Our overall goal in this proposal is to examine the molecular and biological role of the Myc proteins in growth control. Specific DNA binding of c-Myc protein to an """"""""E"""""""" box element (EMS) and transactivation of this element has been shown to be dependent on heterodimer formation with its partner protein, Max. Since Max is constitutively expressed during growth and differentiation, it has been hypothesized that the function of c-myc is dependent solely on the abundance of c-Myc protein. Our recent findings, however, suggest that it is unlikely that the cellular role of c-myc is exerted exclusively through the EMS binding site or by a single c-Myc protein 1 is very different from the AUG- initiated c-Myc 2 protein in terms of regulations, molecular function and biological function. For example, in growing cells the synthesis of c- Myc 1 protein is low relative to c-Myc 2. However, as cells grow to high densities c-Myc 1 protein synthesis is induced to high levels relative to c-Myc 2. In addition, the Myc 1 protein dramatically and specifically transactivates the EFII enhancer sequence through a binding site for the C/EBP family of transcription factors. In contrast, v-Myc protein represses EFII-mediated transcription while c-Myc 2 fails to significantly affect EFII transcription. Finally, overexpression of c- Myc 1, in contrast to c-Myc 2, had a growth inhibitory effect on cells. Therefore, our hypothesis to be tested is that the c-Myc 1 protein has a molecular and biological function distinct from the other forms of Myc protein. To test this hypothesis we propose to: 1) examine the mechanism of transcriptional activation of C/EBP binding sites by c-Myc 1 protein and the DNA binding activities of Myc and Max to C/EBP binding sites; 2) examine the transactivation of target sequences and genes by c-Myc 1; 3) examine the effects of c-Myc 1 overexpression of proliferation, differentiation and apoptosis in fibroblast and keratinocytes using an inducible-active c-Myc 1-estrogen receptor chimeric protein; and 4) determine whether c-Myc 1 can induce tumorigenesis or suppress the c-Myc 2-induced tumorigenesis of mammary epithelium using the tissue-specific, lactogenic hormone-inducible WAP promoter in transgenic mice. Examination of these proposed aims will allow a further understanding of the important and complex role which c-Myc proteins have in the control of cellular proliferation.
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