The Role of HNF4alpha in Cell Proliferation

HNF4α 在细胞增殖中的作用

• 批准号: 8130934
• 负责人: Linh Vuong
• 金额: $ 3.31万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8130934
• 关键词: Address; Adult; Architecture; Binding; Biological Assay; Blood; C-terminal; Cancer cell line; Cell Cycle; Cell Cycle Regulation; Cell Differentiation process; Cell Proliferation; Cells; Cessation of life; Development; Diabetes Mellitus; Disease; Drug Metabolic Detoxication; Embryo; Epithelium; Equilibrium; Event; Fetal Liver; Fetus; Functional disorder; Gene Expression Regulation; Genes; Goals; Hepatic; Hepatocyte; Homeostasis; Investigation; Lead; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Metabolism; Molecular; Molecular Profiling; Morphology; Mus; N-terminal; Nuclear Receptors; Oncogene Proteins; Organ; Pathway interactions; Pattern; Play; Process; Proliferating; Protein Isoforms; RNA Splicing; Reporting; Role; Signal Pathway; Site; System; Techniques; Time; Variant; c-myc Genes; cancer cell; cell type; chromatin immunoprecipitation; embryonic stem cell; fetal; hepatocyte nuclear factor; high throughput technology; human disease; inhibitor/antagonist; oncoprotein p21; postnatal; promoter; stem

DESCRIPTION (provided by applicant): Hepatocyte nuclear factor (HNF) 41, an important nuclear receptor required for the morphology and function of the fetal and adult livers, regulates many liver-specific genes involved in various metabolic processes, blood homeostasis, and epithelium architecture. This highly conserved nuclear receptor has various isoforms that differ in the N-terminal and C- terminal domains. These are generated by the use of two alternative promoters and 3' splicing events. There has been evidence suggesting that these splice variants play different roles in liver development. The P1 isoforms (HNF411/12) are expressed exclusively in lat embryo, postnatal and adult livers while the P2 isoforms (HNF417/18) are expressed only in the fetal liver. How these isoforms regulate the transition from proliferating to differentiating cells is yet to be elucidated. Recently, we have shown that HNF411 upregulates cyclin dependent kinase inhibitor p21, a cell cycle inhibitor; we have also shown that the oncoprotein c-Myc abolishes this activity. Others have shown HNF41 interacts with TCF/LEF which is the downstream of the Wnt/2-catenin pathway. Dysfunction in this pathway is associated with liver and other cancers. Our goal is to decipher the role of HNF41 in cell cycle regulation and to investigate the role of the different HNF41 isoforms in that process. We will incorporate molecular and high throughput technology such as co-immunoprecipitiation (co-IP), cell proliferation assays, expression profiling arrays, and chromatin immunoprecipitation sequencing (ChIP-Seq) techniques in our study. We will use both immortalized cancer cell lines and mouse embryonic stem (mES) cells that we will differentiate into the hepatic lineage. ES cells can proliferate indefinitely, just like cancer cells, but they also can differentiate into any specialized cell type. In short, they mimic normal development. Cancer cell lines, on the other hand, provide a system to examine the pathological consequences of disrupting the delicate proliferation-differentiation balance. These two systems will provide complementary approaches to address the fundamental dichotomy between cell proliferation and cell differentiation in liver development and disease.

描述（由申请人提供）：肝细胞核因子（HNF）41是胎儿和成人肝脏形态和功能所需的重要核受体，调节涉及各种代谢过程、血液稳态和上皮结构的许多肝脏特异性基因。这种高度保守的核受体具有多种亚型，其 N 端和 C 端结构域有所不同。这些是通过使用两个替代启动子和 3' 剪接事件产生的。有证据表明这些剪接变体在肝脏发育中发挥不同的作用。 P1 同工型 (HNF411/12) 仅在晚期胚胎、出生后和成人肝脏中表达，而 P2 同工型 (HNF417/18) 仅在胎儿肝脏中表达。这些亚型如何调节细胞从增殖到分化的转变尚待阐明。最近，我们发现 HNF411 上调细胞周期蛋白依赖性激酶抑制剂 p21（一种细胞周期抑制剂）；我们还表明癌蛋白 c-Myc 可以消除这种活性。其他研究表明 HNF41 与 TCF/LEF 相互作用，TCF/LEF 是 Wnt/2-连环蛋白途径的下游。该途径的功能障碍与肝癌和其他癌症有关。我们的目标是破译 HNF41 在细胞周期调节中的作用，并研究不同 HNF41 亚型在此过程中的作用。我们将在我们的研究中结合分子和高通量技术，例如免疫共沉淀 (co-IP)、细胞增殖测定、表达谱阵列和染色质免疫沉淀测序 (ChIP-Seq) 技术。我们将使用永生化癌细胞系和小鼠胚胎干 (mES) 细胞，并将其分化为肝谱系。 ES 细胞可以像癌细胞一样无限增殖，但它们也可以分化成任何特殊的细胞类型。简而言之，它们模仿正常发育。另一方面，癌细胞系提供了一个系统来检查破坏微妙的增殖分化平衡的病理后果。这两个系统将提供互补的方法来解决肝脏发育和疾病中细胞增殖和细胞分化之间的基本二分法。