Uterine serpin

Uterine serpins were originally described in the uterine secretions of unilaterally-pregnant sheep as a pair of 57 kDa and 55 kDa glycoproteins.{{cite journal |vauthors=Moffatt J, Bazer FW, Hansen PJ, Chun PW, Roberts RM |title=Purification, secretion and immunocytochemical localization of the uterine milk proteins, major progesterone-induced proteins in uterine secretions of the sheep |journal=Biol. Reprod. |volume=36 |issue=2 |pages=419–30 |date=March 1987 |pmid=3580461 |doi= 10.1095/biolreprod36.2.419|doi-access=free }} Termed uterine milk proteins, their identification as members of the serpin superfamily was based on sequencing of the cDNA for the sheep gene.{{cite journal |vauthors=Ing NH, Roberts RM |title=The major progesterone-modulated proteins secreted into the sheep uterus are members of the serpin superfamily of serine protease inhibitors |journal=J. Biol. Chem. |volume=264 |issue=6 |pages=3372–9 |date=February 1989 |doi=10.1016/S0021-9258(18)94076-7 |pmid=2464597 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2464597|doi-access=free }} The pig uterine serpin was first identified because of its association with an iron-binding uterine protein termed uteroferrin.{{cite encyclopedia | url = http://www.copewithcytokines.de/cope.cgi?key=Uteroferrin | title = Uteroferrin | author = Ibelgaufts H | date = 2002-01-01 | encyclopedia = Cytokines & Cells Encyclopedia - COPE | access-date = 2010-12-02 }}{{cite journal |vauthors=Baumbach GA, Ketcham CM, Richardson DE, Bazer FW, Roberts RM |title=Isolation and characterization of a high molecular weight stable pink form of uteroferrin from uterine secretions and allantoic fluid of pigs |journal=J. Biol. Chem. |volume=261 |issue=27 |pages=12869–78 |date=September 1986 |doi=10.1016/S0021-9258(18)67173-X |pmid=3017991 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=3017991|doi-access=free }} and was originally termed uteroferrin-associated protein.{{cite journal |vauthors=Malathy PV, Imakawa K, Simmen RC, Roberts RM |title=Molecular cloning of the uteroferrin-associated protein, a major progesterone-induced serpin secreted by the porcine uterus, and the expression of its mRNA during pregnancy |journal=Mol. Endocrinol. |volume=4 |issue=3 |pages=428–40 |date=March 1990 |pmid=2342477 |doi= 10.1210/mend-4-3-428|doi-access=free }}

The designation of uterine serpins as SERPINA14{{cite journal |vauthors=Padua MB, Kowalski AA, Cañas MY, Hansen PJ |title=The molecular phylogeny of uterine serpins and its relationship to evolution of placentation |journal=FASEB J. |volume=24 |issue=2 |pages=526–37 |date=February 2010 |pmid=19825977 |doi=10.1096/fj.09-138453 |doi-access=free |s2cid=9248169 }} is based on their classification as a highly-divergent group of the α1-antitrypsin or A clade.{{cite journal |vauthors=Irving JA, Pike RN, Lesk AM, Whisstock JC |title=Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function |journal=Genome Res. |volume=10 |issue=12 |pages=1845–64 |date=December 2000 |pmid=11116082 |doi= 10.1101/gr.GR-1478R|doi-access=free }} In other analyses, uterine serpins have been considered as a separate clade in the serpin superfamily.{{cite journal |vauthors=Peltier MR, Raley LC, Liberles DA, Benner SA, Hansen PJ |title=Evolutionary history of the uterine serpins |journal=J. Exp. Zool. |volume=288 |issue=2 |pages=165–74 |date=August 2000 |pmid=10931499 |doi = 10.1002/1097-010X(20000815)288:2<165::AID-JEZ7>3.0.CO;2-R|bibcode=2000JEZ...288..165P }}

