Control of Genomic Stability by Emi1 and Securin

Emi1 和 Securin 控制基因组稳定性

• 批准号: 7557976
• 负责人: NORMAN LEHMAN
• 金额: $ 16.13万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7557976
• 关键词: 26S proteasome; Address; Adrenal Glands; Affect; Anaphase; Aneuploidy; Antimitotic Agents; Automobile Driving; Binding; Biochemical; Biological; Cell Cycle; Cell Cycle Progression; Cell Cycle Stage; Cell Line; Cells; Chromatids; Chromosomal Duplication; Chromosome Segregation; Chromosome abnormality; Chromosomes; Cleaved cell; Colon Carcinoma; Complex; Condition; Congenital Abnormality; Controlled Study; Cultured Cells; Cyclin A; Cyclin B; Cyclin D1; DNA; Diploid Cells; Endometrial Neoplasms; Endometrium; Endopeptidases; Ensure; Ependyma; Frequencies; G2 Phase; Generations; Genetic Transcription; Genome Stability; Genomic Instability; HCT116 Cells; Homeostasis; Human; Human Development; Interphase; Knowledge; Laboratories; Localized; Lung; Malignant Epithelial Cell; Malignant Neoplasms; Mammalian Cell; Mammary Neoplasms; Mediating; Meninges; Metaphase; Metaphase Plate; Mitosis; Mitotic; Mitotic spindle; Molecular; Nature; Neoplasms; Neurologic; Normal tissue morphology; Oncogenes; Ovarian; Ovary; PTTG1 gene; Pathway interactions; Peptide Hydrolases; Phase; Physiological; Pituitary Gland; Pituitary Neoplasms; Polyubiquitination; Principal Investigator; Prometaphase; Property; Protein Overexpression; Proteins; RNA analysis; Rattus; Regulation; Research; Research Personnel; Role; Sampling; Secure; Sister Chromatid; Staining method; Stains; Structure; Transcriptional Activation; Transfection; Ubiquitin; Ubiquitination; Xenopus; anaphase-promoting complex; c-myc Genes; cancer therapy; career; cohesin; daughter cell; egg; experience; genetic regulatory protein; human PTTG1 protein; human STK6 protein; in vivo; inhibitor/antagonist; insight; interest; metaplastic cell transformation; micronucleus; neuro-oncology; neuropathology; osteosarcoma; plasmid DNA; programs; protein function; separase; tool; tumor; tumorigenesis; ubiquitin ligase

DESCRIPTION (provided by applicant): Aneuploidy and chromosomal aberrations are common features of human neuroplasms. Genomic instability, or the tendency for mitotic errors to create chromosomal duplications, losses, and translocations has long been recognized as a major mechanism of tumorigenesis. The study of genomic instability promises new insights into cancer treatment. Recently, significant advances have been made in the understanding of the molecular details of the regulation of mitosis. Securin is a protein that functions to ensure accurate distribution of chromosomes to daughter cells by inhibiting anaphase progression until all chromosomes are properly aligned at metaphase. When cells are manipulated to over-or under-express securin they develop chromosomal abnormalities and micronuclei. Such micronuclei are frequently seen in neurological tumors, especially oligogendrogliomas. Another protein, Emi1, recently discovered by the Peter Jackson Laboratory, is involved in S phase activation and mitotic control. Emi1 blocks the degradation of securin by inhibiting its ubiquitination, but also directly binds to securin. Over-expression of Emi1 causes an abnormal prometaphase block and abnormal mitotic spindle formation. We hypothesize that the direct interaction of Emi1 and securin mediates this effect causing genomic instability. Hct116 colon carcinoma cells are a diploid cell line ideal for mitotic studies. I will use these cells as a tool to study the control of genomic stability by Emi1 and securin. I will also address the possible role of Emi1 and securin in the genesis of neurological tumors. The proposed research will specifically address the following questions. Do endogenous Emi1 and securing interact directly in cells, and if so, during which stage(s) of the cell cycle? Is the Emi1-securin interaction localized within the cell? Which functional domains of Emi1 and securin are important in determining their interaction? Does Emi1 misexpression cause spindle abnormalities or chromosomal missegregation, and is securin required for this effect? Does over- or under-expression of Emi1 produce chromosomal aberrations such as deletions or duplications? If so, do specific cytogenetic abnormalities occur? Does Emi1 over-expression induce cellular transformation, or cooperate with known oncogenes such as ras, myc, or securin, in inducing transformation? Does Emi1 misexpression occur in specific tumor types, including neurological tumors? Does Emi1 expression positively or negatively correlate with securin expression in tumors? Does Emi1 or securin expression correlate with activation of the cyclin D/Rb/E2F pathway in tumors? I will pursue an academic career in neuropathology and will apply the knowledge and experience gained from the proposed studies to translational neuro-oncology research.

