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

Shifeng Su,Amanda J Blackwelder,Gail Grossman,John T Minges,Lingwen Yuan,Steven L Young,Elizabeth M Wilson

doi:10.1074/jbc.m112.372797

Shifeng Su, Amanda J Blackwelder + Show 5 more

Open Access

https://doi.org/10.1074/jbc.m112.372797

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Abstract

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 NH(2)-terminal (110)LLXXVLXXLL(119) 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.

Highlights

Progesterone regulates the cyclic function of the human endometrium through its receptors and coregulatory proteins
melanoma antigen-A11 (MAGE-11) and FK506binding protein 5 (FKBP5) Increase in Early and Mid-secretory Endometrium—Human endometrium undergoes cyclic changes in response to progesterone in preparation for embryo implantation and pregnancy [1]
To investigate a function for MAGE-11 in progesterone-dependent gene regulation, the menstrual cycle-dependent expression of MAGE-11 was compared with progesterone-regulated immunophilin FKBP5 [31, 50]

Summary

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. The menstrual cycle-dependent expression of melanoma antigen-A11 (MAGE11) in the mid-secretory human endometrium suggested a novel function in human PR signaling. Androgens are known to influence human endometrial function [32,33,34], the regulated expression of MAGE-11 in the early and mid-secretory human endometrium during the menstrual cycle suggests that MAGE-11 may influence the activity of PR. The primate-specific expression of MAGE-11, the up-regulation of MAGE-11 in the secretory human endometrium, the close evolutionary relationship between AR and PR, and the importance of AR and PR-B NH2-terminal domains in transactivation all suggest that MAGE-11 could be an important coregulator of human PR-B. The studies suggest that synergy between MAGE-11 and p300 explains the greater transcriptional activity and gene specificity of PR-B relative to PR-A in humans

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