Rap 1-Mediated Protein Transport in Oral Cancer

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DESCRIPTION (provided by applicant): The aggressive surgical and radiologic treatment for oral cancer is physically and emotionally debilitating and has not improved prognosis (<50% 5 year survival) in the past four decades. Since cancer is the endpoint of uncontrolled cell proliferation, elucidation of the signaling cascade controlling cell proliferation in normal and malignant oral keratinocytes is critical to the identification of specific treatment targets. In oral cancer these signaling mechanisms are relatively uncharacterized but an exciting and significant area of research is the signaling cascade triggered by rap1A and rap1B, ras-like proteins that have been shown to have oncogenic and/or tumor suppressive properties in mesenchymal cells. In previous studies we found that inactivation of rap1 by rap1GAP, stimulated proliferation in non-malignant keratinocytes but inhibited proliferation in oral cancer. Rap1GAP inactivates rap1A and rap1B, the 95% identical isoforms, both of which are expressed in normal and malignant keratinocytes. Although rap1A and rap1B have been linked to growth in several cells, the interaction between these proteins in the same cell has not been explored. Furthermore, our laboratory recently discovered that rap1 is strongly expressed in the nucleus of malignant keratinocytes and that growth factors in serum induce nuclear translocation. Hence, it is likely that rap1A and rap1B interact with transport and effector proteins to regulate proliferation. The central hypothesis is that in oral cancer there is a disruption in rap1-mediated nuclear transport with enhanced nuclear translocation of pro-proliferative proteins. The objectives of this proposal are to investigate the interaction between rap1A and rap1B in regulating proliferation in normal and malignant keratinocytes; and to identify the proteins that are transported by rap1A and rap1B to the nucleus to regulate proliferation. The significance of this research is that it explores an important and novel mechanism for nucleocytoplasmic transport of pro-proliferative proteins in oral cancer, thereby identifying novel treatment targets.