The uterine serpins are novel with respect to other serpins by virtue of their limited distribution among mammals. They have been described only in species of the Laurasiatheria superorder of eutherian mammals. Among the clades in which uterine serpin genes exist are the Cetartiodactyla (dolphin, cow, water buffalo, sheep, goat, pig), Perissodactyla (horse) and some carnivores (dog, giant panda){{cite journal |vauthors=Padua MB, Hansen PJ |title=Evolution and function of the uterine serpins (SERPINA14) |journal=Am. J. Reprod. Immunol. |volume=64 |issue=4 |pages=265–74 |date=October 2010 |pmid=20678169 |doi=10.1111/j.1600-0897.2010.00901.x |doi-access=free }} The uterine serpin gene is not expressed in all carnivores since the only uterine serpin identified in the cat is a pseudogene. Examination of completed genomes indicates that uterine serpin genes do not exist in primates, mouse, rat, rabbit, marsupials, platypus, chicken or zebrafish.{{cite journal |vauthors=van Gent D, Sharp P, Morgan K, Kalsheker N |title=Serpins: structure, function and molecular evolution |journal=Int. J. Biochem. Cell Biol. |volume=35 |issue=11 |pages=1536–47 |date=November 2003 |pmid=12824063 |doi= 10.1016/S1357-2725(03)00134-1}}

Image:Uterine serpin localized to endometrial glands in the sheep uterus.jpg

Uterine serpins are products of the endometrial epithelium (Figure 1). Gene expression is limited to epithelial cells of endometrial glands.{{cite journal |vauthors=Stewart MD, Johnson GA, Gray CA, etal |title=Prolactin receptor and uterine milk protein expression in the ovine endometrium during the estrous cycle and pregnancy |journal=Biol. Reprod. |volume=62 |issue=6 |pages=1779–89 |date=June 2000 |pmid=10819783 |doi= 10.1095/biolreprod62.6.1779|doi-access=free }} Late in pregnancy, uterine serpin protein can be found in the lumenal epithelium as well,{{cite journal |vauthors=Stephenson DC, Leslie MV, Low BG, Newton GR, Hansen PJ, Bazer FW |title=Secretion of the major progesterone-induced proteins of the sheep uterus by caruncular and intercaruncular endometrium of the pregnant ewe from days 20-140 of gestation |journal=Domest. Anim. Endocrinol. |volume=6 |issue=4 |pages=349–62 |date=October 1989 |pmid=2620505 |doi= 10.1016/0739-7240(89)90029-5}} perhaps as glandular epithelial cells move to the uterine lumen.

The major regulator of uterine serpin gene expression is progesterone. In the cow, estrogen can also increase uterine serpin gene expression.{{cite journal |vauthors=Bauersachs S, Ulbrich SE, Gross K, etal |title=Gene expression profiling of bovine endometrium during the oestrous cycle: detection of molecular pathways involved in functional changes |journal=J. Mol. Endocrinol. |volume=34 |issue=3 |pages=889–908 |date=June 2005 |pmid=15956356 |doi=10.1677/jme.1.01799 |doi-access=free }}{{cite journal |vauthors=Ulbrich SE, Frohlich T, Schulke K, etal |title=Evidence for estrogen-dependent uterine serpin (SERPINA14) expression during estrus in the bovine endometrial glandular epithelium and lumen |journal=Biol. Reprod. |volume=81 |issue=4 |pages=795–805 |date=October 2009 |pmid=19494250 |doi=10.1095/biolreprod.108.075184 |url=http://www.biolreprod.org/cgi/pmidlookup?view=long&pmid=19494250|doi-access=free |url-access=subscription }}

In addition to expression in the endometrium, bovine uterine serpin is also expressed in the ovary (follicles, corpus luteum, and cumulus-oocyte complex) and by [http://www.vivo.colostate.edu/hbooks/pathphys/reprod/placenta/ruminants.html cotyledons] of the placenta.{{cite journal |vauthors=Khatib H, Schutzkus V, Chang YM, Rosa GJ |title=Pattern of expression of the uterine milk protein gene and its association with productive life in dairy cattle |journal=J. Dairy Sci. |volume=90 |issue=5 |pages=2427–33 |date=May 2007 |pmid=17430947 |doi=10.3168/jds.2006-722 |doi-access=free }}

