HNF4 Isoforms in Physiology and Disease

描述（申请人提供）：分化与增殖的阴阳关系是多细胞生物发展的基本原则，也是癌症的基础。转录因子（TFs），如核受体（NRs），调节负责执行这些细胞过程的基因。HNF4¿是配体依赖性tf的NR超家族中高度保守的成员。在过去的20多年里，HNF4¿因其在早期发育、肝脏分化和遗传性糖尿病（MODY1）中的作用而得到了很好的表征。最近，HNF4¿在肠/结肠中发挥了作用，并与癌症有几个联系。有趣的是，HNF4¿在癌症中的作用似乎取决于HNF4¿的特定异构体：有九个异构体由两个可选的启动子P1和P2驱动。在此，我们建议跟进上一轮融资的结果，在上一轮融资中，我们确定了在人类结肠癌中P1和p2驱动的HNF4¿亚型的差异调节机制。该机制涉及癌基因Src酪氨酸激酶，并受到HNF4基因单核苷酸多态性（snp）的影响。我们将追求以下三个具体目标：1)通过小鼠模型、人类培养模型和人体组织分析确定P1-与P2- HNF4¿亚型在结肠中的作用；2)利用小鼠模型和尖端的“组学”方法，确定P2- HNF4¿在肝癌及其发展中的作用，以破译同种异构体差异的分子基础；3)通过小鼠和人模型阐明Src酪氨酸激酶通路对HNF4¿的影响。提出的实验不仅将为癌症的分子机制提供宝贵的见解，而且还将为分化和增殖之间的二分法以及核受体作用的分子机制提供宝贵的见解。它们将产生可用于临床的结果，以帮助正确诊断和治疗肝癌和结肠癌。

DESCRIPTION (provided by applicant): The ying/yang relationship of differentiation versus proliferation is a fundamental tenet in the development of multicellular organisms, as well as the basis for cancer. Transcription factors (TFs), such as nuclear receptors (NRs), regulate the genes responsible for carrying out these cellular processes. HNF4¿ is a highly conserved member of the NR superfamily of ligand dependent TFs. During the past 20+ years, HNF4¿ has been well characterized for its role in early development, liver differentiation and an inherited form of diabetes (MODY1). More recently, a role for HNF4¿ has emerged in the intestine/colon and several links to cancer have been reported. Intriguingly, the role for HNF4¿ in cancer seems to depend on the particular isoform of HNF4¿: there are nine isoforms driven by two alternative promoters, P1 and P2. Here, we propose to follow up on the results from the previous round of funding in which we identified the mechanism responsible for differential regulation of the P1- and P2-driven HNF4¿ isoforms in human colon cancer. That mechanism involves the oncogene Src tyrosine kinase and is impacted by single nucleotide polymorphisms (SNPs) in the HNF4¿ gene. We will pursue the following three Specific Aims: 1) Determine the role of the P1- versus P2- HNF4¿ isoforms in the colon by using mouse models, human culture models and human tissue analysis; 2) Determine the role of P2- HNF4¿ in liver cancer and development by using mouse models and cutting edge "-omic" approaches to decipher the molecular basis for the differences in the isoforms; and 3) Elucidate the effects of the Src tyrosine kinase pathway on HNF4¿ using mouse and human models. The proposed experiments will provide invaluable insights not just into the molecular mechanisms of cancer but also into the dichotomy between the differentiation and proliferation and molecular mechanisms of nuclear receptor action. They will generate results that could be of use in the clinic to help properly diagnose and treat liver and colon cancer.