The proliferation of mammalian cells is a complex process carefully controlled by stimulatory and inhibitory mechanisms. A number of growth regulated genes which may regulate cell proliferation contain within their transcribed sequences or in their flanking regions regulatory elements to which putative suppressor and activator transcriptional factor may bind in a coordinated manner. Genes which control cell proliferation in normal cells are abnormally regulated in leukemic cells, thereby providing leukemic cells with variable degrees of growth advantage over non-leukemic cells. The growth advantage of leukemic cells might be due to the effect of inappropriate binding of cellular factors to regulatory sequences of genes which control cell proliferation in normal cells. The differentiation arrest of leukemic cells may also result from altered regulation of genes which control cell proliferation. Therefore main objectives of this project are to establish if a different binding of nuclear factors to regulatory regions of growth-regulated genes (c-myc,p53, calcyclin) occurs under normal conditions of growth and in leukemia, and if the introduction of constitutively expressed growth regulated genes (c-myc, p53, calcyclin) in myeloid cell lines inhibits their differentiation along the myelomonocytic pathway. These studies should provide insights on the molecular basis of growth advantage and differentiation arrest of leukemic cells.
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