There are two lines of evidence to indicate that uterine serpins do not function as protease inhibitors. Uterine serpins from the sheep and pig are not inhibitory towards a variety of proteases.{{cite journal |vauthors=Liu WJ, Hansen PJ |title=Progesterone-induced secretion of dipeptidyl peptidase-IV (cluster differentiation antigen-26) by the uterine endometrium of the ewe and cow that costimulates lymphocyte proliferation |journal=Endocrinology |volume=136 |issue=2 |pages=779–87 |date=February 1995 |pmid=7835310 |doi= 10.1210/endo.136.2.7835310}}{{cite journal |vauthors=Mathialagan N, Hansen TR |title=Pepsin-inhibitory activity of the uterine serpins |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue=24 |pages=13653–8 |date=November 1996 |pmid=8942989 |pmc=19381 |doi= 10.1073/pnas.93.24.13653|bibcode=1996PNAS...9313653M |doi-access=free }} In addition, several key amino acids in the hinge region of the reactive center loop which are important for protease inhibitory activity have not been conserved in uterine serpins. Bovine uterine serpin does inhibit pepsin but probably through a mechanism distinct from the prototypical mechanism used by serpins.

There are two possible biological roles for uterine serpins during pregnancy. The first is as a binding protein. Porcine uterine serpin binds non-covalently to uteroferrin in a way that stabilizes the iron-binding capacity of uteroferrin. Uteroferrin is transferred across the placenta where it gives up its iron to fetal transferrin.{{cite journal |vauthors=Buhi WC, Ducsay CA, Bazer FW, Roberts RM |title=Iron transfer between the purple phosphatase uteroferrin and transferrin and its possible role in iron metabolism of the fetal pig |journal=J. Biol. Chem. |volume=257 |issue=4 |pages=1712–23 |date=February 1982 |doi=10.1016/S0021-9258(19)68096-8 |pmid=7056739 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=7056739|doi-access=free }} Ovine uterine serpin binds pregnancy-associated glycoproteins, which are inactive aspartic proteases secreted in large amounts by the ungulate placenta.{{cite journal |vauthors=Green JA, Xie S, Roberts RM |title=Pepsin-related molecules secreted by trophoblast |journal=Rev. Reprod. |volume=3 |issue=1 |pages=62–9 |date=January 1998 |pmid=9509990 |doi= 10.1530/ror.0.0030062}} Ovine uterine serpin also binds to activin,{{cite journal |vauthors=McFarlane JR, Foulds LM, O'Connor AE, etal |title=Uterine milk protein, a novel activin-binding protein, is present in ovine allantoic fluid |journal=Endocrinology |volume=140 |issue=10 |pages=4745–52 |date=October 1999 |pmid=10499534 |doi= 10.1210/en.140.10.4745|doi-access=free }} IgM and IgA.{{cite journal |vauthors=Hansen PJ, Newton GR |title=Binding of immunoglobulins to the major progesterone-induced proteins secreted by the sheep uterus |journal=Arch. Biochem. Biophys. |volume=260 |issue=1 |pages=208–17 |date=January 1988 |pmid=3341741 |doi= 10.1016/0003-9861(88)90442-0}}

Another possible role for uterine serpins is in the inhibition of immune cell proliferation during pregnancy to provide protection for the allogeneically-distinct conceptus. In particular, sheep uterine serpin can inhibit lymphocyte and natural killer cell function in vitro and reduce natural-killer cell mediated abortion in a mouse model.{{cite journal |author=Hansen PJ |title=Regulation of uterine immune function by progesterone--lessons from the sheep |journal=J. Reprod. Immunol. |volume=40 |issue=1 |pages=63–79 |date=October 1998 |pmid=9862257 |doi= 10.1016/S0165-0378(98)00035-7}}

A single nucleotide polymorphism at position 1269 of the bovine uterine serpin gene has been associated with productive life{{cite web | url = http://www.extension.purdue.edu/dairy/genetics/nmerit.htm | title = Using Net Merit To Select Dairy Bulls | author = Schutz M | publisher = Purdue University | access-date = 2010-12-02 }} in cattle populations.

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• [http://www.animal.ufl.edu/hansen PJ Hansen Homepage]

{{Serpins}}

Category:Serine protease inhibitors

Category:Human pregnancy

Category:Fertility

Category:Hormones of the pregnant female

Category:Hormones of the ovary

Category:Uterus