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Biology of Reproduction 62, 1772-1778 (2000)
© 2000 Society for the Study of Reproduction, Inc.

Articles

Keratinocyte Growth Factor: Expression by Endometrial Epithelia of the Porcine Uterus

Hakhyun Kaa, Thomas E. Spencera, Greg A. Johnsona, and Fuller W. Bazer1,a

a Center for Animal Biotechnology and Genomics, Institute of Biosciences and Technology, Texas A&M University System Health Science Center and Department of Animal Science, Texas A&M University, College Station, Texas 77843-2471


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Keratinocyte growth factor/fibroblast growth factor-7 (KGF/FGF-7) is an established paracrine mediator of hormone-regulated epithelial growth and differentiation. In all organs studied, KGF is uniquely expressed in cells of mesenchymal origin. To determine whether KGF and its receptor, keratinocyte growth factor receptor (KGFR) or fibroblast growth factor receptor-2IIIb, were expressed in the porcine uterus as a potential paracrine system mediating progesterone action, we cloned KGF and KGFR partial cDNAs from the porcine endometrium. KGF and KGFR expression was detected in endometrium by Northern blot hybridization. Interestingly, in situ hybridization results demonstrated that KGF was expressed by endometrial epithelia and was particularly abundant between Days 12 and 15 of the estrous cycle and pregnancy. KGF secretion into the lumen of the porcine uterus was also detected on Day 12 of the estrous cycle and pregnancy. KGFR was expressed in both endometrial epithelia and conceptus trophectoderm. These novel findings suggest that KGF may act on the uterine endometrial epithelium in an autocrine manner and on the conceptus trophectoderm in a paracrine manner in the pig, which is the only species possessing a true epitheliochorial type of placentation.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Epithelial-mesenchymal interactions (EMI) play important roles in organ morphogenesis and differentiated function [1–3]. In the uterus, EMI are crucial for maintaining hormonal responsiveness and conceptus (embryo and associated placental membranes) growth and development [4]. The ovarian hormones, estrogen and progesterone, are primary regulators of mammalian uterine function. Progesterone from the corpus luteum is an essential and universal requirement for establishment and maintenance of pregnancy. At estrus, progesterone receptors (PR) are expressed in all uterine cell types; however, progesterone negatively autoregulates expression of its own receptor, particularly in the endometrial luminal (LE) and glandular epithelium (GE). In all mammals studied, PR expression in LE declines to undetectable levels before implantation [5–7]. In the pig, PR expression after Day 11 to 12 of the estrous cycle and pregnancy can be detected only in the deeper endometrial GE, stroma, and myometrium [5]. This event coincides with maternal recognition of pregnancy and the initiation of superficial implantation [8]. However, the actions of progesterone on the uterus are required throughout pregnancy in all mammals. Thus, PR in uterine stromal cells appears to mediate effects of progesterone on the endometrial epithelium during pregnancy.

Currently, keratinocyte growth factor (KGF), fibroblast growth factor-10 (FGF-10), and hepatocyte growth factor are the only known growth factors secreted by stromal cells that act on epithelial cells via a paracrine mechanism [9–11]. KGF is a member of the FGF family with a distinctive pattern of target cell specificity [9, 12]. Unlike other members of this family, KGF is produced by cells of mesenchymal origin of various tissues, including reproductive organs such as the ovary [13], prostate [14], and uterus [15]. In these tissues, KGF functions in mesenchymal induction of epithelial growth as a stromal-derived paracrine regulator of epithelial proliferation. In the prostate [14] and uterus [16], KGF is considered an andromedin and a progestamedin, respectively. A protective role of KGF to block apoptosis and to prevent oxidative damage has also been suggested for alveolar epithelial cells, hepatocytes, and keratinocytes [17–20].

The KGFR is an alternative splicing product of the bek gene, which encodes FGF receptor 2 (FGFR2) and KGFR [21]. The difference between KGFR and FGFR2 is in the carboxy-terminal half of the third immunoglobulin domain (Ig III). The KGFR has an Ig IIIb domain, while FGFR2 has an Ig IIIc domain as a result of alternative splicing of the bek gene [21]. These domains are responsible for ligand-binding specificity. KGFR can bind KGF and acidic FGF with high affinity, and basic FGF with low affinity, whereas FGFR2 can bind acidic and basic FGF with high affinity but does not bind KGF [22–24]. KGFR can also bind FGF-10 with high affinity [25]. The KGFR expression is restricted to epithelial cells in the skin [26], prostate [14], and uterus [15]. KGF and KGFR expression in the uterus of several species has been reported, but KGF and KGFR expression and their function(s) have not been determined in porcine uterus. This study tested the hypothesis that KGF of mesenchymal origin mediates EMI through KGFR in epithelial cells in porcine endometrium.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals and Tissue Collection

