Characterization of a putative GTP-binding protein as a novel tumor marker.

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DESCRIPTION (provided by applicant): Studies are proposed to characterize a novel gene DOC45 (DNA damage-regulated overexpressed in cancer 45) that encodes a highly conserved putative GTP-binding protein of 45 kDa. GTP-binding proteins control various important processes including, protein translation and trafficking, signal transduction, cell growth, survival and transformation. Preliminary results presented here indicate that DOC45 mRNA expression is down-regulated by genotoxic stress (DNA damage) as well as by tumor suppressor p53. However, DOC45 down-regulation following genotoxic stress appears to also occur in a p53-independent manner. In addition, DOC45 is overexpressed in several cancer types including colorectal cancer. Based on our preliminary results, we hypothesize that DOC45 could be a high-value tumor marker and its down-regulation by DNA damage and p53 may be a critical event for DNA damage and p53-mediated growth inhibition and/or cell death. Furthermore, alterations in DOC45 expression and DOC45-mediated signaling events could be part of the mechanisms underlying the development and/or progression of selected human malignancies including colorectal cancer. We have proposed two specific aims to further characterize DOC45. Specific Aim 1 is to investigate the expression of DOC45, at mRNA as well as protein levels, in primary colorectal cancers and matching normal tissues. Specific Aim 2 is to determine the GTP-binding potential of DOC45 and its role in cellular response to DNA damage. The outcome of these studies will provide valuable information about the utility of DOC45 as a high-value molecular tumor marker, and its role in DNA damage response particularly in context to the development and/or progression of human colorectal cancer.