A common denominator of growth factor signal transduction is the transcription of a set of nuclear proto-oncogenes, including c-myc, which appear to regulate cell proliferation and differentiation. Despite intense research efforts the specific function of c- myc, a nuclear DNA-binding phosphoprotein which has structural hallmarks of a transcription factor, has remained an enigma. Growth factor dependent hematopoietic cell lines are an attractive model system to study the regulation and function of genes since thay only require a single ligand for proliferation and viability. The long term goal of this proposed research is to define the specific function c-myc protein provides in regulating myeloid cell growth and differentiation. Introduction of a retroviral vector which constitutively expresses murine c-myc into murine myeloid cells which require Interleukin-3 (IL-3) results of three biological consequences. First, constitutive c-myc expression results in the constitutive expression of the ODC gene. Second, these cells continue to progress through the cell cycle under limiting growth conditions and exhibit accelerated cell death. Third, c-myc virus infected myeloid cells are blocked in their ability to terminally differentiate. We hypothesize that these biologic consequences are the result of c-myc's function as a transcriptional regulator pf a subset of genes which are required for DNA synthesis.
The Specific Aims of this proposed project are: 1) Identification of c-myc Domains Required for Biologic Effects in Myeloid Cells. 2) Identification of c-myc Responsive Elements in the ODC gene. The proposed research will contribute to our general understanding of those mechanisms regulating hematopoietic cell cycle progression and differentiation which are dependent upon c-myc function.
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