Sexually mature crossbred female pigs (gilts) were assigned randomly to either cyclic or pregnant status. Forty-eight gilts were hysterectomized on either Days 9, 12, or 15 of the estrous cycle and Days 9, 10, 12, 13, 14, 15, 20, 25, 30, 35, 40, 60, or 85 of pregnancy (n = 3 gilts per day). Uterine flushings from Days 9, 12, and 15 of the estrous cycle and pregnancy were obtained by introducing and recovering 40 ml sterile saline at hysterectomy. The flushings were clarified by centrifugation (3000 x g for 10 min at 4°C), aliquoted, and frozen at -80°C until analyzed. Tissue samples for paraffin sections and RNA extraction were prepared as described previously [6]. All experimental and surgical procedures involving animals were approved by the agricultural animal care and use committee of Texas A&M University (Animal Use Protocol 7-127).

KGF and KGFR cDNA Cloning

A porcine KGF cDNA of 690 base pairs (bp) was amplified using the polymerase chain reaction (PCR) with primers to a rat KGF cDNA sequence (GenBank accession no. X56551; forward, 5'-AATCTACAATTCACAGATAGGA; reverse, 5'TTAAGTTATT GCCATAGGAAGAAAGTG) and a reverse-transcribed template from Day 12 pregnant porcine endometrial total RNA and cloned into the pCR II vector (Invitrogen, Carlsbad, CA). A KGFR cDNA of 104 bp was amplified using PCR with primers to a human KGFR cDNA sequence containing KGFR-specific exon K (GenBank accession no. M80637; forward, 5'-TCTGTTCAATGTGACCGAGG; reverse, 5'-GTTTTGGCA GGACAGTGAGC) and cloned into the pCR II vector.

RNA Isolation and Analysis

Total cellular RNA was isolated from endometrial tissue samples using Trizol reagent (Gibco-BRL, Grand Island, NY), and polyadenylated mRNA was extracted from endometrial tissues using Poly(A)Pure kit (Ambion, Austin, TX), according to the manufacturer's directions. Northern blot hybridization analyses were performed as described previously [27] to determine the size of KGF and KGFR transcripts using radiolabeled antisense cRNA probes generated against a linearized 690-bp KGF partial cDNA or a 104-bp KGFR partial cDNA. Twenty micrograms of endometrial total cellular RNA for KGF and 1 microgram polyadenylated mRNA for KGFR from cyclic and pregnant gilts were used. Steady-state levels of KGF mRNA were assessed in endometrial total RNA samples through slot-blot hybridization analysis as described previously [27] using 20 µg of endometrial total RNA and an antisense KGF cRNA probe. The radioactivity in each slot was quantitated using a Packard Instant Imager (Packard, Meriden, CT) and expressed as total counts. The location of KGF and KGFR expression in uterine tissue sections and conceptuses was determined by in situ hybridization analysis as described previously [27]. Deparaffinized, rehydrated, and deproteinated uterine tissues (5–6 µm) were hybridized with 35S-radiolabeled sense and anti-sense cRNA probes for KGF and KGFR. Autoradiography was accomplished using Kodak NTB-2 liquid photographic emulsion (Eastman Kodak, Rochester, NY). Slides were stored at 4°C for 1 wk for KGF and 4 wk for KGFR, developed in Kodak D-19 developer, and counterstained with hematoxylin (Fisher Scientific, Fairlawn, NJ). Photomicrographs of brightfield and darkfield images were captured using a Zeiss Axioplan 2 photomicroscope (Carl Zeiss, New York, NY) fitted with a Hamamatsu chilled 3CCD color camera (Hamamatsu, Bridgewater, NJ).

Western Blot Analysis of KGF Protein in Uterine Flushes

KGF was purified from 1 mg total protein from each uterine flushing by incubating with 200 µl of heparin-beaded agarose (Sigma, St. Louis, MO) at 4°C overnight. Proteins bound to heparin-beaded agarose were denatured in Laemmli buffer and immunoblotted with either goat polyclonal antibodies against human KGF synthetic peptide (Santa Cruz Biotechnology, Santa Cruz, CA) or normal goat IgG (Sigma), followed by rabbit anti-goat IgG conjugated to peroxidase (KPL, Bethesda, MD) and chemiluminescence detection (Amersham Pharmacia Biotech, Piscataway, NJ). To show the specificity of immunostaining, goat anti-hKGF IgG was neutralized with 5- and 10-fold (by weight) excess blocking peptide (Santa Cruz Biotechnology) using uterine flushing from Day 12 of pregnancy for Western blotting.

