Nutritional Regulation of hnRNP-E1 and Related Genes

hnRNP-E1及相关基因的营养调控

基本信息

批准号：
7450994
负责人：
Asok Antony
金额：
$ 28.7万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7450994
关键词：
Abbreviations Adverse effects Affect Affinity Anemia Apoptosis Binding Capsid Proteins Cardiovascular Diseases Cataloging Catalogs Cell Proliferation Cells Condition Consensus Cysteine Diet Elements Ep-1 Epigenetic Process Ethylmaleimide Fishes Folate Folic Acid Deficiency Future Generations Genes Glyceraldehyde Hela Cells Heterogeneous-Nuclear Ribonucleoproteins Homocysteine Homocystine Human Human Genome Human Papillomavirus Human papillomavirus 16 E1 protein Hyperhomocysteinemia Impaired cognition Indium KH Domain L2 viral capsid protein Laboratories Maleimides Malignant - descriptor Malignant Neoplasms Malignant neoplasm of cervix uteri Malnutrition Messenger RNA Methods Minor Modification Mus Neural Tube Defects Nuclear Nude Mice Numbers Nutritional Osteoporosis Papillomavirus Pathology Physiological Poly U Post-Transcriptional Regulation Post-Translational Protein Processing Pregnancy Complications Premalignant Proteins Public Health RNA RNA-Binding Proteins Regulation Reverse Transcriptase Polymerase Chain Reaction Role Time Tissues Transcriptional Activation Untranslated Regions Up-Regulation Viral Xenograft procedure analytical method base cancer cell feeding folate-binding protein genetic regulatory protein insight keratinocyte novel nutrition particle

项目摘要

DESCRIPTION (provided by applicant): This proposal focuses on a previously unappreciated and potentially powerful role that inadequate nutrition can have to modify the expression and function of heterogeneous nuclear ribonucleoprotein E1 (hnRNP-E1). HnRNP-E1 binds a multitude of RNA with common c/s-elements including those within the genome of human papillomavirus (HPV) that are involved in the synthesis of HPV viral capsid proteins. Our overarching hypothesis is that intracellular homocysteine which accumulates in folate deficiency derivatizes hnRNP-E1 by a post-translational specific modification that transforms homocysteine-derivatized hnRNP-E1 into a high-affinity RNA-binding protein which up-regulates itself and modulates the expression of a host of other proteins at the post-transcriptional level by regulating their mRNA. We will study the covalent modification of hnRNP-E1 protein by conventional analytical methods and the mechanism of translational auto-regulation of hnRNP-E1 in cervical cancer xenografts propagated in folate- deficient mice by methods recently established in our laboratory. We will also use homocysteine-derivatized hnRNP-E1 as a hook to fish out, amplify, characterize, and catalog as yet undiscovered RNA with common RNA c/s-elements that are likely to be regulated in folate-deficient cells. In addition, we will investigate the mechanism whereby homocysteine-derivatized hnRNP-E1 can quench the generation of HPV viral capsid proteins in pre-malignant HPV-infected keratinocytes that are propagated under conditions of low folate. This is significant because perturbation of the incorporation of both the major (L1) and minor (L2) viral capsid proteins into HPV viral particles can profoundly affect both the infectivity of HPV, and may also eventually influence the potential for HPV to eventually transform infected cells into cancer. These studies can uncover new insight into mechanism(s) by which a common nutritional deficiency can profoundly induce an epigenetic posttranslational change of a key multifunctional RNA-binding protein that can, in turn, influence the post-transcriptional regulation and expression of many other critical proteins involved in cell proliferation, differentiation and apoptosis. And if indeed nutrition can influence the capacity to generate authentic infectious HPV viral particles, this could open the field for future studies to investigate the role of nutrition in modulation of HPV-infectivity and malignant transformation of HPV-infected cells.

描述（由申请人提供）：该提案重点关注营养不足可能改变异质核核糖核蛋白 E1 (hnRNP-E1) 的表达和功能的先前未被认识到的潜在强大作用。 HnRNP-E1 与多种具有常见顺式/顺式元件的 RNA 结合，包括人乳头瘤病毒 (HPV) 基因组内参与 HPV 病毒衣壳蛋白合成的元件。我们的总体假设是，叶酸缺乏时积累的细胞内同型半胱氨酸通过翻译后特异性修饰衍生化 hnRNP-E1，将同型半胱氨酸衍生的 hnRNP-E1 转化为高亲和力 RNA 结合蛋白，该蛋白上调自身并调节通过调节 mRNA，在转录后水平上调节许多其他蛋白质。我们将通过常规分析方法研究hnRNP-E1蛋白的共价修饰，并通过我们实验室最近建立的方法研究叶酸缺乏小鼠中宫颈癌异种移植物中hnRNP-E1翻译自动调节的机制。我们还将使用同型半胱氨酸衍生的 hnRNP-E1 作为钩子，以捞出、扩增、表征和编录尚未发现的 RNA，其中包含可能在叶酸缺乏细胞中受到调节的常见 RNA c/s 元件。此外，我们将研究同型半胱氨酸衍生的 hnRNP-E1 能够抑制在低叶酸条件下繁殖的癌前 HPV 感染角质形成细胞中 HPV 病毒衣壳蛋白产生的机制。这是很重要的，因为主要 (L1) 和次要 (L2) 病毒衣壳蛋白掺入 HPV 病毒颗粒的扰动可以深刻影响 HPV 的感染性，并且还可能最终影响 HPV 最终转化受感染细胞的潜力变成癌症。这些研究可以揭示对机制的新见解，通过这种机制，常见的营养缺乏可以深刻地诱导关键多功能RNA结合蛋白的表观遗传翻译后变化，进而影响许多其他关键蛋白的转录后调节和表达。参与细胞增殖、分化和凋亡的蛋白质。如果营养确实可以影响产生真正的感染性 HPV 病毒颗粒的能力，这可能为未来研究营养在 HPV 感染性调节和 HPV 感染细胞恶性转化中的作用开辟新的研究领域。