描述(申请人提供)：非整倍体和染色体异常是人类神经质的共同特征。基因组不稳定，或有丝分裂错误造成染色体复制、丢失和易位的趋势，长期以来一直被认为是肿瘤发生的主要机制。对基因组不稳定性的研究有望为癌症治疗提供新的见解。最近，在对有丝分裂调控的分子细节的理解方面取得了重大进展。Securin是一种蛋白质，它的功能是通过抑制后期进展，直到所有染色体在中期正确排列，从而确保染色体准确分配到子代细胞。当细胞被操纵过高或过低表达Securin时，它们会出现染色体异常和微核。这种微核常见于神经肿瘤，尤其是少原胶质细胞瘤。另一种蛋白质，Emi1，是最近由Peter Jackson实验室发现的，参与S期的激活和有丝分裂的控制。Emi1通过抑制Securin的泛素化来阻断Securin的降解，但也直接与Securin结合。Emi1的过度表达导致异常的前中期阻滞和异常的有丝分裂纺锤体形成。我们假设，Emi1和securin的直接相互作用介导了这一效应，导致基因组不稳定。HCT116结肠癌细胞系是研究有丝分裂的理想二倍体细胞系。我将利用这些细胞作为工具来研究Emi1和Securin对基因组稳定性的控制。我还将讨论Emi1和Securin在神经肿瘤发生中的可能作用。拟议的研究将具体解决以下问题。内源性EMI1和SECURING在细胞中是否直接相互作用，如果是，在细胞周期的哪个阶段(S)？Emi1-securin相互作用是否局限于细胞内？Emi1和Securin的哪些功能结构域在决定它们之间的相互作用方面是重要的？Emi1的错误表达是否会导致纺锤体异常或染色体错误分离，这种作用是否需要Securin？Emi1的过度或过低表达是否会产生染色体异常，如缺失或复制？如果是这样，是否会发生特定的细胞遗传学异常？Emi1过表达是诱导细胞转化，还是与已知的癌基因如ras、myc或securin协同诱导转化？Emi1错误表达是否发生在特定的肿瘤类型中，包括神经肿瘤？Emi1与Securin在肿瘤中的表达是正相关还是负相关？在肿瘤中，Emi1或Securin的表达是否与细胞周期蛋白D/Rb/E2F通路的激活有关？我将从事神经病理学的学术生涯，并将从拟议的研究中获得的知识和经验应用于神经肿瘤学的翻译研究。

项目成果

Can permeability measurements add to blood volume measurements in differentiating tumefactive demyelinating lesions from high grade gliomas using perfusion CT?

• DOI: 10.1007/s11060-009-0030-2
• 发表时间: 2010-05
• 期刊: Journal of neuro-oncology
• 影响因子: 3.9
• 作者: Jain R;Ellika S;Lehman NL;Scarpace L;Schultz LR;Rock JP;Rosenblum M;Mikkelsen T
• 通讯作者: Mikkelsen T

Primary paraspinal leiomyosarcoma invading the cervical spinal canal successfully treated with surgery, radiotherapy, and chemotherapy. Case report.

原发性椎旁平滑肌肉瘤侵犯颈椎管，通过手术、放疗和化疗成功治愈。

• DOI: 10.3171/spi.2007.6.5.441
• 发表时间: 2007
• 期刊: Journal of neurosurgery. Spine
• 作者: Lehman,NormanL;Jacobs,CharlotteD;Holsten,PhillipA;Jaikumar,Sivakumar;Lehman,TrangD;Gibbs,IrisC;Shuer,LawrenceM
• 通讯作者: Shuer,LawrenceM

Aurora-A kinase is differentially expressed in the nucleus and cytoplasm in normal Müllerian epithelium and benign, borderline and malignant serous ovarian neoplasms.

• DOI: 10.1186/s13000-021-01158-4
• 发表时间: 2021-10-27
• 期刊: Diagnostic pathology
• 影响因子: 2.6
• 作者: Alkhateeb KJ;Crane JE;Sak M;Jorgensen CJ;O'Donnell JP;Zumbar CT;Wozniak JA;Salazar CR;Parwani AV;Lehman NL
• 通讯作者: Lehman NL

Gliosarcoma stem cells undergo glial and mesenchymal differentiation in vivo.

• DOI: 10.1002/stem.264
• 发表时间: 2010-02
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: DeCarvalho, Ana C.;Nelson, Kevin;Lemke, Nancy;Lehman, Norman L.;Arbab, Ali S.;Kalkanis, Steven;Mikkelsen, Tom
• 通讯作者: Mikkelsen, Tom

Firm, non-tender mass in right breast · worsening, nonproductive cough · pleuritic pain · Dx?

右乳房坚硬、无压痛肿块 · 咳嗽恶化 · 胸膜炎性疼痛 · Dx？

• 发表时间: 2017
• 期刊: The Journal of family practice
• 作者: Lehman,TrangD;Damania,Zubin;Tschetter,CliffordN;Lehman,NormanL
• 通讯作者: Lehman,NormanL