We have: observed that p68 RNA helicase acquired substantially higher level of phosphorylation(s) at tyrosine residues in both metastatic cancer cell lines and tissue samples compared to that in non-metastatic cancer cell lines and tissue samples. P68 is not phosphorylated in non-cancerous tissues. We also found that phosphorylation of p68 at tyrosine 593 is required for epithelial-mesenchymal-transition (EMT), a critical event for cancer metastasis. The phosphorylated p68 promotes EMT by facilitating beta-catenin nuclear translocation and activating transcription of Snail gene. Our hypothesis is that the phosphorylated p68 is a new and important regulatory factor that plays important role(s) in promoting EMT and tumor progression/metastasis. The goals of this research proposal are two fold: (1) to gain a comprehensive understanding of the molecular mechanism by which the phospho-p68 promotes EMT, and (2) to extensively test the role of the phospho-p68 in promoting cancer metastasis.
In specific aim 1, we propose experiments to test the role of the p68 phosphorylation in promoting cancer metastasis both in xenograft mice model and in tissue samples from cancer patients.
In specific aim 2, we design experiments to elucidate the mechanism by which the phospho-p68 activates Snail gene transcription. We will test whether the phospho- p68 use its protein-dependent ATPase activity to 'displace'HDAC1 from remodeling and deacetylation complex (NuRD) at Snail promoter. Most cancer-related deaths are the consequence of the cancer metastasis. Although an outline picture about the process of cancer metastasis is emerge, the detailed mechanism is still far beyond fully understanding, especially the cellular factors that contribute to each steps of cancer metastasis.
In specific aim 3, we propose experiments to test whether the phospho-p68 actively 'transports'cytoplasmic beta-catenin to the nucleus. Our study will uncover a new molecular factor that is involved in cancer metastasis. Understanding the functional role of phospho-p68 will ultimately be applied to develop new strategies to the diagnosis/prognosis and treatment for cancer metastasis.
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