Genomes and Genes
Role of NIAM, A Putative Cancer Gene, in Chromosomal Instability and Glioblastoma
Principal Investigator: SARA MARIE FRANCIS-REED
Abstract: DESCRIPTION (provided by applicant): Uncontrolled cellular proliferation, altered p53 tumor suppressor signaling, and chromosomal instability (CIN) are signature features of tumorigenesis. My thesis laboratory discovered a new activator of p53 signaling called NIAM (Nuclear Interactor of ARF and Mdm2). NIAM is a novel protein that prevents CIN and inhibits cell proliferation, and its mRNA is reduced in human cancers such as glioblastoma multiforme (GBM). NIAM has functional connections with ARF, Mdm2 and p53 yet it can suppress proliferation and CIN independent of all three factors. Thus, NIAM functions in multiple anti-cancer pathways. How NIAM maintains chromosome stability and its significance in cancer are unknown. A major cause of CIN is faulty DNA damage repair. Our preliminary data reveal NIAM is a chromatin-associated protein that localizes to DNA repair foci, enhances the DNA damage response, and binds the histone acetyltransferase Tip60. Like NIAM, Tip60 binds chromatin, activates p53 and interacts functionally with ARF and Mdm2. Tip60 can also act independently of ARF-Mdm2- p53 to activate DNA damage checkpoints, promote DNA repair, and maintain chromosome stability. Based on these observations, I hypothesize that NIAM is a tumor suppressor that inhibits CIN and cancer through its interaction with Tip60 and/or promoting DNA repair. Three aims are proposed to test that hypothesis and define the biological function of NIAM using complementary molecular, biological and genomic approaches. Aim 1: Determine if NIAM maintains chromosomal stability through chromatin association and DNA damage repair. Aim 2: Define the molecular basis and significance of NIAM-Tip60 association. Aim 3: Determine if there is a link between NIAM loss, CIN and cancer. These studies are novel and significant because they will define the mechanisms by which NIAM, a putative tumor suppressor, maintains chromosomal stability and thus genomic integrity. Experiments (Aim 3) also explore the significance of altered NIAM expression and CIN in GBM, the most aggressive and prevalent type of adult brain cancer. This work may improve the diagnosis and treatment of GBM, a deadly cancer which still lack effective therapies. Importantly, this is a multi-disciplinar thesis project that will greatly advance my skills in molecular cell biology and teach me how to study the mechanisms, biology and genomics of cancer. My ultimate goal is to become an independent physician scientist studying pediatric cancers. I am excited that this training experience will effectively prepare me for such a career in translational cancer research.
Funding Period: 2012-09-01 - 2015-08-31
more information: NIH RePORT
- Nuclear interactor of ARF and Mdm2 regulates multiple pathways to activate p53Sara M Reed
Department of Pharmacology University of Iowa College of Medicine Iowa City, IA USA Medical Scientist Training Program University of Iowa College of Medicine Iowa City, IA USA
Cell Cycle 13:1288-98. 2014..Thus, NIAM regulates 2 critical pathways that control p53 function and are altered in human cancers, implying an important role for NIAM in tumorigenesis. ..
- Mechanisms of Esophageal CarcinogenesisAnil K Rustgi; Fiscal Year: 2013..abstract_text> ..
- Molecular Pathogenesis of Basal-like Breast CancerRichard J Baer; Fiscal Year: 2013..e., metastasis, and develop strategies for therapy. ..
- NK Cells, Their Receptors and Unrelated Donor TransplantJeffrey S Miller; Fiscal Year: 2013..The program also promises to change practice of allogeneic transplantation, to the greater benefit of patients with advanced leukemia. ..
- Center for Molecular Imaging Research at MGH/HMSRalph Weissleder; Fiscal Year: 2013....
- The MIT Center for Single-Cell Dynamics in Cancer (SCDC)Scott R Manalis; Fiscal Year: 2013..These facilities and all reagents generated by the cores will be made available to other PS-OCs. ..
- Structural Cell Biology of DNA Repair MachinesJohn A Tainer; Fiscal Year: 2013..abstract_text> ..
- University of Maryland Greenebaum Cancer Center Support GrantKevin J Cullen; Fiscal Year: 2013..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
- THERAPY OF LYMPHOMA/LEUKEMIA WITH MONOCLONAL ANTIBODIESOliver W Press; Fiscal Year: 2013..We anticipate that the investigations described in this application will allow us to maximize the therapeutic efficacy and minimize the toxicity of myeloablative RIT for hematologic malignancies. ..
- PROTON RADIATION THERAPY RESEARCHThomas F DeLaney; Fiscal Year: 2013..abstract_text> ..
- Processing of Complex Lesions in the Mammalian GenomeRandy J Legerski; Fiscal Year: 2013..These approaches have excellent potential to yield useful technical and therapeutic advances in genetic manipulation. ..
- A Pathway-based Approach to Investigate Oncogenic Mechanisms in Ovarian CancerMichael L Gatza; Fiscal Year: 2013....
- Characterization of Pathways Controlling Cancer at the Level of Gene RegulationPhillip A Sharp; Fiscal Year: 2013..The interactions and involvement of Rb and miRNAs in induction of cell death following DNA damage will also be studied. ..
- CSHL CANCER CENTER SUPPORT GRANTBRUCE W STILLMAN; Fiscal Year: 2013....
- UNMC EPPLEY CANCER CENTER SUPPORT GRANTKenneth H Cowan; Fiscal Year: 2013....
- SPORE in Soft Tissue SarcomaSamuel Singer; Fiscal Year: 2013..abstract_text> ..