Altered expression of many 'cancer genes' or oncogenes have been implicated in the genesis of various cancers and hematologic neoplasms. The c-myc oncogene is prominent among these oncogenes for its involvement in lymphomas, leukemias, and in normal hematopoiesis. Despite the abundant knowledge of c-myc gene structure and expression, there is a relative paucity of information on the c-myc protein (c-Myc) domains and how c-Myc structure is related to function. We have a set of human c-myc mutants which was instrumental in delineating the domains of c-Myc which are involved in cell transformation, nuclear localization, non-specific DNA binding, and in c-Myc protein self-association. We were able to inhibit the wild-type c-Myc transforming activity with an inactive trans-dominant c-Myc mutant that can oligomerize with the wild-type Myc polypeptide to form inactive multimers. We hypothesize that c-Myc oligomerization, which occurs via its carboxyl-terminal domain containing repeats of leucines at every seventh amino acid ('leucine zipper'), is necessary for c-Myc to interact with nuclear targets such as DNA via a separate carboxyl-terminal basic region of c-Myc. An amino terminal region of c-Myc, which is required for transformation, is hypothesized to facilitate binding to other nuclear proteins which are necessary for c-Myc function. Using our available c-myc mutants, we propose to investigate the following: 1) the roles of different c-Myc regions in the proliferation and differentiation of a murine erythroleukemia (MEL) cell line and the use of the trans- dominant myc mutant to impede c-Myc activity in MEL and other cells; 2) the role of the c-Myc leucine residues in the 'leucine zipper' domain in c-Myc protein self-association; 3) the identification of proteins and specific DNA sequences which specifically interact with c-Myc. These studies will provide valuable information on the role of c-Myc in cell growth and differentiation and provide the basis to generate armamentarium for anti- oncogene manipulations and therapy using transdominant mutants. Structural studies on the c-Myc 'leucine zipper' domain will be crucial in our understanding of how this important motif affects protein-protein interactions in general. Identification of proteins and specific DNA sequences which associate with c-Myc will increase our understanding of c- Myc function and may allow recognition of additional genes involved in hematopoiesis.
| Le, Anne; Stine, Zachary E; Nguyen, Christopher et al. (2014) Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia-cell cycle dual reporter. Proc Natl Acad Sci U S A 111:12486-91 |
| Dang, Chi V (2010) Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res 70:859-62 |
| Dang, Chi V (2009) MYC, microRNAs and glutamine addiction in cancers. Cell Cycle 8:3243-5 |
| Dang, Chi V (2009) PKM2 tyrosine phosphorylation and glutamine metabolism signal a different view of the Warburg effect. Sci Signal 2:pe75 |
