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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS045077-05
Application #
7269767
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2003-08-01
Project End
2007-08-22
Budget Start
2007-08-01
Budget End
2007-08-22
Support Year
5
Fiscal Year
2007
Total Cost
$7,237
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Lehman, Norman L; Hattab, Eyas M; Mobley, Bret C et al. (2017) Morphological and molecular features of astroblastoma, including BRAFV600E mutations, suggest an ontological relationship to other cortical-based gliomas of children and young adults. Neuro Oncol 19:31-42
Hong, Xin; O'Donnell, James P; Salazar, Clarence R et al. (2014) The selective Aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation. Cancer Chemother Pharmacol 73:983-90
Kanagal-Shamanna, Rashmi; Lehman, Norman L; O'Donnell, James P et al. (2013) Differential expression of aurora-A kinase in T-cell lymphomas. Mod Pathol 26:640-7
Lehman, Norman L; O'Donnell, James P; Whiteley, Lisa J et al. (2012) Aurora A is differentially expressed in gliomas, is associated with patient survival in glioblastoma and is a potential chemotherapeutic target in gliomas. Cell Cycle 11:489-502
Dulai, Mohanpal S; Caccamo, Dario V; Briley, Anita L et al. (2010) Intramedullary papillary ependymoma with choroid plexus differentiation and cerebrospinal fluid dissemination to the brain. J Neurosurg Pediatr 5:511-7
Lehman, Norman L (2009) The ubiquitin proteasome system in neuropathology. Acta Neuropathol 118:329-47
Lehman, Norman L (2008) Patterns of brain infiltration and secondary structure formation in supratentorial ependymal tumors. J Neuropathol Exp Neurol 67:900-10
Dulai, Mohanpal S; Moes, Gregory S; Briley, Anita L et al. (2008) Gliosarcoma with melanocytic differentiation. Acta Neuropathol 115:357-61
Lehman, Norman L (2008) Central nervous system tumors with ependymal features: a broadened spectrum of primarily ependymal differentiation? J Neuropathol Exp Neurol 67:177-88
Verschuren, Emmy W; Ban, Kenneth H; Masek, Marilyn A et al. (2007) Loss of Emi1-dependent anaphase-promoting complex/cyclosome inhibition deregulates E2F target expression and elicits DNA damage-induced senescence. Mol Cell Biol 27:7955-65

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