We have shown that p19ARF protein binds and colocalizes with c-Myc protein, both exogenously and endogenously. ARF binding to c-Myc inhibits c-Myc transactivation of target genes and c- Myc-induced hyperproliferation and transformation. Furthermore, ARF does not inhibit repression of c-Myc target genes and actually appears necessary for Inr-mediated repression and enhances c- Myc-induced apoptosis. ARF also inhibits the proteolysis of c-Myc. The further characterization and functional relevance of this interaction is the focus of this proposal. Our hypothesis is that direct ARF interaction with c-Myc selectively regulates the activity of c-Myc protein. Therefore, loss of this important checkpoint control would contribute to deregulation of c-Myc function leading to hyperproliferation, transformation and inhibition of apoptosis. To test this hypothesis the following specific aims will be performed.
Specific Aim I will be to characterize the biochemical interaction between c-Myc and ARF.
Specific Aim 2 will be to determine the molecular mechanism that mediates the regulation of c-Myc activity by ARF.
Specific Aim 3 will be to determine the biological role of the interaction of ARF with c-Myc. Our novel findings and the results of experiments proposed in these specific aims will have major implications for the function of c-Myc, ARF and p53. Our findings have already impacted the controversial model on the molecular function of c-Myc and will likely continue to impact the course of c-Myc studies on how c-Myc functions at the molecular level to elicit such powerful control over cellular proliferation, tumorigenesis and apoptosis. Finally, the inhibition of c-Myc-induced transformation and enhancement of c-Myc-induced apoptosis by ARF has direct therapeutic significance for cancer treatment.
| Li, Z; Hann, S R (2013) Nucleophosmin is essential for c-Myc nucleolar localization and c-Myc-mediated rDNA transcription. Oncogene 32:1988-94 |
| Boone, David N; Qi, Ying; Li, Zhaoliang et al. (2011) Egr1 mediates p53-independent c-Myc-induced apoptosis via a noncanonical ARF-dependent transcriptional mechanism. Proc Natl Acad Sci U S A 108:632-7 |
| Li, Zhaoliang; Hann, Stephen R (2009) The Myc-nucleophosmin-ARF network: a complex web unveiled. Cell Cycle 8:2703-7 |
| Li, Zhaoliang; Boone, David; Hann, Stephen R (2008) Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation. Proc Natl Acad Sci U S A 105:18794-9 |
| Gregory, Mark A; Qi, Ying; Hann, Stephen R (2005) The ARF tumor suppressor: keeping Myc on a leash. Cell Cycle 4:249-52 |
