Mechanisms of arsenic-induced chromosomal instability and carcinogenesis

砷引起的染色体不稳定和致癌机制

基本信息

批准号：
8413001
负责人：
WEI DAI
金额：
$ 39.29万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2012-01-16 至 2016-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8413001
关键词：
Adenocarcinoma Affect Aneuploidy Arsenic Arsenic Trioxide Arsenicals Attenuated Biological Bladder Bowen&apos s Disease Cancer Intervention Carcinogens Cell Cycle Checkpoint Cell Cycle Progression Cell Line Cell division Cells Chromatids Chromosomal Instability Chromosomal Stability Chromosome Breakage Chromosome Segregation Chromosome abnormality Chromosomes Chronic Colon Colon Carcinoma Complement Cyclin B Cytogenetics DNA DNA Damage DNA Repair DNA biosynthesis Development Dicentric chromosome Double Minutes Embryo Environmental Carcinogens Epidemiologic Studies Epidemiology Epigenetic Process Exposure to Fibroblasts Geminin Genes Genetic Genomic Instability Goals Growth HCT116 Cells Hela Cells Human Hyperplasia In Vitro Knockout Mice Laboratory Research Laboratory Study Lead Licensing Factor Lung MXI1 gene Maintenance Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of urinary bladder Melanoma Cell Microcephaly Microtubules Mitosis Mitotic Molecular Molecular Target Mus Mutation Neoplastic Cell Transformation Nuclear Oncogenic Organ Paclitaxel Play Population Study Process Property Protein Deregulation Proteins Reactive Oxygen Species Regulation Replication Licensing Research Role Side Sister Sister Chromatid Sister Chromatid Exchange Skin Skin Cancer Solid Neoplasm Stomach System Testing Tissues Tubulin anaphase-promoting complex base carcinogenesis carcinogenicity daughter cell driving force human PTTG1 protein in vivo micronucleus polymerization premature segregation skin lesion tumor tumor progression tumorigenesis ultraviolet irradiation

项目摘要

DESCRIPTION (provided by applicant): Chronic exposure to arsenic is highly associated with the occurrence of several types of malignancies, including skin, lung and bladder cancer. Despite extensive studies in the past, the mechanism by which arsenic compounds promote carcinogenesis remains largely unclear. Epidemiological studies reveal that arsenic exposure induces the formation of micronuclei, chromosomal aberrations, and aneuploidy, which may be a culprit in the genesis of cancer since most solid tumors are aneuploid. High fidelity DNA replication and faithful distribution of the chromosomal complement to daughter cells during cell division are of paramount importance to the maintenance of chromosomal stability. We previously demonstrated that arsenic trioxide [As(III)] compromises paclitaxel-induced mitotic arrest in both p53-deficient and proficient cells. We have recently shown that As(III) induces chromosomal instability by suppressing the activation of BubR1, a cell cycle checkpoint protein, leading to unscheduled activation of anaphase promoting complex/cyclosome (APC/C) in melanoma and HeLa cells. Activated APC/C apparently causes premature separation of sister chromatids, aberrant sister chromatid exchanges, and diplochromosome formation in cells with wild-type p53. Moreover, mice with haploinsufficiency of BubR1 are prone to the development of skin lesions (hyperplasia) after exposure to UV irradiation. Given the documented effect of As(III) on the induction of nuclear abnormalities, we hypothesize that As(III) compromises the BubR1-dependent spindle checkpoint, resulting in unscheduled activation of APC/C, chromosomal instability, and neoplastic transformation owing to dysregulation of DNA replication and chromosome segregation processes. To test this hypothesis, we will (1) elucidate the molecular basis by which As(III) induces chromosomal instability with an emphasis on studying the Emi1->APC/C->geminin->Cdt1 regulatory axis, (2) determine if As(III) synergizes with spindle checkpoint deficiency in promoting chromosomal instability and oncogenic transformation in vitro, (3) determine if As(III) enhances spontaneous tumor development in BubR1 haploinsufficient mice and investigate if As(III) functions as a co-carcinogen in promoting skin tumorigenesis induced by UV irradiation in these mice. The long term goal of the project is to understand whether the biological properties associated with As(III) are at least partly due to its action on the perturbation of APC/C activities, causing deregulation of proteins crucial for the control of DNA replication and chromosomal segregation during cell division. We anticipate that this line of research will lead to the identification of key molecular targets for cancer intervention, as well as for ameliorating the detrimental effects of arsenic compounds.

描述（由申请人提供）：长期暴露于砷与发生多种类型的恶性肿瘤（包括皮肤，肺癌和膀胱癌）高度相关。尽管过去进行了广泛的研究，但砷化合物促进癌变的机制仍然在很大程度上不清楚。流行病学研究表明，砷暴露会诱导微核形成，染色体畸变和非整倍性，这可能是癌症起源的罪魁祸首，因为大多数实体瘤是非整倍性的。在细胞分裂期间，染色体补体对子细胞的高保真DNA复制和忠实分布对于维持染色体稳定性至关重要。我们先前证明了三氧化物[AS（iii）]损害了紫杉醇诱导的p53缺陷和熟练细胞中的有丝分裂停滞。我们最近表明，AS（III）通过抑制BUBR1的激活（一种细胞周期检查点蛋白，从而诱导染色体不稳定性，从而导致黑色素瘤和HELA细胞中促进复合物/循环体（APC/C）的过期激活的激活。活化的APC/C显然会导致姐妹染色单体，异常姐妹染色单体交换和具有野生型p53的细胞中的二氧染色体形成过早分离。此外，暴露于紫外线照射后，具有单倍体不足的BUBR1的小鼠容易发生皮肤病变（增生）。鉴于AS（III）对核异常诱导的效果，我们假设（III）损害了BUBR1依赖性纺锤体检查点，从而导致APC/C，染色体不稳定性的激活，染色体不稳定性，并导致染色体转化，并导致DNA重复的疾病不断变化。 To test this hypothesis, we will (1) elucidate the molecular basis by which As(III) induces chromosomal instability with an emphasis on studying the Emi1->APC/C->geminin->Cdt1 regulatory axis, (2) determine if As(III) synergizes with spindle checkpoint deficiency in promoting chromosomal instability and oncogenic transformation in vitro, (3) determine如果AS（III）增强了BUBR1单倍体肿瘤的自发性肿瘤的发育，并研究AS（III）是否在促进这些小鼠中紫外线辐照引起的皮肤肿瘤发生方面起作用（III）。该项目的长期目标是了解与AS（III）相关的生物学特性至少部分是由于其对APC/C活性扰动的作用，从而导致对控制DNA复制和细胞分裂过程中染色体隔离至关重要的蛋白质。我们预计，这一研究将导致鉴定癌症干预的关键分子靶标，并改善砷化合物的有害作用。