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的细胞和器官分化、发育和生理学中起着关键作用。不足为奇的是，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向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，细胞开始重新分配或下调与维持细胞黏附和紧密连接有关的蛋白质。这些变化和其他变化促进了细胞-细胞和细胞-基质相互作用的丧失，并允许细胞移动和侵袭邻近组织。虽然所有癌症死亡中约90%是由于肿瘤转移而发生的，但有效防止转移的治疗方法很少。克服这一局限的一种方法是完全了解促进和调节肿瘤细胞运动和转移的遗传和信号网络。人类Thanatos相关蛋白(Thanatos Association Protein，TAP)家族由12个成员组成，只有3个成员具有部分特征。最近，我们观察到THAP11是TAPP家族的成员之一，在癌细胞中差异表达。THAP11过表达对癌细胞功能的影响是完全未知的，因此代表着一个令人兴奋和新颖的研究领域。根据我们的初步结果，我们假设THAP11是一个转录抑制因子，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过程中的一个关键初始事件，我们认为THAP11是癌细胞功能的一个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、生理和基因组分析，以确定THAP11过表达的影响及其在三个整合的特定目标中的作用机制。所提出的研究将极大地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.