The ultimate goal of the program is to elucidate the molecular nature of processes causing human cancer so that methods to treat or control this disease can be devised. The properties which distinguish a cancer cell from a normal cell reflect genetic changes that activate dominant oncogenes or inactivate anti-oncogenes. Both types of genetic alterations commonly result in changes of gene regulation. The central theme of this grant is the study of the malignant state by analysis of regulation of gene expression, particularly at the stage of initiation of transcription. We will address this theme by (a) study of the role of the Wilm's anti- oncogene in suppression transformation, (b) analysis of the nuclear events regulating transcription from the fos promoter caused by activation of a cell surface receptor by the oncogene protein PDGF, (c) use of a retroviral promoter trap vector to identify cellular genes critical for cell transformation by oncogenes and anti-oncogenes, (d) analysis of cell division and differentiation by studying the role of promoter specific and basal factors in regulating transcription by RNA polymerase II. The four programs constituting the grant have a conceptual and methodological unity which insure their synergistic interactions in accomplishing these objectives. This unity is reflected in the recent discovery that the Wilm's anti-oncogene protein contains a structural motif common of many sequence-specific DNA binding-proteins. The research will help reveal the cellular and biochemical mechanisms responsible for alterations in control of cell division and differentiation that cause malignant transformation. Understanding the cancer cell at the level of biochemical processes will generate new opportunities for intervening in the progression of the disease.
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