Statistical Analysis

Slot-blot hybridization data were subjected to least squares ANOVA using the General Linear Models procedures of SAS [28]. The model included day, pregnancy status (cyclic or pregnant), and their interaction as sources of variation. Data were adjusted for differences in sample loading using the 18S rRNA data as a covariate in ANOVA. Data are presented as least square means with SE.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
To determine whether KGF is expressed by porcine uterine endometrium, we cloned a 690-bp partial cDNA (GenBank accession no. AF217463) by reverse transcription-polymerase chain reaction (RT-PCR). This partial KGF cDNA detected a single 2.4-kilobase (kb) mRNA transcript, which is similar to that in the human [12], in total endometrial RNA from cyclic and pregnant pigs (Fig. 1A). The KGFR transcript of about 4.5 kb, similar in size to that in the human [29], was also detected in endometrium by Northern blot hybridization using polyadenylated endometrial mRNA and a 104-bp partial KGFR cDNA cloned by RT-PCR (Fig. 1B).



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  		FIG. 1. Northern blot analysis of KGF (A) and KGFR (B) mRNA expression in porcine endometrium. Twenty micrograms of total RNA for KGF and 1 microgram of poly(A)+ mRNA for KGFR were hybridized using a 32P-labeled antisense porcine KGF and KGFR cRNA probe, respectively. Positions of the 28S (4.7 kb) and 18S (1.8 kb) rRNA are indicated. D, Day; C, estrous cycle; P, pregnancy

Changes in endometrial expression of KGF mRNA during the estrous cycle and pregnancy were determined by slot-blot hybridization analysis (Fig. 2). KGF expression was undetectable on Day 9 of the estrous cycle, but was present on Day 12 and highest on Day 15. During pregnancy, low levels of KGF mRNA were detected on Day 9, but had increased dramatically by Day 12. Although endometrial mRNA levels were lower thereafter, KGF mRNA expression was detected throughout pregnancy. Steady-state levels of KGF mRNA expression on Day 12 of pregnancy were about 3-fold greater than on Day 12 of the estrous cycle (day x status, P < 0.05).



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  		FIG. 2. Steady-state levels of KGF mRNA in porcine cyclic and pregnant endometrium. Twenty micrograms of total RNA from each gilt was hybridized with a 32P-labeled antisense porcine KGF cRNA probe. KGF mRNA levels, expressed as total counts with SE, were highest on Day 12 in pregnant gilts and Day 15 in cyclic gilts, and greater on Day 12 of pregnancy than on Day 12 of the estrous cycle (day x status, P < 0.05)

In situ hybridization revealed that KGF mRNA was expressed predominantly in epithelial cells (Fig. 3). Abundant levels of KGF mRNA were detected in LE between Days 12 and 15 of the estrous cycle and pregnancy. KGF mRNA was then low in endometrium between Days 30 and 40 of pregnancy, before increasing in GE on Days 60 and 85 of pregnancy (term: 114 days). Using a partial porcine KGFR cDNA, KGFR mRNA expression was detected in endometrial epithelia, particularly LE (Fig. 4A). KGFR expression in fetal skin, as a positive control, was detected in epidermis, particularly the basal layer, as expected. Trophectoderm of conceptuses also expressed KGFR, but not KGF (Fig. 4B).



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  		FIG. 3. In situ hybridization analysis of KGF and KGFR mRNA in porcine endometrium. KGF was expressed by LE during the estrous cycle and early pregnancy and GE on Days (D) 60 and 85. KGF expression was not detected in trophectoderm (TE) and stroma (ST). In fetal skin, a positive control, KGF was expressed by dermis (Der), but not epidermis (Epi) as expected. The white line at the surface of the epidermis is a result of keratinized cells that nonspecifically reflected light under darkfield microscopy. Representative uterine section from Day 12 of pregnancy, hybridized with radiolabeled sense KGF cRNA probe (Sense) as a negative control, is shown. C, Estrous cycle; P, pregnancy. Original magnification x260



