title: Proto-oncogene activity of melanoma antigen-A11 (MAGE-A11) regulates retinoblastoma-related p107 and E2F1 proteins.
abstract: Melanoma antigen-A11 (MAGE-A11) is a low-abundance, primate-specific steroid receptor coregulator in normal tissues of the human reproductive tract that is expressed at higher levels in prostate cancer. Increased expression of MAGE-A11 enhances androgen receptor transcriptional activity and promotes prostate cancer cell growth. Further investigation into the mechanisms of MAGE-A11 function in prostate cancer demonstrated interactions with the retinoblastoma-related protein p107 and Rb tumor suppressor but no interaction with p130 of the Rb family. MAGE-A11 interaction with p107 was associated with transcriptional repression in cells with low MAGE-A11 and transcriptional activation in cells with higher MAGE-A11. Selective interaction of MAGE-A11 with retinoblastoma family members suggested the regulation of E2F transcription factors. MAGE-A11 stabilized p107 by inhibition of ubiquitination and linked p107 to hypophosphorylated E2F1 in association with the stabilization and activation of E2F1. The androgen receptor and MAGE-A11 modulated endogenous expression of the E2F1-regulated cyclin-dependent kinase inhibitor p27(Kip1). The ability of MAGE-A11 to increase E2F1 transcriptional activity was similar to the activity of adenovirus early oncoprotein E1A and depended on MAGE-A11 interactions with p107 and p300. The immunoreactivity of p107 and MAGE-A11 was greater in advanced prostate cancer than in benign prostate, and knockdown with small inhibitory RNA showed that p107 is a transcriptional activator in prostate cancer cells. These results suggest that MAGE-A11 is a proto-oncogene whose increased expression in prostate cancer reverses retinoblastoma-related protein p107 from a transcriptional repressor to a transcriptional activator of the androgen receptor and E2F1.
authors.affiliation: Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Su
authors.forename: John T
authors.initials: JT
authors.lastname: Minges
authors.forename: Gail
authors.initials: G
authors.lastname: Grossman
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Blackwelder
authors.forename: James L
authors.initials: JL
authors.lastname: Mohler
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Wilson
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055550:Protein Stability; D000090063:Proto-Oncogene Mas; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D017500:Adenovirus E1A Proteins; D000951:Antigens, Neoplasm; C436291:CDKN1B protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C110882:MAGEA11 protein, human; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; C493844:RBL1 protein, human; D011944:Receptors, Androgen; D050720:Retinoblastoma-Like Protein p107; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
keywords: Androgen Receptor; Cell Cycle Regulation; E2F Transcription Factor; Gene Transcription; MAGE-A11; Melanoma Antigen-A11; Prostate Cancer; Retinoblastoma (Rb); Steroid Receptor Coregulator; p107