Molecular Mechanisms in Neoplasia View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

1976-2010

FUNDING AMOUNT

5986429.0 USD

ABSTRACT

DESCRIPTION (provided by applicant): Myc is an important oncogene widely studied in model systems and implicated in many human cancers. We have uncovered evidence for a robust genetic instability phenotype, involving DNA palindrome formation and gene copy number change, associated with constitutive Myc oncogene over expression, and resultant lymphomagenesis, in the chicken bursa of Fabricius. We propose to characterize this phenomenon more completely. To accomplish this general goal we have developed several tools for genomic analysis including a chicken cDNA microarray effective for array-based comparative genome hybridization (Array CGH) and genome-wide analysis of palindrome formation (GAPF) for analysis of lymphoma derived cell lines, and of tissues representing early and late stages of neoplastic bursal development in vivo. Specific planned experiments employ DT40, a myc-over expressing bursal lymphoma-derived cell line that demonstrates extensive DNA copy number change and palindrome formation that differs in different clonal isolates. We will:(a) determine the time scale over which these changes occur,(b) attempt to test effects of lower c-myc expression levels on stability, and (c) test the effects of deletion of several DNA repair genes including those demonstrated to be important for recombination in DT40: Myc is known to bind DNA at many loci, both in transcriptional regulatory regions and other regions of unknown function. We will map sites of Myc binding in the DT40 genome and determine if there is a relationship between Myc binding sites and sites of palindrome formation. We have observed that many sites of palindrome formation in bursal lymphomas and DT40 are expressed as RNA. We will adapt our array-based technology to determine whether RNA expressed from DNA palindromes formed during tumorigenesis has double-stranded character. Such dsRNAs are potential substrates for the formation of functional small interfering RNA which could play a role in gene silencing during tumor development. Finally, we will determine if Myc-ihduced instability occurs in mammalian systems. Palindrome formation will be assessed in Emu-c-myc transgenic mice which develop lympomas. In human P493-6 B-cells, in which Myc can be experimentally regulated, we will determine if induction of Myc results in palindrome formation at sites of Myc binding. In this fashion we hope to establish whether Myc-induced genomic instability merits wider exploration in human neoplasm. More... »

URL

http://projectreporter.nih.gov/project_info_description.cfm?aid=7495055

Related SciGraph Publications

  • 2006-05-01. Genomic instability during Myc-induced lymphomagenesis in the bursa of Fabricius in ONCOGENE
  • 2005-02-04. Development of a cDNA array for chicken gene expression analysis in BMC GENOMICS
  • 2004-04-05. Reduced Myc overexpression and normal B-cell differentiation mediate resistance to avian leukosis virus lymphomagenesis in ONCOGENE
  • 2003-12-22. Microarray analysis identifies Autotaxin, a tumour cell motility and angiogenic factor with lysophospholipase D activity, as a specific target of cell transformation by v-Jun in ONCOGENE
  • 2003-02-19. Functional genomic analysis reveals distinct neoplastic phenotypes associated with c-myb mutation in the bursa of Fabricius in ONCOGENE
  • 2001-05-31. Blocked B cell differentiation and emigration support the early growth of Myc-induced lymphomas in ONCOGENE
  • 2000-05-25. Angiogenesis is an early event in the generation of myc-induced lymphomas in ONCOGENE
  • 1986-01-01. Expression of the c-myb proto-oncogene during cellular proliferation in NATURE
  • 1985-03. Levels of c-myc oncogene mRNA are invariant throughout the cell cycle in NATURE
  • 1984-02. Alteration of c-myc chromatin structure by avian leukosis virus integration in NATURE
  • 1983-03-10. Molecular cloning and nucleotide sequence of a transforming gene detected by transfection of chicken B-cell lymphoma DNA in NATURE
  • 1981-08. Two distinct candidate transforming genes of lymphoid leukosis virus-induced neoplasms in NATURE
  • 1980-10. Transforming genes of neoplasms induced by avian lymphoid leukosis viruses in NATURE
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