Role of a Novel THAP-Family Protein in Transcription and Cancer Cell Function

描述（由申请人提供）：转录调控在人类正常细胞和器官分化、发育和生理学中起关键作用。毫不奇怪，转录因子及其辅助调节因子的上调或下调与肿瘤的发展以及恶性和转移阶段的进展密切相关。癌细胞主要来源于上皮组织。越来越多的证据表明，在癌症进展过程中，细胞开始重新分布或下调参与维持细胞粘附和紧密连接的蛋白质。这些变化和其他变化促进细胞-细胞和细胞-基质相互作用的丧失，并允许细胞运动和侵入邻近组织。虽然大约90%的癌症死亡是由于肿瘤转移而发生的，但很少有有效预防转移的治疗方法。克服这一限制的一种方法是获得对促进和调节肿瘤细胞运动和转移的遗传和信号网络的完整理解。Thanatos相关蛋白（THAP）家族在人类中由12个成员组成，只有3个成员被部分表征。最近，我们观察到THAP家族成员THAP 11在癌细胞中差异表达。THAP 11过表达如何促进癌细胞功能是完全未知的，因此代表了一个令人兴奋的新研究领域。基于我们的初步结果，我们假设THAP 11是一种转录抑制因子，通过直接调节参与细胞间和细胞-基质相互作用的关键基因的表达，在癌细胞功能中发挥关键作用。由于这些相互作用的改变是转移的关键初始事件，我们提出THAP 11代表了癌细胞功能的一种新的和关键的转录调节因子。我们将进行最先进的分子，细胞，生理和全基因组分析，以确定THAP 11过表达的影响及其在三个综合特定目标中的癌细胞功能的作用机制。这些研究将大大提高我们对癌症进展和转移的认识，并可能为治疗干预提供分子靶点。公共卫生相关性：虽然大约90%的癌症死亡是由于肿瘤转移而发生的，但很少有有效预防转移的治疗方法。克服这一限制的一种方法是获得对促进和调节肿瘤细胞运动和转移的遗传和信号网络的完整理解。在这项工作中，我们将确定一种名为THAP 11的新型人类蛋白质在癌细胞功能中的作用。这些研究将大大提高我们对癌症进展和转移的认识，并可能为治疗干预提供分子靶点。

DESCRIPTION (provided by applicant): Transcriptional regulation plays a critical role in normal cell and organ differentiation, development and physiology in humans. Not surprisingly, up or downregulation of transcription factors and their coregulators has been tightly linked to tumor development and the progression to malignant and metastatic stages. Cancer cells originate primarily from epithelial tissues. Accumulating evidence suggests that during cancer progression, cells begin to redistribute or downregulate proteins involved in maintaining cell adherens and tight junctions. These changes and others promote a loss of cell-cell and cell-matrix interactions and permit cell motility and invasion of neighboring tissues. While approximately 90% of all cancer deaths occur because of tumor metastasis, very few therapies are available that are effective in preventing metastasis. One way to overcome this limitation is to gain a complete understanding of the genetic and signaling networks that promote and modulate tumor cell motility and metastasis. The Thanatos associated protein (THAP) family is comprised of 12 members in the human, and only 3 members have been partially characterized. Recently we observed that THAP11, a member of the THAP family is differentially expressed in cancer cells. How THAP11 overexpression contributes to cancer cell function is completely unknown and thus represents an exciting and novel field of investigation. Based on our preliminary results, we hypothesize that THAP11 is a transcriptional repressor that plays a critical role in cancer cell function by directly regulating expression of key genes involved in intercellular and cell-matrix interactions. Since alteration of these interactions is a key initial event in metastasis, we propose that THAP11 represents a novel and critical transcriptional regulator of cancer cell function. We will undertake state-of-the-art molecular, cellular, physiologic and genome-wide analyses to define the impact of THAP11 overexpression and its mechanism of action in cancer cell function in three integrated specific aims. The proposed studies will greatly advance our knowledge of cancer progression and metastasis, and may provide a molecular target for therapeutic intervention. PUBLIC HEALTH RELEVANCE: While approximately 90% of all cancer deaths occur because of tumor metastasis, very few therapies are available that are effective in preventing metastasis. One way to overcome this limitation is to gain a complete understanding of the genetic and signaling networks that promote and modulate tumor cell motility and metastasis. In this work, we will determine the role of a novel human protein termed THAP11 in cancer cell function. The proposed studies will greatly advance our knowledge of cancer progression and metastasis, and may provide a molecular target for therapeutic intervention.