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  		FIG. 4. In situ hybridization analysis of KGFR mRNA expression in porcine endometrium (A) and KGF and KGFR mRNA expression in porcine conceptus (B). KGFR was expressed only by LE and GE during the estrous cycle and pregnancy. KGF was not expressed by trophectoderm of conceptuses between Days 9 and 15 of pregnancy, but KGFR was expressed by trophectoderm of conceptuses between Days 9 and 15 of pregnancy. Representative uterine or conceptus sections from Day 12 of pregnancy, hybridized with radiolabeled sense KGF and KGFR cRNA probes (Sense) as a negative control, are shown. Original magnification x260

To test whether KGF protein was secreted into the uterine lumen, KGF was affinity purified from uterine flushings using heparin beads, and KGF protein was detected by Western blot analysis (Fig. 5A). An immunoreactive KGF-like protein of about 25 kDa, similar in size to human KGF [30], was detected only in uterine flushings collected on Day 12 of both the estrous cycle and pregnancy. Detection of this KGF band was blocked by pretreatment with KGF blocking peptide (Fig. 5B). Although KGF mRNA expression was high until Day 15 of the estrous cycle and pregnancy, KGF was detectable only in uterine flushings from Day 12.



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  		FIG. 5. (A) Detection of KGF in porcine uterine flushings from Days (D) 9, 12, and 15 of the estrous cycle (C) and pregnancy (P). Each lane represents analysis of uterine flushings from different gilts. Immunoreactive proteins were detected using either polyclonal goat anti-human KGF IgG (Goat anti-hKGF) or goat immunoglobulin (Goat IgG). Positions of prestained molecular mass standards (kDa) are indicated. Immunoreactive KGF was detected in uterine flushings from both cyclic and pregnant gilts, but only on Day 12. (B) Neutralization of anti-hKGF IgG with 5- and 10-fold (by weight) excess blocking peptide, using uterine flushing from Day 12 of pregnancy. Detection of the KGF band was blocked, but the nonspecific bands were unaffected by pretreatment with blocking peptide


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This is the first report of KGF gene expression in the epithelial component of any epitheliomesenchymal organ or tissue. This pattern of expression of KGF mRNA in porcine endometrial epithelia is novel, since KGF has previously been found exclusively in the mesenchymal component of every epitheliomesenchymal organ [9]. Before this study, we hypothesized that KGF was expressed by stromal cells to mediate progesterone actions on LE during the estrous cycle and pregnancy in porcine uterine endometrium, because KGF was reported to be expressed exclusively by cells of mesenchymal origin and to act only on epithelia that express KGFR [12, 14, 30]. This finding may relate to the unique type of placentation in the pig, which is the only species known to have a true epitheliochorial type of placentation. Since stromal cells of mesenchymal origin lack KGF expression during the estrous cycle and pregnancy, KGF may not be considered a stromal cell-derived progestamedin that affects LE and GE in porcine endometrium. The pregnancy-specific amplification of KGF mRNA during pregnancy recognition may be in response to estrogen and/or interleukin-1ß (IL-1ß) secreted by the conceptus [31, 32]. IL-1ß is known to stimulate KGF expression in fibroblasts [33, 34]. In addition to estrogen and IL-1ß, androgens in uterine secretions may increase KGF expression in LE, since concentrations of androgens in the uterine lumen of pigs between Days 9 and 15 of pregnancy are very high and much higher than for nonpregnant gilts [35]. The KGF promoter region is androgen responsive [36], and androgen receptors are present in endometrial epithelia of primates [37, 38]. Treatment of ovariectomized monkeys with estradiol and testosterone or estradiol and progesterone increased androgen receptors in endometrial epithelial and stromal cells [37]. The increase in KGF expression during the estrous cycle and early pregnancy coincides with the decline and absence of detectable PR in LE [5–7]. Thus, it is also possible that down-regulation of PR by progesterone up-regulates KGF expression. Detailed mechanisms for regulation of epithelial expression of KGF in pigs remain to be determined.

The in situ hybridization results in porcine endometrium and conceptuses suggest that KGF has the potential to act on the LE in an autocrine manner and on the trophectoderm of conceptuses in a paracrine manner. KGFR on LE may bind FGF-10, which is also a ligand for KGFR [25]. FGF-10 expression has been detected in porcine uterine endometrium by RT-PCR between Days 12 and 15 of pregnancy, but the specific uterine cell types expressing FGF-10 have not been determined (unpublished results). Recent results from our laboratory indicated that both KGF and FGF-10 are expressed in the ovine uterus, but by different cell types, suggesting their independent roles in ovine uterine function [39].

