(PROVIDE BY APPLICANT): The v-Myb oncogene causes acute monoblastic leukemia in chickens and induces the leukemic transformation of myelomonocytic cells in culture. c-Myb, the normal cellular gene from which v-Myb arose, is essential for vertebrate hematopoiesis. The v-Myb and the c-Myb proteins are nuclear, bind to the same specific DNA sequence, and are capable of regulating the transcription of other genes. Previous experiments suggested a correlation between oncogenic transformation and transcriptional activation by v-Myb. However, we have recently described several mutants of v-Myb that activate transcription but are incapable of oncogenic transformation. Because the regulation of v-Myb and c-Myb differ in many respects, and because v-Myb represents a highly mutated form of c-Myb, we have decided to refocus our efforts on understanding gene regulation by the normal c-Myb protein. Interestingly, although c-Myb is expressed in immature hematopoietic cells, most of the genes identified as targets for transcriptional activation by c-Myb continue to be expressed in mature differentiated hematopoietic cells in the absence of c-Myb. These results suggest that c-Myb may be required for the initiation but not the maintenance of gene expression during hematopoietic differentiation. Consistent with this hypothesis, a number of proteins that contain Myb repeats have been shown to regulate the structure and function of chromatin (e.g., SWL3, ISW1. ADA2. N-CoR, REBI, RAP1, TRF, TAZ). Therefore, our specific aims for the next grant period are: 1) to test the hypothesis that c-Myb regulates gene expression by altering the structure of chromatin; 2) to determine the function of the highly conserved acidic patch within the DNA-binding domain of c-Myb and other Myb-related proteins; 3) to identify additional genes that are directly regulated by c-Myb and determine their mode of regulation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cell Development and Function Integrated Review Group (CDF)
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Cole, John S
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Stanford University
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