Mechanisms of BAP1 activity in human cancer development

BAP1 活性在人类癌症发展中的机制

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要该应用研究了癌变中基因和环境相互作用的机制。恶性间皮瘤（mm）经常在连续暴露于致癌的个体中石棉和erionite之类的纤维，但在有限或没有暴露的纤维中很少见。遗传学影响对MM的敏感性。我们最近证明了种系BAP1突变的载体增加了多种癌症类型的事件，包括MM（我们将此情况命名为“ BAP1）癌症综合症”。在一些BAP1携带家庭中，MM占50％以上死亡，我们发现这可能是由于对MM的敏感性增加，从暴露到适中通常不会在普通人群中引起MM的石棉量。我们还发现除石棉外，杂合BAP1种系突变还增加了对恶性的敏感性暴露于电离辐射和紫外线（UV）光线后的转换 - 可能解释 BAP1突变携带者中黑色素瘤和皮肤癌的高患病率。 BAP1是第一个，到目前为止，唯一显示了调节环境癌变的基因。该机制突变的BAP1引起MM发病机理正在阐明。肌醇1,4,5-三磷酸（IP3）结合，并结合激活IP3受体（IP3RS）。我们证明了内质网中存在BAP1 （ER）它调节IP3-受体-3（IP3R3）的活性，这是控制Ca2+的主要ER通道从ER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突变载体中BAP1的水平会损害细胞凋亡，并有利于细胞转化暴露于石棉，IR和紫外线后积累DNA损伤的细胞。我们也发现了杂合种系BAP1突变的载体的“正常”原代细胞从有氧运动中得出能量糖酵解，称为Warburg效应，到目前为止，该作用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Warburg效应相关的特定代谢特征在杂合种系BAP1突变的载体血浆中。我们的中心假设是变化 Ca2+浓度导致含有BAP1突变对凋亡的细胞的抗性增加代谢途径的变化又导致了在 BAP1突变载体。为了解决这一假设，我们将研究以下具体目的：目的1：研究BAP1突变引起“ Warburg效应”的机制。目的2：研究沃堡效应在BAP1 +/-细胞中独立于HIF-1α的假设。目的3：研究因生殖线BAP1引起的钙信号传导和代谢改变的贡献 MM开发的突变。为了阐明BAP1对I P 3 R 3的活性以及对癌症渗透率的相关影响，我们有组装了一个独特的携带种系BAP1突变的家庭队列，并可以访问独特从这些家庭派出的志愿者衍生的试剂。这些独特的试剂包括：原始细胞培养物源自遗传种系BAP1突变以及性别和年龄的家庭成员来自相同家族的匹配对照，血清和血浆的种系BAP1突变载体和匹配的对照，杂合BAP1小鼠模型和衍生的细胞培养物。另外，我们组装了一组独特的杂合BAP1和IP3R3小鼠，这些小鼠概括了人类状况这使我们能够研究暴露于致癌物的体内BAP1突变的影响。与该领域的一些领先专家的合作，博士。 Pinton和Giorgi，CA2+专家信号传导和线粒体代谢； Mikoshiba博士，IP3R3活动，完成和与两个MPI的专业知识协同作用。这些研究将与多个Malignancys有关在BAP1突变的载体和开发的人中，与BAP1癌症综合征相关肿瘤发育过程中BAP1的体细胞突变。