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（由申请人提供）：非整倍性和染色体畸变是人类神经肿瘤的常见特征。基因组不稳定性或有丝分裂错误产生染色体重复，损失和易位的趋势长期以来被认为是肿瘤发生的主要机制。基因组不稳定性的研究有望对癌症治疗的新见解。最近，在理解有丝分裂调节的分子细节方面已取得了重大进展。 Securin是一种蛋白质，其功能可通过抑制后期进展，直到将所有染色体正确排列在中期时，以确保染色体准确地分布到子细胞上。当细胞被操纵至过度表达状态时，它们会产生染色体异常和微核。这种微核经常在神经系统肿瘤中，尤其是寡糖瘤。彼得·杰克逊（Peter Jackson）实验室最近发现的另一种蛋白质EMI1参与了S相激活和有丝分裂控制。 EMI1通过抑制其泛素化来阻止Securin的降解，但也直接与Securin结合。 EMI1的过表达会导致异常的起源阶段块和异常有丝分裂主轴形成。我们假设EMI1和Securin的直接相互作用介导了这种效应，从而导致基因组不稳定性。 HCT116结肠癌细胞是二倍体细胞系，是有丝分裂研究的理想选择。我将使用这些细胞作为研究EMI1和Secuin对基因组稳定性的控制的工具。我还将解决EMI1和Securin在神经系统肿瘤起源中的可能作用。拟议的研究将专门解决以下问题。内源性EMI1和固定是否直接在细胞中相互作用，如果是，则在细胞周期的哪个阶段？ EMI1-苏蛋白相互作用是否位于细胞内？ EMI1和Secuin的哪些功能域对于确定其相互作用很重要？ emi1 misexpression是否会导致纺锤体异常或染色体错误进行分解，并且这种效果是否需要Securin？ EMI1的过度表达是否会产生染色体畸变，例如缺失或重复？如果是这样，是否会发生特定的细胞遗传学异常？ EMI1的过表达是否诱导细胞转化，或与已知的肿瘤基因（例如Ras，Myc或Securin）合作，以诱导转化？ emi1 misexpression是否发生在包括神经肿瘤在内的特定肿瘤类型中？ EMI1表达是否与肿瘤中的Securin表达呈正相关？ EMI1或Securin表达是否与肿瘤中细胞周期蛋白D/RB/E2F途径的激活相关？我将从事神经病理学的学术生涯，并将拟议研究中获得的知识和经验应用于转化神经肿瘤研究。

项目成果

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

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

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

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

Comprehensive genomic characterization defines human glioblastoma genes and core pathways.

