Domain-specific c-Myc ubiquitylation controls c-Myc transcriptional and apoptotic activity.

Abstract

The oncogenic transcription factor c-Myc causes transformation and tumorigenesis, but it can also induce apoptotic cell death. Although tumor suppressors are necessary for c-Myc to induce apoptosis, the pathways and mechanisms are unclear. To further understand how c-Myc switches from an oncogenic protein to an apoptotic protein, we examined the mechanism of p53-independent c-Myc-induced apoptosis. We show that the tumor suppressor protein ARF mediates this switch by inhibiting ubiquitylation of the c-Myc transcriptional domain (TD). Whereas TD ubiquitylation is critical for c-Myc canonical transcriptional activity and transformation, inhibition of ubiquitylation leads to the induction of the noncanonical c-Myc target gene, Egr1, which is essential for efficient c-Myc-induced p53-independent apoptosis. ARF inhibits the interaction of c-Myc with the E3 ubiquitin ligase Skp2. Overexpression of Skp2, which occurs in many human tumors, inhibits the recruitment of ARF to the Egr1 promoter, leading to inhibition of c-Myc-induced apoptosis. Therapeutic strategies could be developed to activate this intrinsic apoptotic activity of c-Myc to inhibit tumorigenesis.

• Authors: Qin Zhang, Erick Spears, David N Boone, Zhaoliang Li, Mark A Gregory, Stephen R Hann
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 3 Pg. 978-83 (Jan 15 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23277542 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cdkn2a protein, mouse
• Cyclin-Dependent Kinase Inhibitor p16
• Early Growth Response Protein 1
• Egr1 protein, mouse
• Myc protein, mouse
• Proto-Oncogene Proteins c-myc
• S-Phase Kinase-Associated Proteins

Topics

• Amino Acid Substitution
• Animals
• Apoptosis (genetics, physiology)
• Binding, Competitive
• Cell Transformation, Neoplastic
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p16 (metabolism)
• Early Growth Response Protein 1 (genetics)
• Gene Knockout Techniques
• Genes, myc
• HeLa Cells
• Humans
• Mice
• Mutagenesis, Site-Directed
• Protein Structure, Tertiary
• Proto-Oncogene Proteins c-myc (chemistry, genetics, metabolism)
• S-Phase Kinase-Associated Proteins (metabolism)
• Transcription, Genetic
• Ubiquitination