Gene regulation and physiological function of placental leucine aminopeptidase/oxytocinase during pregnancy.
Human pregnancy serum and placenta have the ability to degrade uterotonic peptide oxytocin (OT). Placental leucine aminopeptidase (P-LAP), which is also called cystine aminopeptidase, is the only membrane aminopeptidase known to functionally degrade OT as oxytocinase (OTase). P-LAP/OTase hydrolyzes several peptides other than OT including vasopressin and angiotensin III. P-LAP/OTase predicted from cDNA sequence is a type II integral membrane protein, which is converted to a soluble form existing in maternal serum by metalloproteases, possibly ADAM (a disintegrin and metalloproteinase) members. P-LAP/OTase activity increases with normal gestation, while decreases in the patients with preterm delivery and severe preeclampsia. In placenta, P-LAP/OTase is predominantly expressed in differentiated trophoblasts, syncytiotrophoblasts. Activator protein-2 (AP-2) and Ikaros transcription factors play significant roles in exerting high promoter activity of P-LAP/OTase in the trophoblastic cells. Moreover, P-LAP/OTase is transcriptionally regulated in a trophoblast-differentiation-dependent fashion via up-regulation of AP-2, putatively AP-2alpha. P-LAP/OTase may be involved in maintaining pregnancy homeostasis via metabolizing peptides such as OT and vasopressin.
Nomura
Seiji
S
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine Nagoya, 466-8550, Japan. snomura@med.nagoya-u.ac.jp
Ito
Tomomi
T
Yamamoto
Eiko
E
Sumigama
Seiji
S
Iwase
Akira
A
Okada
Mayumi
M
Shibata
Kiyosumi
K
Ando
Hisao
H
Ino
Kazuhiko
K
Kikkawa
Fumitaka
F
Mizutani
Shigehiko
S
D010122:Cystinyl Aminopeptidase / Q000096:biosynthesis* / Q000097:blood / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D005333:Fetus / Q000201:enzymology; D005786:Gene Expression Regulation; D006801:Humans; D051740:Ikaros Transcription Factor; D007743:Labor, Obstetric / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D010121:Oxytocin / Q000378:metabolism*; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy / Q000502:physiology*; D011248:Pregnancy Complications / Q000201:enzymology; D017434:Protein Structure, Tertiary; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000502:physiology; D014327:Trophoblasts / Q000201:enzymology
D004268:DNA-Binding Proteins; C497239:IKZF1 protein, human; D008565:Membrane Proteins; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D051740:Ikaros Transcription Factor; D010121:Oxytocin; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase