Nuclear functions of the tumor suppressor protein APC

描述（由申请人提供）：结直肠癌是美国第二大致命恶性肿瘤。腺瘤性息肉病螺旋（Apc）肿瘤抑制基因的突变引发大多数结直肠癌。然而，目前尚不清楚Apc突变如何使细胞易于发生息肉和结直肠癌。虽然APC被发现在细胞-细胞连接处，结合微管，并在细胞核中，很少有人知道核APC的功能。我们发现随着人类结肠组织从正常到息肉再到肿瘤的进展，细胞质APC增加。在培养的细胞中，APC定位响应细胞增殖和磷酸化。此外，使用这个模型，我们发现，核APC调节癌蛋白β-连环蛋白的活性。我们假设APC定位的变化，由APC核定位信号的突变启动，将导致伴随的β-连环蛋白调节的改变，细胞水平的增殖和分化，以及组织水平的息肉形成。 我们将在小鼠胚胎干细胞和整个动物中检测APC的核定位信号，以研究在生理条件下核APC的功能。我们将使用这两个创新的模型系统，直接测试核APC是否参与β-连环蛋白调节（Aim 1），细胞增殖（Aim 2）和分化（Aim 3）。我们将对缺乏核APC的小鼠进行病理学检查，以测试核APC是否在肿瘤抑制中起作用（目的4）。对APC在正常细胞中功能的更多了解将提高我们对APC在肿瘤发生中的作用的理解，并最终照亮治疗干预的新点。

DESCRIPTION (provided by applicant): Colorectal cancer is the second deadliest malignancy in the United States. Mutation of the adenomatous polyposis coil (Apc) tumor suppressor gene initiates most colorectal carcinomas. However, it is not known how Apc mutation predisposes a cell to polyp development and colorectal carcinogenesis. Although APC is found at cell-cell junctions, binding to microtubules, and in the nuclei, little is known about nuclear APC function. We discovered increased cytoplasmic APC as human colon tissue progressed from normal, to polyp, to tumor. In cultured cells, APC localization responded to cell proliferation and phosphorylation. Furthermore, using this model we found that nuclear APC regulated the activity of the oncoprotein beta-catenin. We hypothesize changes in APC localization, initiated by mutation of the APC nuclear localization signals, will result in concomitant alterations in beta-catenin regulation, proliferation and differentiation at the cellular level, and polyp formation at the tissue level. We will inactivate APC's nuclear localization signals in mouse embryo-derived stem (ES) cells and whole animals to study nuclear APC function under physiological conditions. We will use these two innovative model systems to test directly if nuclear APC is involved in beta-catenin regulation (Aim 1), cellular proliferation (Aim 2), and differentiation (Aim 3). We will perform pathologic examinations on mice lacking nuclear APC to test if nuclear APC functions in tumor suppression (Aim 4). Greater knowledge of APC function in normal cells will improve our understanding of APC's role in tumorigenesis and ultimately illuminate new points for therapeutic intervention.