Mechanisms of BAP1 activity in human cancer development

BAP1 活性在人类癌症发展中的机制

• 批准号: 10528437
• 负责人: MICHELE CARBONE
• 金额: $ 44.46万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-13 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528437
• 关键词: Address; Affect; Age; Alleles; Apoptosis; Asbestos; Binding; Calcium; Calcium Channel; Calcium Signaling; Carcinogens; Cell Culture Techniques; Cell Death; Cell Differentiation process; Cell Nucleus; Cell Survival; Cells; Cessation of life; Citric Acid Cycle; Collaborations; Complement; Cutaneous Melanoma; Cytoplasm; Cytosol; DNA; DNA Damage; DNA Repair; Data; Development; Disease; Dose; Endoplasmic Reticulum; Environment; Environmental Carcinogens; Enzymes; Exposure to; Family; Family member; General Population; Genes; Genetic; Genetic Transcription; Germ-Line Mutation; Growth; HMGB1 gene; Heterozygote; High Prevalence; Human; Hypoxia; Impairment; Incidence; Individual; Induced Mutation; Inherited; Inositol; Lead; Link; Malignant - descriptor; Malignant Neoplasms; Malignant mesothelioma; Mesothelioma; Metabolic; Metabolic Pathway; Metabolism; Mineral Fibers; Mitochondria; Multiprotein Complexes; Mus; Mutate; Mutation; Names; Nature; Nuclear; Pathogenesis; Pathway interactions; Penetrance; Phenotype; Plasma; Predisposition; Prevalence; Primary Cell Cultures; Proliferating; Reagent; Regulation; Resistance; Risk; Role; Skin Cancer; Skin Carcinoma; Somatic Mutation; Syndrome; Testing; Therapeutic Intervention; Time; Tumor Promotion; UV induced; Ultraviolet Rays; Uveal Melanoma; Warburg Effect; Wild Type Mouse; aerobic glycolysis; cancer cell; cancer type; carcinogenesis; carcinogenicity; cell transformation; cohort; environmental carcinogenesis; erionite; in vivo; inorganic phosphate; ionization; irradiation; melanoma; metaplastic cell transformation; mitochondrial metabolism; mouse model; mutation carrier; novel; receptor; response; sarcoma; sex; stem; synergism; tripolyphosphate; tumor; tumor growth; uptake; volunteer

PROJECT SUMMARY This application investigates mechanisms of gene and environment interaction in carcinogenesis. Malignant mesothelioma (MM) is frequent in individuals continuously exposed to carcinogenic mineral fibers such as asbestos and erionite, but it is very rare in those with limited or no exposure. Genetics influences susceptibility to MM. We have recently demonstrated that carriers of germline BAP1 mutations have increased incidence of multiple cancer types, including MM (we named this condition the “BAP1 cancer syndrome”). In some BAP1-mutation carrying families, MM accounts for more than 50% of deaths, and we found that this may be due to increased susceptibility to MM from exposure to modest amounts of asbestos that would normally not cause MM in the general population. We also found that heterozygous BAP1 germline mutations in addition to asbestos, also increase susceptibility to malignant transformation following exposure to Ionizing Irradiation and ultraviolet (UV) light –which may account for the high prevalence of melanomas and skin carcinomas in carriers of BAP1 mutations. BAP1 is the first and so far the only gene shown to regulate environmental carcinogenesis. The mechanism(s) by which mutated BAP1 causes MM pathogenesis are being elucidated. Inositol 1,4,5-trisphosphate (IP3) binds and activates the IP3 receptors (IP3Rs). We demonstrated that BAP1 is present in the endoplasmic reticulum (ER) where it regulates the activity of the IP3-Receptor-3 (IP3R3), the main ER channel that controls Ca2+ release from the ER to the cytoplasm to the mitochondria, regulating apoptosis. We discovered that reduced levels of BAP1 in carriers of heterozygous BAP1 mutations impair apoptosis and favor cellular transformation of cells that accumulated DNA damage following exposure to asbestos, IR and UV-light. We also discovered that “normal” primary cells of carriers of heterozygous germline BAP1 mutations derive energy from aerobic glycolysis, known as Warburg effect, which so far had been considered a hallmark of cancer cells. We identified a specific metabolic signature associated with the Warburg effect by studying the metabolites present in the plasma of carriers of heterozygous germline BAP1 mutations. Our central hypothesis is that changes in Ca2+ concentration lead to increased resistance of cells containing BAP1 mutations to apoptosis and to changes in metabolic pathways that in turn are responsible for the very high cancer penetrance observed in BAP1 mutation carriers. To address this hypothesis we will examine the following specific Aims: AIM 1: To study the mechanisms by which BAP1 mutations induce a “Warburg effect”. AIM 2: To study the hypothesis that the Warburg effect is HIF-1α-independent in BAP1+/- cells. AIM 3: To study the contributions of calcium signaling and metabolic alterations due to germline BAP1 mutations to MM development. To elucidate the activity of BAP1 on the I P 3 R 3 and the related effects on cancer penetrance, we have assembled a unique cohort of families carrying germline BAP1 mutations and have access to unique reagents derived from volunteers from these families. These unique reagents include: primary cell cultures derived from family members that inherited germline BAP1 mutations as well as from sex- and age- matched controls from the same families, sera and plasma from germline BAP1 mutation carriers and matched controls, and a heterozygous BAP1 mouse model and derived cell cultures. In addition, we assembled a unique sets of heterozygous BAP1 and IP3R3 mice that recapitulate the human condition and that allow us to study the effects of BAP1 mutations in vivo upon exposure to carcinogens. Collaborations with some of the leading experts in the field, Drs. Pinton and Giorgi, experts in Ca2+ signaling and mitochondrial metabolism; and Dr. Mikoshiba, expert in IP3R3 activities, complement and synergize with the expertise of the two MPIs. These studies will be relevant to the multiple malignancies associated with the BAP1 cancer syndrome, in both carriers of BAP1 mutations and those who develop somatic mutations of BAP1 during tumor development.

