Notorious resistance of melanoma cells to radiation and chemotherapy has been a major obstacle in the treatment of this tumor type. Studies performed during the current funding period have demonstrated that ATF2 is an important player in melanoma resistance to radiation and chemical treatment. We have demonstrated that ATF2 and its upstream kinases, including TRAF2, GCK and p38 play an important role in the regulation of Fas and TNFa, which are among major death signaling pathways that govern late stage melanoma ability to undergo apoptosis. Our more recent studies on the regulation of Fas expression revealed that STAT3 cooperates with c-Jun to suppress Fas transcription, which results in low level of cell surface Fas expression in human melanoma that are resistant to treatment and are highly metastatic. The suppression of Fas promoter by STAT3 and c-Jun is independent of conventional STAT3 dependent transactivation of a multimerized GAS element reporter. As apoptosis induced by Fas ligation is frequently lost during tumor progression, in most cases, as a consequence of Fas downregulation. It is our working hypothesis that Stat3-Jun cooperation serves as a primary mechanism to silence Fas transcription. The proposed studies aim at testing this hypothesis via elucidating the mechanisms underlying Stat3-Jun cooperation to silence Fas transcription and their direct implications towards melanoma ability to resist therapy and metastasize. To this end we propose to carry out the following specific aims: (1) Identify the post-translational modifications of Stat3 and c-Jun that enables their association to result in suppression of Fas transcription. (2) Characterizes the mechanism underlying Jun-Stat3 cooperation in the silencing of Fas transcription. (3) Assess the implication of altered Stat3/Jun expression in the tumorigenicity and metastic capacity of human melanoma cells in nude mice and (4) Determine whether Stat3/Jun suppression is limited to Fas or could also be identified on other promoter elements, which consist of GAS and AP1 sequences in the same proximity, including the p53 tumor suppressor gene. Completion of these specific aims will reveal the underlying mechanisms for Stat3 oncogenic activities, which is highlighted through its cooperation with c-Jun, resulting in down regulation of Fas expression, and will provide the implications of such cooperation to the ability of melanoma tumors to resist therapy and metastasize.
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