therapeutic modalities. Our proposed studies are designed to answer key questions that emerge from our recent discovery of ATF2 addiction to PKC?, using cell biology, and new relevant genetic mouse melanoma models. Among the cardinal questions we will address are: what underlies PKC? upregulation in melanoma, the significance of ATF2's tumor suppressor activities and the mechanisms underlying oncogenic ATF2 activity. We will establish conditional ATF2 knock-in mice, which will allow us to define oncogenic and tumor suppressor functions of ATF2, respectively. Lastly, we will use a high- content screen, already established, to identify natural compounds that promote nuclear export of ATF2 in melanoma cells, thereby offering a novel therapeutic modality for melanoma.