Cancer cell signaling through lipids complexed to proteins

通过脂质与蛋白质复合的癌细胞信号传导

基本信息

批准号：
8426060
负责人：
Raymond Daniel Blind
金额：
$ 11.22万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-11 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8426060
关键词：
1-Phosphatidylinositol 3-Kinase Accounting Acute Myelocytic Leukemia Adult African American American Cancer Society Antineoplastic Agents Binding Biochemistry Cancer Biology Cancer cell line Cell Nucleus Cells Cellular biology Chemicals Colorectal Cancer Complex Crystallography Data Deuterium Development Endometrial Carcinoma Enzymatic Biochemistry Enzyme Kinetics Enzymes Genetic Programming Hispanics Holly Human Human Cell Line Hydrogen In Vitro Incidence Intestinal Cancer Link Lipid Binding Lipids Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of pancreas Manuscripts Maps Mediating Membrane Mentored Research Scientist Development Award Mentors Methods Molecular Molecular Structure Multienzyme Complexes Mutation Nuclear Nuclear Protein Nuclear Proteins Nuclear Receptors PTEN gene Pathway interactions Patients Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipids Phosphoric Monoester Hydrolases Phosphotransferases Physiology Protein Chemistry Proteins Reporting Research Research Personnel Risk Roentgen Rays Role Science Signal Transduction Structure Surface Therapeutic Tissues Training Tumor Suppressor Proteins United States Woman Work X-Ray Crystallography anticancer research base cancer cell enzyme structure enzyme substrate enzyme substrate complex essential phospholipids experience high reward high risk improved inhibitor/antagonist inositol polyphosphate multikinase interfacial killings novel programs protein protein interaction simulation small molecule structural biology success tool transcription factor tumor tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The American Cancer Society's 2012 report revealed that incidence rates are decreasing or stable for most cancers in the United States since 1999. Some notable exceptions are liver cancer in African Americans and Hispanics, endometrial cancer in African American women, colorectal cancer in patients under 50, and pancreatic cancer in every demographic. In all these tissues, NR5A nuclear receptors (NR5A1 and NR5A2) mediate genetic programs that are essential determinants of development, differentiation and adult function. At the molecular level, these two transcription factors bind phosphoinositides (PIPs), phospholipids that are essential to PI-3 kinase signaling in PTEN-dependent cancers. However almost nothing is known about how these lipids regulate NR5A transcriptional functions, or how dysregulation of those mechanisms contributes to the cancers mentioned above. Based on a manuscript currently in revision at Science, we hypothesize that PIP lipids bound to NR5As (and other nuclear proteins) are directly remodeled by the PI3- kinase inositol polyphosphate multikinase (IPMK) and the PTEN lipid phosphatase in cancer cells. This hypothesis is a clear departure from the standard dogma that PI3- kinases & PTEN only act on phosphoinositides in membranes. In Aim 1, we will determine how currently available small molecules inhibit IPMK using enzymology and crystallography, accelerating improvements of these inhibitors and training the PI in crystallography, X-ray diffraction methods and molecular structure determination, taking advantage of a relatively low-risk project. In Aim 2, we will use mutational analyses to map the interface between NR5A1 and IPMK, and attempt to crystallize NR5A/PIP/IPMK to determine the interfacial structure of this complex. This high-risk high-reward structure is hedged by Aim 1. In Aim 3, we will identify novel protein/PIP complexes that are substrates of PTEN and IPMK, using hypothesis-driven biochemistry. The candidate has had extensive training in protein chemistry, enzymology, biochemistry and cell biology, but has not had any training in structural biology. The mentor Holly Ingraham and advisory team have extensive experience in structural biology, particularly Robert Fletterick in NR5A structure and its links to pancreatic cancer, and Natalia Jura in kinase structure and membrane cancer biology. The candidate will expand his research program as an independent investigator with the training afforded by this K01 award, opening new avenues to cancer research.

描述（由申请人提供）：美国癌症协会的2012年报告显示，自1999年以来，美国大多数癌症的发病率正在降低或稳定。非裔美国人和西班牙裔人的肝癌，非裔美国人的子宫内膜癌，非裔美国人女性的子宫内膜癌，50岁以下患者的大肠癌以及每个人口统计学的panccreatic癌症。在所有这些组织中，NR5A核受体（NR5A1和NR5A2）介导了发展，分化和成人功能的基本决定因素。在分子水平上，这两个转录因子结合磷酸肌醇（PIPS），对于PTEN依赖性癌症中PI-3激酶信号至关重要的磷脂。然而，这些脂质如何调节NR5A转录函数，或这些机制的失调如何对上述癌症造成影响。基于当前在科学修订中的手稿，我们假设与NR5AS（和其他核蛋白）结合的PIP脂质直接被PI3-激酶肌醇肌醇多磷酸多磷酸多磷酸酶（IPMK）和癌细胞中的PTEN脂质磷酸酶进行重塑。该假设与PI3激酶和PTEN仅作用于膜中的磷酸肌醇的标准教条明显不同。在AIM 1中，我们将确定当前可用的小分子如何使用酶学和晶体学抑制IPMK，加速这些抑制剂的改进，并利用相对低风险的项目，在晶体学，X射线衍射方法和分子结构测定中训练PI。在AIM 2中，我们将使用突变分析来绘制NR5A1和IPMK之间的接口，并尝试结晶NR5A/PIP/IPMK来确定该复合物的界面结构。这种高风险的高回报结构由AIM 1进行对冲。在AIM 3中，我们将使用假设驱动的生物化学确定新型的蛋白质/PIP复合物为PTEN和IPMK的底物。该候选人在蛋白质化学，酶学，生物化学和细胞生物学方面接受过广泛的培训，但在结构生物学方面没有任何培训。导师Holly Ingraham和咨询团队在结构生物学方面拥有丰富的经验，尤其是Robert Fletterick在NR5A结构方面及其与胰腺癌的联系，以及在激酶结构和膜癌生物学方面的Natalia Jura。候选人将在该K01奖获得的培训中扩大他作为独立研究人员的研究计划，为癌症研究开辟了新的途径。