title: c-Abl phosphorylation of Mdm2 facilitates Mdm2-Mdmx complex formation.
abstract: Mdm2 and Mdmx are oncoproteins that have essential yet nonredundant roles in development and function as part of a multicomponent ubiquitinating complex that targets p53 for proteasomal degradation. However, in response to DNA damage, Mdm2 and Mdmx are phosphorylated and protect p53 through various mechanisms. It has been predicted that Mdm2-Mdmx complex formation modulates Mdm2 ligase activity, yet the mechanism that promotes formation of Mdm2-Mdmx complexes is unknown. Here, we show that optimal Mdm2-Mdmx complex formation requires c-Abl phosphorylation of Mdm2 both in vitro and in vivo. In addition, Abl phosphorylation of Mdm2 is required for efficient ubiquitination of Mdmx in vitro, and eliminating c-Abl signaling, using c-Abl(-/-) knock-out murine embryonic fibroblasts, led to a decrease in Mdmx ubiquitination. Further, p53 levels are not induced as efficiently in c-Abl(-/-) murine embryonic fibroblasts following DNA damage. Overall, these results define a direct link between genotoxic stress-activated c-Abl kinase signaling and Mdm2-Mdmx complex formation. Our results add an important regulatory mechanism for the activation of p53 in response to DNA damage.
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Waning
authors.forename: Jason A
authors.initials: JA
authors.lastname: Lehman
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Batuello
authors.forename: Lindsey D
authors.initials: LD
authors.lastname: Mayo
mesh_terms: D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D004249:DNA Damage; D055786:Gene Knockout Techniques; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D000068877:Imatinib Mesylate; D051736:Proto-Oncogene Proteins c-mdm2; D016315:Proto-Oncogene Proteins c-abl