The principal goal of this program project application is to understand and define the nature of these changes in the genetic information which may specifically activate cellular oncogenes and which may also be responsible for the normal and abnormal developmental control of gene expression. The mechanisms responsible for the activation of cellular oncogenes may involve: 1) local changes or mutations in genes involving base changes or small deletions which alter the functional properties of the gene product; 2) gross changes in the relative position of genes which may either involve translocations of structural gene information from one chromosomal location to another or the introduction of activators such as viral LTRs adjacent to genes, such that the frequency of gene expression is enhanced; 3) changes in the numbers of genes involving gene amplification mechanisms which may obviously increase the abundance of specific gene products; and 4) changes in the activity of oncogene promoters either by changing the base sequence itself or by altering structure in the vicinity of regulatory information, as may be envisaged through changes in the pattern of methylation, the degree of supercoiling or other aspects of chromatin structure. Experiments are described to elucidate the possible role of the mechanisms in normal cell differentiation and in aberrant differentiation characteristic of tumor cells.
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