Primate-specific Melanoma Antigen-A11 Regulates Isoform-specific Human Progesterone Receptor-B Transactivation

• Published in: The Journal of biological chemistry Vol. 287; no. 41; pp. 34809 - 34824
• Main Authors: Su, Shifeng, Blackwelder, Amanda J., Grossman, Gail, Minges, John T., Yuan, Lingwen, Young, Steven L., Wilson, Elizabeth M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05-10-2012; American Society for Biochemistry and Molecular Biology
• Subjects: Adolescent; Adult; Amino Acid Motifs; Animals; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Cancer-Testis Antigen; Cell Line, Tumor; Chlorocebus aethiops; COS Cells; Down-Regulation - physiology; Embryo Implantation - physiology; Endometrium - cytology; Endometrium - metabolism; Female; FKBP5; FKBP51; Gene Regulation; Human Endometrium; Humans; MAGE-11; MAGE-A11; Melanoma Antigen-A11; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Nuclear Receptors; p300; Pregnancy - physiology; Progesterone; Progesterone Receptor; Protein Multimerization - physiology; Protein Structure, Tertiary; ras Proteins - biosynthesis; ras Proteins - genetics; RASD1; Receptor Structure-Function; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; Response Elements - physiology; Steroid Hormone Receptor; Tacrolimus Binding Proteins - biosynthesis; Tacrolimus Binding Proteins - genetics; Transcriptional Activation - physiology; Up-Regulation - physiology; Melanoma Antigen-A11; Receptor Structure-Function; Steroid Hormone Receptor; MAGE-11; Gene Regulation; p300; Progesterone Receptor; RASD1; Human Endometrium; Progesterone; Cancer-Testis Antigen; FKBP51; Nuclear Receptors; FKBP5; MAGE-A11
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.372797

Progesterone acting through the progesterone receptor (PR) and its coregulators prepares the human endometrium for receptivity to embryo implantation and maintains pregnancy. The menstrual cycle-dependent expression of melanoma antigen-A11 (MAGE-11) in the mid-secretory human endometrium suggested a novel function in human PR signaling. Here we show that MAGE-11 is an isoform-specific coregulator responsible for the greater transcriptional activity of human PR-B relative to PR-A. PR was recruited to progesterone response regions of progesterone-regulated FK506-binding protein 5 (FKBP5) immunophilin and small Ras family G protein cell growth inhibitor RASD1 genes. Expression of MAGE-11 lentivirus shRNA in human endometrial Ishikawa cells expressing PR-B showed that MAGE-11 is required for isoform-specific PR-B up-regulation of FKBP5. In contrast, MAGE-11 was not required for progesterone up-regulation of RASD1 in endometrial cells expressing the PR-A/B heterodimer. Target gene specificity of PR-B depended on the synergistic actions of MAGE-11 and p300 mediated by the unique PR-B NH2-terminal 110LLXXVLXXLL119 motif that interacts with the MAGE-11 F-box region in a phosphorylation- and ubiquitinylation-dependent manner. A progesterone-dependent mechanism is proposed in which MAGE-11 and p300 increase PR-B up-regulation of the FKBP5 gene. MAGE-11 down-regulates PR-B, similar to the effects of progesterone, and interacts with FKBP5 to stabilize a complex with PR-B. We conclude that the coregulator function of MAGE-11 extends to isoform-specific regulation of PR-B during the cyclic development of the human endometrium.
Background: Progesterone regulates the cyclic function of the human endometrium through its receptors and coregulatory proteins.
Results: Primate-specific melanoma antigen-A11 (MAGE-11) interacts with the human progesterone receptor-B (PR-B) unique NH2-terminal region to coregulate progesterone-dependent gene activation.
Conclusion: MAGE-11 is an isoform-specific coregulator of human PR-B.
Significance: PR-B and progesterone regulation of human endometrium requires a primate-specific steroid receptor coregulator.