ADAMs, a disintegrin and metalloproteinases, mediate shedding of oxytocinase.
Placental leucine aminopeptidase (P-LAP), a type-II transmembrane protease responsible for oxytocin degradation during pregnancy, is converted to a soluble form through proteolytic cleavage. The goal of this study was to determine the nature of the P-LAP secretase activity. The hydroxamic acid-based metalloprotease inhibitors GM6001 and ONO-4817 as well as the TNF-alpha protease inhibitor-2 (TAPI-2) reduced P-LAP release, while tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2, which are matrix metalloproteinase inhibitors, had no effect on P-LAP release in Chinese hamster ovary (CHO) cells stably overexpressing P-LAP, thus indicating possible involvement of ADAM (a disintegrin and metalloproteinase) members in P-LAP shedding. Furthermore, overexpression of ADAM9 and ADAM12 increased P-LAP release in P-LAP-CHO transfectants. Immunohistochemical analysis in human placenta demonstrated strong expression of ADAM12 in syncytiotrophoblasts, while little expression of ADAM9 was detected throughout the placenta. Our results suggest ADAM members, at least including ADAM12, are involved in P-LAP shedding in human placenta.
Ito
Norio
N
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, 466-8550, Nagoya, Japan.
Nomura
Seiji
S
Iwase
Akira
A
Ito
Tomomi
T
Kikkawa
Fumitaka
F
Tsujimoto
Masafumi
M
Ishiura
Shoichi
S
Mizutani
Shigehiko
S
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D010122:Cystinyl Aminopeptidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology
D011480:Protease Inhibitors; D045726:Metalloproteases; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase