title: Melanoma antigen-A11 regulates substrate-specificity of Skp2-mediated protein degradation.
abstract: Melanoma antigen-A11 (MAGE-A11) is a proto-oncogene involved in androgen receptor signaling and androgen-dependent cell growth. In this report we provide evidence that MAGE-A11 interacts with Skp2 (S phase kinase-associated protein), the substrate recognition protein of the Skp1-Cullin1-F-box E3 ubiquitin ligase, and with Skp2 binding protein, cyclin A. A similar cyclin A binding motif in MAGE-A11 and Skp2 was consistent with a competitive relationship between MAGE-A11 and Skp2 in binding cyclin A. Skp2 inhibited MAGE-A11 interaction with cyclin A. Differential effects of MAGE-A11 on Skp2-mediated protein degradation were also revealed. MAGE-A11 increased Skp2-mediated degradation of cyclin A and retinoblastoma-related protein p130. In contrast, MAGE-A11 decreased Skp2-mediated degradation of E2F1 and Skp2 self-ubiquitination. Stabilization of E2F1 by MAGE-A11 was associated with sequestration and inactivation of Skp2 through the formation of an E2F1-MAGE-A11-Skp2 complex. We conclude that direct interactions of MAGE-A11 with Skp2 and cyclin A regulate the substrate-specificity of Skp2-mediated protein degradation.
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Su
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Geng
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Minges
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Gail
authors.initials: G
authors.lastname: Grossman
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: emw@med.unc.edu.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wilson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D019925:Cyclin A / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016086:Lentivirus / Q000378:metabolism; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D054875:Ubiquitination
chemical_list: D000951:Antigens, Neoplasm; D019925:Cyclin A; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C110882:MAGEA11 protein, human; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D050717:Retinoblastoma-Like Protein p130; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: Androgen receptor; Cyclin A; E2F1; MAGE-A11; Melanoma antigen-A11; Skp2