Primate-specific melanoma antigen-A11 regulates isoform-specific human progesterone receptor-B transactivation.
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.
Laboratories for Reproductive Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Shifeng
S
Su
Amanda J
AJ
Blackwelder
Gail
G
Grossman
John T
JT
Minges
Lingwen
L
Yuan
Steven L
SL
Young
Elizabeth M
EM
Wilson
D000293:Adolescent; D000328:Adult; D020816:Amino Acid Motifs; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000502:physiology; D010064:Embryo Implantation / Q000502:physiology; D004717:Endometrium / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy / Q000502:physiology*; D055503:Protein Multimerization / Q000502:physiology; D017434:Protein Structure, Tertiary; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D022021:Tacrolimus Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics; D000099159:Tacrolimus Binding Protein 5
D000951:Antigens, Neoplasm; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D011980:Receptors, Progesterone; D022021:Tacrolimus Binding Proteins; D018631:ras Proteins; D000099159:Tacrolimus Binding Protein 5; C110882:MAGEA11 protein, human; C400132:RASD1 protein, human; C101118:progesterone receptor A; C097314:progesterone receptor B