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

描述（由申请人提供）： 研究提出了一种新的基因DOC 45（DNA损伤调节过表达的癌症45），编码一个高度保守的推定GTP结合蛋白的45 kDa的特征。GTP结合蛋白控制各种重要过程，包括蛋白质翻译和运输、信号转导、细胞生长、存活和转化。这里提出的初步结果表明，DOC 45 mRNA表达下调的遗传毒性应激（DNA损伤），以及肿瘤抑制基因p53。然而，遗传毒性应激后DOC 45下调似乎也以不依赖于p53的方式发生。此外，DOC 45在包括结直肠癌在内的几种癌症类型中过表达。基于我们的初步结果，我们假设DOC 45可能是一个高价值的肿瘤标志物，DNA损伤和p53对其的下调可能是DNA损伤和p53介导的生长抑制和/或细胞死亡的关键事件。此外，DOC 45表达和DOC 45介导的信号传导事件的改变可能是选定的人类恶性肿瘤（包括结直肠癌）发生和/或进展的机制的一部分。我们提出了两个具体的目标，以进一步表征DOC 45。具体目的1是研究DOC 45在原发性结直肠癌和匹配的正常组织中在mRNA和蛋白水平上的表达。具体目标2是确定DOC 45的GTP结合潜力及其在细胞对DNA损伤的反应中的作用。这些研究的结果将提供有关DOC 45作为高价值分子肿瘤标志物的实用性及其在DNA损伤反应中的作用的有价值的信息，特别是在人类结直肠癌的发展和/或进展的背景下。

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.