• DOI: 10.1038/nature07385
• 发表时间: 2008-10-23
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Chin, L.;Meyerson, M.;Aldape, K.;Bigner, D.;Mikkelsen, T.;VandenBerg, S.;Kahn, A.;Penny, R.;Ferguson, M. L.;Gerhard, D. S.;Getz, G.;Brennan, C.;Taylor, B. S.;Winckler, W.;Park, P.;Ladanyi, M.;Hoadley, K. A.;Verhaak, R. G. W.;Hayes, D. N.;Spellman, Paul T.;Absher, D.;Weir, B. A.;Ding, L.;Wheeler, D.;Lawrence, M. S.;Cibulskis, K.;Mardis, E.;Zhang, Jinghui;Wilson, R. K.;Donehower, L.;Wheeler, D. A.;Purdom, E.;Wallis, J.;Laird, P. W.;Herman, J. G.;Schuebel, K. E.;Weisenberger, D. J.;Baylin, S. B.;Schultz, N.;Yao, Jun;Wiedemeyer, R.;Weinstein, J.;Sander, C.;Gibbs, R. A.;Gray, J.;Kucherlapati, R.;Lander, E. S.;Myers, R. M.;Perou, C. M.;McLendon, Roger;Friedman, Allan;Van Meir, Erwin G;Brat, Daniel J;Mastrogianakis, Gena Marie;Olson, Jeffrey J;Lehman, Norman;Yung, W. K. Alfred;Bogler, Oliver;Berger, Mitchel;Prados, Michael;Muzny, Donna;Morgan, Margaret;Scherer, Steve;Sabo, Aniko;Nazareth, Lynn;Lewis, Lora;Hall, Otis;Zhu, Yiming;Ren, Yanru;Alvi, Omar;Yao, Jiqiang;Hawes, Alicia;Jhangiani, Shalini;Fowler, Gerald;San Lucas, Anthony;Kovar, Christie;Cree, Andrew;Dinh, Huyen;Santibanez, Jireh;Joshi, Vandita;Gonzalez-Garay, Manuel L.;Miller, Christopher A.;Milosavljevic, Aleksandar;Sougnez, Carrie;Fennell, Tim;Mahan, Scott;Wilkinson, Jane;Ziaugra, Liuda;Onofrio, Robert;Bloom, Toby;Nicol, Rob;Ardlie, Kristin;Baldwin, Jennifer;Gabriel, Stacey;Fulton, Robert S.;McLellan, Michael D.;Larson, David E.;Shi, Xiaoqi;Abbott, Rachel;Fulton, Lucinda;Chen, Ken;Koboldt, Daniel C.;Wendl, Michael C.;Meyer, Rick;Tang, Yuzhu;Lin, Ling;Osborne, John R.;Dunford-Shore, Brian H.;Miner, Tracie L.;Delehaunty, Kim;Markovic, Chris;Swift, Gary;Courtney, William;Pohl, Craig;Abbott, Scott;Hawkins, Amy;Leong, Shin;Haipek, Carrie;Schmidt, Heather;Wiechert, Maddy;Vickery, Tammi;Scott, Sacha;Dooling, David J.;Chinwalla, Asif;Weinstock, George M.;O'Kelly, Michael;Robinson, Jim;Alexe, Gabriele;Beroukhim, Rameen;Carter, Scott;Chiang, Derek;Gould, Josh;Gupta, Supriya;Korn, Josh;Mermel, Craig;Mesirov, Jill;Monti, Stefano;Nguyen, Huy;Parkin, Melissa;Reich, Michael;Stransky, Nicolas;Garraway, Levi;Golub, Todd;Protopopov, Alexei;Perna, Ilana;Aronson, Sandy;Sathiamoorthy, Narayan;Ren, Georgia;Kim, Hyunsoo;Kong, Sek Won;Xiao, Yonghong;Kohane, Isaac S.;Seidman, Jon;Cope, Leslie;Pan, Fei;Van Den Berg, David;Van Neste, Leander;Yi, Joo Mi;Li, Jun Z.;Southwick, Audrey;Brady, Shannon;Aggarwal, Amita;Chung, Tisha;Sherlock, Gavin;Brooks, James D.;Jakkula, Lakshmi R.;Lapuk, Anna V.;Marr, Henry;Dorton, Shannon;Choi, Yoon Gi;Han, Ju;Ray, Amrita;Wang, Victoria;Durinck, Steffen;Robinson, Mark;Wang, Nicholas J.;Vranizan, Karen;Peng, Vivian;Van Name, Eric;Fontenay, Gerald V.;Ngai, John;Conboy, John G.;Parvin, Bahram;Feiler, Heidi S.;Speed, Terence P.;Socci, Nicholas D.;Olshen, Adam;Lash, Alex;Reva, Boris;Antipin, Yevgeniy;Stukalov, Alexey;Gross, Benjamin;Cerami, Ethan;Wang, Wei Qing;Qin, Li-Xuan;Seshan, Venkatraman E.;Villafania, Liliana;Cavatore, Magali;Borsu, Laetitia;Viale, Agnes;Gerald, William;Topal, Michael D.;Qi, Yuan;Balu, Sai;Shi, Yan;Wu, George;Bittner, Michael;Shelton, Troy;Lenkiewicz, Elizabeth;Morris, Scott;Beasley, Debbie;Sanders, Sheri;Sfeir, Robert;Chen, Jessica;Nassau, David;Feng, Larry;Hickey, Erin;Schaefer, Carl;Madhavan, Subha;Buetow, Ken;Barker, Anna;Vockley, Joseph;Compton, Carolyn;Vaught, Jim;Fielding, Peter;Collins, Francis;Good, Peter;Guyer, Mark;Ozenberger, Brad;Peterson, Jane;Thomson, Elizabeth
• 通讯作者: Thomson, Elizabeth