Characterization of Tumor Suppression by the APC Gene

APC 基因抑制肿瘤的特性

基本信息

批准号：
7674600
负责人：
Joanna Louise Groden
金额：
$ 25.69万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-12-13 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7674600
关键词：
APC gene Adenomatous Polyposis Coli Protein Affect Apoptosis Apoptotic Binding Caspase Cell Adhesion Cell Cycle Cell Cycle Checkpoint Cell Cycle Regulation Cell Death Cells Chromosome Segregation Chromosomes Colon Carcinoma Colorectal Neoplasms Cyclin D1 Cyclin-Dependent Kinases DNA Binding DNA biosynthesis Development EB1 microtubule binding proteins Event Family G2/M Transition Gene Expression Genetic Transcription Goals Growth Immunohistochemistry Immunoprecipitation In Vitro Inherited Length Malignant Epithelial Cell Mass Spectrum Analysis Matrilysin Measures Mediating Microtubules Mitochondrial Proteins Mitosis Mitotic Checkpoint Modification Mutation N-terminal Pathway interactions Phase Phosphorylation Post-Translational Protein Processing Proteins Research Personnel Role Signal Pathway Site Site-Directed Mutagenesis System TCF Transcription Factor Testing Therapeutic Time Transfection Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Work beta catenin c-myc Genes cancer cell cell growth colon cancer cell line design mutant nucleocytoplasmic transport oncology prevent protein expression protein protein interaction survivin tumor

项目摘要

DESCRIPTION (provided by applicant): Mutation of the APC tumor suppressor gene is believed to be a rate-limiting and necessary event in the development of most colorectal tumors, both inherited and sporadic. The APC gene product is a component of the Wnt signaling pathway; its ability to interact with and down-regulate beta-catenin is controlled by GSK3IB phosphorylation and affects the expression of genes regulated by transcription factors of the TCF/LEF family (Clevers and van de Wetering, 1997). Therefore, mutation of APC indirectly alters the transcription profile of cells through changes in the expression of genes such as c-myc and cyclin D1 that promote cell growth (He et al., 1998; Tetsu and McCormack, 1999), survivin that inhibits apoptosis (Zhang et al., 2001), and matrilysin that mediates differentiation (Crawford et al., 1999). The role of APC in non-transcriptional mechanisms of growth control and differentiation is less emphasized, but includes effects on cell adhesion, microtubules and chromosome dynamics (Nathke et al., 1996; Kaplan et al., 2001; Mogensen era/., 2002; Bienz and Hamada, 2004). Further functional characterization of APC and its gene product in normal and malignant cells is important for a complete understanding of how its disruption is associated with tumor formation. We have shown that introduction of the APC gene into colon carcinoma cells induces apoptosis and prevents entry into S-phase of the cell cycle through beta-catenin-dependent and -independent mechanisms (Heinen et al., 2002; Carson et al., 2004; Qian et al, 2005). Transcriptionally silent in vitro systems show that full-length APC and defined protein segments accelerate apoptosis and inhibit DNA replication (Steigerwald et al., 2005; Qian et al., 2005; Sarnaik et al., 2005). In addition, we have shown that APC phosphorylation by the cyclin-dependent kinase p34 at M-phase of the cell cycle mediates protein interactions that in turn affect a mitotic checkpoint (Trzepacz et al., 1997; Carson et al., 2005). We will now test the hypothesis that APC contributes to cell cycle control and cell death independently of beta-catenin-induced transcription by determining the post-translational modifications of APC and its dynamic protein-protein interactions. Our immediate goal is to determine the mechanisms by which APC regulates the cell cycle and apoptosis. Our long-term goals are to elucidate the mechanisms and pathways through which APC functions and, by doing so, to contribute to the design of better therapeutic strategies in oncology.

描述（由申请人提供）：据信APC肿瘤抑制基因的突变是遗传和零星的大多数结直肠肿瘤的限制和必要事件。 APC基因产物是Wnt信号通路的组成部分。它与β-catenin相互作用和下调的能力受GSK3IB磷酸化的控制，并影响由TCF/LEF家族转录因子调节的基因的表达（Clevers and van de Wetering，1997）。因此，APC的突变通过改变促进细胞生长的基因（例如C-Myc和Cyclin d1）的表达的变化来间接改变细胞的转录谱（He等，1998; Tetsu和McCormack，1999），Survivin抑制凋亡的源源不断（Zhang等人，2001年，2001年），以及Medrilysins an。 APC在生长控制和分化的非转录机制中的作用不太强调，但包括对细胞粘附，微管和染色体动力学的影响（Nathke等，1996; Kaplan等，2001; Mogensen ERA/。在正常和恶性细胞中，APC及其基因产物的进一步功能表征对于完全理解其破坏与肿瘤形成如何相关的重要性。我们已经表明，将APC基因引入结肠癌细胞会诱导细胞凋亡，并通过β-Catenin依赖性和非依赖性机制阻止进入细胞周期的S相（Heinen等，2002; Carson等，2004; Qian等，2005）。转录沉默的体外系统表明，全长APC和定义的蛋白质片段加速了凋亡并抑制DNA复制（Steigerwald等，2005； Qian等，2005； Sarnaik等，2005）。此外，我们已经表明，在细胞周期的m期间，细胞周期蛋白依赖性激酶p34的APC磷酸化介导了蛋白质相互作用，进而影响有丝分裂检查点（Trzepacz等，1997; Carson等，2005）。现在，我们将通过确定APC的翻译后修饰及其动态蛋白质 - 蛋白质相互作用来检验APC促进细胞周期控制和细胞死亡的有助于细胞周期控制和细胞死亡。我们的直接目标是确定APC调节细胞周期和凋亡的机制。我们的长期目标是阐明APC功能以及这样做的机制和途径，以促进肿瘤学中更好的治疗策略的设计。