STRESS INDUCTION OF GLUCOSE REGULATED PROTEIN GRP78/BiP

葡萄糖调节蛋白 GRP78/BiP 的应激诱导

• 批准号: 7848451
• 负责人: AMY S LEE
• 金额: $ 1.3万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848451
• 关键词: Acetylation; Acidosis; Address; Affect; Alleles; Anoxia; Antineoplastic Agents; Apoptotic; Binding; Binding Sites; Breast; Breast Cancer Model; Calcium; Calcium Binding; Cell Death; Cell Nucleus; Cells; Chromatin; Clinical; Clinical Trials; Development; Disease; Drug resistance; Endoplasmic Reticulum; Equilibrium; Functional disorder; GRP78 gene; Gene Activation; Genetic; Genetic Transcription; Glucose; Grant; Growth; Health; Histone Deacetylase; Histone Deacetylase Inhibitor; Homeostasis; Human; Immunoglobulin binding proteins; Immunoglobulins; Incidence; Inhibition of Apoptosis; Intrinsic factor; Investigation; Kinetics; Knock-out; Knockout Mice; Lead; Malignant Neoplasms; Membrane Proteins; Modification; Molecular; Molecular Chaperones; Monitor; Mus; Neoplasm Metastasis; Organ Preservation; Organelles; Pathogenesis; Pathway interactions; Physiological; Play; Prognostic Marker; Property; Prostate; Protein Acetylation; Protein Binding; Proteins; Reagent; Repression; Research; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Stress; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transcriptional Regulation; Up-Regulation; Virulence; Xenograft Model; Yeasts; cancer cell; chemotherapeutic agent; clinical application; deprivation; dosage; endoplasmic reticulum stress; glucose metabolism; glucose-regulated proteins; histone acetyltransferase; improved; in vivo; insight; mouse model; neoplastic cell; novel; overexpression; programs; promoter; protein degradation; protein folding; resistance mechanism; response; sensor; tissue culture; transcription factor; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The unfolded protein response (UPR) triggers multiple pathways to allow cells to respond to stress conditions that target the endoplasmic reticulum (ER). The ER is a cellular organelle where secretory and membrane proteins are synthesized and modified and is also a major intracellular calcium storage compartment. The glucose regulated protein GRP78, also referred to as the immunoglobulin binding protein, BiP, is a central regulator for ER function due to its role in protein folding and assembly, targeting misfolded protein for degradation, ER calcium binding and controlling the activation of transmembrane ER stress sensors. The activation of the gene encoding GRP78 (Grp78) is widely used as a monitor for ER stress and has led to the discoveries of several unique signaling pathways whereby stress in this critical organelle is transmitted to the nucleus to initiate the UPR. Further, due to its anti-apoptotic property, stress induction of GRP78 represents an important pro-survival component of the UPR. As a master regulator of ER function, GRP78 is uniquely poised to have a major role in regulating cellular homeostasis and the balance between cancer cell death and aggressive growth, as well as modulating the sensitivity to chemotherapeutic agents. During the past grant period, we discovered that histone deacetylase (HDAC) inhibitors are novel inducers of Grp78 transcription and act synergistically with ER stress inducers resulting in upregulation of GRP78. Since HDAC inhibitors are currently being exploited as a promising new class of anti-cancer agents, we have discovered a novel UPR target affected by these compounds. The central hypothesis of the current proposal is that Grp78 transcription is regulated by the acetylation of chromatin and transcription factors binding to the Grp78 promoter, and that changes in GRP78 expression influence the development of tumors and their responses to therapeutic intervention by HDAC inhibitors. Through genetic targeting, we have created novel mouse models where GRP78 expression is reduced or can be knocked out in specific tissues and this will allow us to test directly the role of GRP78 in the pathogenesis of cancer. We have three specific aims. In Aim 1, we will determine the mechanisms whereby HDAC inhibitors activate Grp78 transcription. In Aim 2, we will determine whether enhanced-induction of GRP78 by HDAC inhibitors currently being tested in clinical trials confers drug resistance in cancer cells through inhibition of apoptosis. In Aim 3, we will determine whether reduction or conditional knockout of GRP78 will lead to suppression of cancer progression and metastasis. If our hypothesis is correct, it will establish GRP78 as a prognostic marker for cancer progression and resistance against HDAC inhibitor therapy. Further, targeted inhibition of GRP78 could be used to halt tumor progression and overcome resistance to HDAC inhibitor therapy.

描述（由申请人提供）：未折叠蛋白反应（UPR）触发多种途径，使细胞能够对针对内质网（ER）的应激条件做出反应。 ER 是分泌蛋白和膜蛋白合成和修饰的细胞器，也是主要的细胞内钙储存室。葡萄糖调节蛋白 GRP78，也称为免疫球蛋白结合蛋白 BiP，由于其在蛋白质折叠和组装、靶向错误折叠蛋白降解、ER 钙结合和控制跨膜 ER 激活中的作用，是 ER 功能的中心调节因子压力传感器。编码 GRP78 (Grp78) 的基因的激活被广泛用作 ER 应激的监测器，并导致发现了几种独特的信号传导途径，通过这些途径，这一关键细胞器中的应激被传递到细胞核以启动 UPR。此外，由于其抗凋亡特性，GRP78 的应激诱导代表了 UPR 的重要促生存成分。作为 ER 功能的主要调节因子，GRP78 在调节细胞稳态、癌细胞死亡与侵袭性生长之间的平衡以及调节对化疗药物的敏感性方面发挥着独特的重要作用。在过去的资助期内，我们发现组蛋白脱乙酰酶 (HDAC) 抑制剂是 Grp78 转录的新型诱导剂，并与 ER 应激诱导剂协同作用，导致 GRP78 上调。由于 HDAC 抑制剂目前被开发为一类有前景的新型抗癌药物，我们发现了受这些化合物影响的新 UPR 靶点。目前提议的中心假设是，Grp78 转录受到染色质乙酰化和与 Grp78 启动子结合的转录因子的调节，并且 GRP78 表达的变化影响肿瘤的发展及其对 HDAC 抑制剂治疗干预的反应。通过基因靶向，我们创建了新型小鼠模型，其中特定组织中的 GRP78 表达减少或可以被敲除，这将使我们能够直接测试 GRP78 在癌症发病机制中的作用。我们有三个具体目标。在目标 1 中，我们将确定 HDAC 抑制剂激活 Grp78 转录的机制。在目标 2 中，我们将确定目前正在临床试验中测试的 HDAC 抑制剂对 GRP78 的增强诱导是否通过抑制细胞凋亡而赋予癌细胞耐药性。在目标 3 中，我们将确定 GRP78 的减少或条件性敲除是否会导致癌症进展和转移的抑制。如果我们的假设正确，GRP78 将成为癌症进展和对 HDAC 抑制剂治疗耐药的预后标志物。此外，GRP78 的靶向抑制可用于阻止肿瘤进展并克服对 HDAC 抑制剂治疗的耐药性。