项目概要 该应用研究了致癌过程中基因和环境相互作用的机制。 恶性间皮瘤 (MM) 在持续接触致癌矿物质的个体中很常见 石棉和毛沸石等纤维，但在接触有限或没有接触的人中非常罕见。遗传学 影响MM的易感性。我们最近证明，种系 BAP1 突变的携带者 多种癌症类型的发病率增加，包括 MM（我们将这种情况命名为“BAP1 癌症综合征”）。在一些BAP1突变携带家庭中，MM占50%以上 死亡，我们发现这可能是由于接触适度的环境而增加了对 MM 的易感性。 石棉的含量通常不会在一般人群中引起 MM。我们还发现 杂合的 BAP1 种系突变除了石棉之外，还会增加对恶性肿瘤的易感性 暴露于电离辐射和紫外线 (UV) 光后发生转变——这可能是 BAP1 突变携带者黑色素瘤和皮肤癌的患病率很高。 BAP1 是第一个并且 迄今为止唯一被证明可以调节环境致癌的基因。其机制 BAP1突变导致MM的发病机制正在被阐明。肌醇 1,4,5-三磷酸 (IP3) 结合并 激活 IP3 受体 (IP3R)。我们证明 BAP1 存在于内质网中 (ER)，它调节 IP3-Receptor-3 (IP3R3) 的活性，IP3R3 是控制 Ca2+ 的主要 ER 通道 从内质网释放到细胞质再到线粒体，调节细胞凋亡。我们发现减少了 杂合 BAP1 突变携带者中的 BAP1 水平会损害细胞凋亡并有利于细胞转化 暴露于石棉、红外线和紫外线后累积 DNA 损伤的细胞。我们还发现 杂合种系 BAP1 突变携带者的“正常”原代细胞从有氧运动中获取能量 糖酵解，称为瓦伯格效应，迄今为止一直被认为是癌细胞的标志。我们 通过研究存在的代谢物，确定了与瓦尔堡效应相关的特定代谢特征 杂合种系 BAP1 突变携带者的血浆中。我们的中心假设是，变化 Ca2+浓度导致含有BAP1突变的细胞对细胞凋亡和细胞凋亡的抵抗力增加 代谢途径的变化反过来又导致了在癌症中观察到的非常高的癌症外显率 BAP1突变携带者。为了解决这个假设，我们将研究以下具体目标： 目的1：研究BAP1突变诱导“Warburg效应”的机制。 目标 2：研究 BAP1+/- 细胞中 Warburg 效应不依赖于 HIF-1α 的假设。 目标 3：研究种系 BAP1 对钙信号传导和代谢改变的贡献 MM 发育的突变。 为了阐明 BAP1 对 I P 3 R 3 的活性以及对癌症外显率的相关影响，我们有 组建了一群携带种系 BAP1 突变的独特家庭，并能够获得独特的 来自这些家庭的志愿者的试剂。这些独特的试剂包括： 原代细胞培养物 源自遗传种系 BAP1 突变的家庭成员以及性别和年龄 来自相同家族的匹配对照、来自种系 BAP1 突变携带者的血清和血浆以及 匹配的对照、杂合 BAP1 小鼠模型和衍生细胞培养物。此外，我们 组装了一组独特的杂合 BAP1 和 IP3R3 小鼠，再现了人类的状况 这使我们能够在体内研究 BAP1 突变对暴露于致癌物质的影响。 与该领域的一些领先专家合作，博士。 Pinton 和 Giorgi，Ca2+ 专家 信号传导和线粒体代谢；和IP3R3活动专家Mikoshiba博士补充和 与两个 MPI 的专业知识产生协同作用。这些研究将与多种恶性肿瘤相关 与 BAP1 癌症综合征相关，无论是 BAP1 突变携带者还是患有 BAP1 突变的人 肿瘤发展过程中 BAP1 的体细胞突变。