Control of c-Myc Function by the Tumor Suppressor p19ARF

Summary

Principal Investigator: STEPHEN HANN
Abstract: 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.
Funding Period: 2004-07-06 - 2010-04-30
more information: NIH RePORT

Top Publications

  1. pmc Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation
    Zhaoliang Li
    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 2175, USA
    Proc Natl Acad Sci U S A 105:18794-9. 2008
  2. pmc The Myc-nucleophosmin-ARF network: a complex web unveiled
    Zhaoliang Li
    Department of Cell and Developmental Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA
    Cell Cycle 8:2703-7. 2009
  3. pmc Egr1 mediates p53-independent c-Myc-induced apoptosis via a noncanonical ARF-dependent transcriptional mechanism
    David N Boone
    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 2175, USA
    Proc Natl Acad Sci U S A 108:632-7. 2011
  4. pmc Nucleophosmin is essential for c-Myc nucleolar localization and c-Myc-mediated rDNA transcription
    Z Li
    Department of Cell and Developmental Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 2175, USA
    Oncogene 32:1988-94. 2013

Detail Information

Publications4

  1. pmc Nucleophosmin interacts directly with c-Myc and controls c-Myc-induced hyperproliferation and transformation
    Zhaoliang Li
    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 2175, USA
    Proc Natl Acad Sci U S A 105:18794-9. 2008
    ..Therefore, NPM is a key cofactor for the transforming activity of c-Myc and the interaction with c-Myc may mediate the enhancement of proliferation and transformation induced by NPM overexppression...
  2. pmc The Myc-nucleophosmin-ARF network: a complex web unveiled
    Zhaoliang Li
    Department of Cell and Developmental Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA
    Cell Cycle 8:2703-7. 2009
    ..Therefore, the fate of a cell to undergo apoptosis or become transformed is dependent on this complex interacting network of oncogenic and tumor suppressor proteins...
  3. pmc Egr1 mediates p53-independent c-Myc-induced apoptosis via a noncanonical ARF-dependent transcriptional mechanism
    David N Boone
    Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 2175, USA
    Proc Natl Acad Sci U S A 108:632-7. 2011
    ..These findings also provide evidence that cofactors can differentially regulate specific transcriptional programs of c-Myc leading to different biological outcomes...
  4. pmc Nucleophosmin is essential for c-Myc nucleolar localization and c-Myc-mediated rDNA transcription
    Z Li
    Department of Cell and Developmental Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 2175, USA
    Oncogene 32:1988-94. 2013
    ..Taken together, these results demonstrate an essential role for NPM in c-Myc nucleolar localization and c-Myc-mediated rDNA transcription...