title: 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.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232-2175, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Erick
authors.initials: E
authors.lastname: Spears
authors.forename: David N
authors.initials: DN
authors.lastname: Boone
authors.forename: Zhaoliang
authors.initials: Z
authors.lastname: Li
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gregory
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hann
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001667:Binding, Competitive; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics; D055786:Gene Knockout Techniques; D016259:Genes, myc; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D054875:Ubiquitination
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D044786:S-Phase Kinase-Associated Proteins