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致命的恶性肿瘤。腺瘤性息肉线圈（Apc）肿瘤抑制基因突变引发大多数结直肠癌。然而，目前尚不清楚Apc突变如何使细胞易发生息肉和结直肠癌。尽管APC存在于细胞-细胞连接处、与微管结合以及细胞核中，但对核APC的功能知之甚少。我们发现，随着人类结肠组织从正常、息肉到肿瘤的发展，细胞质APC增加。在培养细胞中，APC定位响应细胞增殖和磷酸化。此外，使用该模型，我们发现核APC调节癌蛋白β -连环蛋白的活性。我们假设由APC核定位信号突变引发的APC定位变化将导致β -连环蛋白调控、细胞水平上的增殖和分化以及组织水平上的息肉形成的改变。

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.