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: Shifeng Su, John T Minges, Gail Grossman, Amanda J Blackwelder, James L Mohler, Elizabeth M Wilson
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 34 Pg. 24809-24 (Aug 23 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23853093 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adenovirus E1A Proteins
• Antigens, Neoplasm
• CDKN1B protein, human
• E2F1 Transcription Factor
• E2F1 protein, human
• MAGEA11 protein, human
• MAS1 protein, human
• Neoplasm Proteins
• Proto-Oncogene Mas
• RBL1 protein, human
• Receptors, Androgen
• Retinoblastoma-Like Protein p107
• Cyclin-Dependent Kinase Inhibitor p27
• E1A-Associated p300 Protein
• EP300 protein, human

Topics

• Adenovirus E1A Proteins (genetics, metabolism)
• Animals
• Antigens, Neoplasm (genetics, metabolism)
• COS Cells
• Chlorocebus aethiops
• Cyclin-Dependent Kinase Inhibitor p27 (genetics, metabolism)
• E1A-Associated p300 Protein (genetics, metabolism)
• E2F1 Transcription Factor (genetics, metabolism)
• HeLa Cells
• Humans
• Male
• Neoplasm Proteins (genetics, metabolism)
• Phosphorylation (genetics)
• Prostatic Neoplasms (genetics, metabolism, pathology)
• Protein Stability
• Proto-Oncogene Mas
• Receptors, Androgen (biosynthesis, genetics)
• Retinoblastoma-Like Protein p107 (genetics, metabolism)
• Transcription, Genetic