Post-translational Down-regulation of Melanoma Antigen-A11 (MAGE-A11) by Human p14-ARF Tumor Suppressor.
X-linked primate-specific melanoma antigen-A11 (MAGE-A11) is a human androgen receptor (AR) coactivator and proto-oncogene expressed at low levels in normal human reproductive tract tissues and at higher levels in castration-resistant prostate cancer where it is required for androgen-dependent cell growth. In this report, we show that MAGE-A11 is targeted for degradation by human p14-ARF, a tumor suppressor expressed from an alternative reading frame of the p16 cyclin-dependent kinase inhibitor INK4a/ARF gene. MAGE-A11 degradation by the proteasome was mediated by an interaction with p14-ARF and was independent of lysine ubiquitination. A dose-dependent inverse relationship between MAGE-A11 and p14-ARF correlated with p14-ARF inhibition of the MAGE-A11-induced increase in androgen-dependent AR transcriptional activity and constitutive activity of a splice variant-like AR. Reciprocal stabilization between MAGE-A11 and AR did not protect against degradation promoted by p14-ARF. p14-ARF prevented MAGE-A11 interaction with the E2F1 oncoprotein and inhibited the MAGE-A11-induced increase in E2F1 transcriptional activity. Post-translational down-regulation of MAGE-A11 promoted by p14-ARF was independent of HDM2, the human homologue of mouse double minute 2, an E3 ubiquitin ligase inhibited by p14-ARF. However, MAGE-A11 had a stabilizing effect on HDM2 in the absence or presence of p14-ARF and cooperated with HDM2 to increase E2F1 transcriptional activity in the absence of p14-ARF. We conclude that degradation of MAGE-A11 promoted by the human p14-ARF tumor suppressor contributes to low levels of MAGE-A11 in nontransformed cells and that higher levels of MAGE-A11 associated with low p14-ARF increase AR and E2F1 transcriptional activity and promote the development of castration-resistant prostate cancer.
From the Laboratories for Reproductive Biology, Department of Pediatrics.
John T
JT
Minges
From the Laboratories for Reproductive Biology, Department of Pediatrics.
Gail
G
Grossman
Lentivirus Core Facility.
Ping
P
Zhang
Lentivirus Core Facility, Lineberger Comprehensive Cancer Center, Gene Therapy Center, and Departments of Microbiology and Immunology and.
Tal
T
Kafri
From the Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599 emw@med.unc.edu.
Elizabeth M
EM
Wilson
D000951:Antigens, Neoplasm / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism*; D010641:Phenotype; D064129:Prostatic Neoplasms, Castration-Resistant / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D000090063:Proto-Oncogene Mas; D014158:Transcription, Genetic; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*
D000951:Antigens, Neoplasm; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C110882:MAGEA11 protein, human; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D000090063:Proto-Oncogene Mas; D025803:Tumor Suppressor Protein p14ARF; D046988:Proteasome Endopeptidase Complex
E2F transcription factor; androgen receptor; prostate cancer; transcriptional coactivator; tumor suppressor gene