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

描述(由申请人提供)： 有人建议研究一个新的基因DOC45(DNA损伤调节的在癌症45中过度表达)，它编码一个高度保守的假定的45 kDa的GTP结合蛋白。GTP结合蛋白控制着多种重要的过程，包括蛋白质的翻译和运输、信号转导、细胞生长、存活和转化。初步结果表明，DOC45mRNA的表达受遗传毒性应激(DNA损伤)和肿瘤抑制基因P53的下调。然而，在遗传毒性应激后，DOC45的下调似乎也以一种不依赖于p53的方式发生。此外，DOC45在包括结直肠癌在内的几种癌症中都有过度表达。根据我们的初步结果，我们推测DOC45可能是一个高价值的肿瘤标志物，它可能是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，DOC45表达和DOC45介导的信号事件的改变可能是包括结直肠癌在内的特定人类恶性肿瘤发生和/或进展的部分机制。我们提出了两个具体目标来进一步描述DOC45。具体目的1是研究DOC45在原发结直肠癌及其配对的正常组织中的表达。具体目标2是确定DOC45的GTP结合潜力及其在细胞对DNA损伤的反应中的作用。这些研究的结果将为DOC45作为一种高价值分子肿瘤标记物的用途以及它在DNA损伤反应中的作用提供有价值的信息，特别是在人类结直肠癌的发生和/或发展的背景下。

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.