The secretory activity of porcine endometrium increases rapidly after Day 30 of pregnancy and is maximal between Days 60 and 75 of pregnancy [40]. The increase in KGF expression in GE between Days 60 and 85 of pregnancy suggests that this change may be related to progesterone level, because it is the main regulator of secretory activity during this period. KGF may affect GE secretory function, but mechanisms for the regulation and function of KGF during this period remain to be determined.

An immunoreactive KGF-like protein was detected in uterine flushings by Western blotting, but only on Day 12 of the estrous cycle and pregnancy. This may result from very low levels of KGF secretion after Day 12 of the estrous cycle and pregnancy. Biological activity of KGF secreted into uterine lumen on Day 12 may be regulated by heparan sulfate proteoglycan present on the apical surfaces of the trophectoderm and endometrium [41, 42]. Heparan sulfate proteoglycan appears to maintain the stability and half-life of FGFs, sequester FGFs to regulate receptor binding, and/or present FGFs to their receptors [43].

Potential functions of KGF in porcine endometrium include regulation of differentiation and/or proliferation of conceptus trophectoderm. For example, transforming growth factor {alpha} (TGF-{alpha}) expression is increased by KGF in cultured keratinocytes [44], and TGF-{alpha} is important for preimplantation conceptus development in many species [45–47]. KGF may also induce functional and morphological changes in endometrial epithelial cells by an autocrine mechanism. KGF may regulate extracellular matrix of trophoblast and/or epithelial cells of endometrium, such as syndecan-1 [48], which is found on the surface of epithelial cells and fibroblasts and contains heparan sulfate and chondroitin sulfate. KGF may also protect uterine epithelial cells and trophectoderm from apoptosis and oxidative stress, as shown for several other epithelial cells [17–20, 49]. However, the mechanisms of KGF action in the porcine uterus and conceptus remain to be determined.

In summary, our novel findings indicate that KGF is expressed by porcine endometrial LE and GE and may play a crucial role in epithelial-epithelial interactions between conceptus and uterus during early pregnancy, rather than mediating its effects through classical EMI.


   FOOTNOTES
 
First decision: 30 November 1999.

1 Correspondence: Fuller W. Bazer, Department of Animal Science and Center for Animal Biotechnology and Genomics, 442D Kleberg Center, Texas A&M University, College Station, TX 77843-2471. FAX: 409 862 2662; fbazer{at}cvm.tamu.edu Back

Accepted: January 14, 2000.

Received: October 27, 1999.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Cunha GR, Donjacour AA, Cooke PS, Mee S, Bigsby RM, Higgins SJ, Sugimura Y. The endocrinology and developmental biology of the prostate. Endocr Rev 1987; 8:338–362.[Medline]
  2. Cunha GR. Role of mesenchymal-epithelial interactions in normal and abnormal development of the mammary gland and prostate. Cancer 1994; 74:1030–1044.[CrossRef][Medline]
  3. Warburton D, Zhao J, Berberich MA, Bernfield M. Molecular embryology of the lung: then, now, and in the future. Am J Physiol 1999; 276:L697-L704.
  4. Cooke PS, Buchanan DL, Kurita T, Lubahn DB, Cunha GR. Stromal-epithelial cell communication in the female reproductive tract. In: Bazer FW (ed.), The Endocrinology of Pregnancy. Chapter 17. Totowa, NJ: Humana Press Inc.; 1998: 491–506.
  5. Geisert RD, Pratt TN, Bazer FW, Mayes JS, Watson GH. Immunocytochemical localization and changes in endometrial progestin receptor protein during the porcine oestrous cycle and early pregnancy. Reprod Fertil Dev 1994; 6:749–760.[CrossRef][Medline]
  6. Spencer TE, Bazer FW. Temporal and spatial alterations in uterine estrogen receptor and progesterone receptor gene expression during the estrous cycle and early pregnancy in the ewe. Biol Reprod 1995; 53:1527–1543.[Abstract]
  7. Brenner RM, West NB, McClellan MC. Estrogen and progestin receptors in the reproductive tract of male and female primates. Biol Reprod 1990; 42:11–19.[Abstract]
  8. Bazer FW, Spencer TE, Ott TL. Placental interferons. Am J Reprod Immunol 1996; 35:297–308.
  9. Rubin JS, Bottaro DP, Chedid M, Miki T, Ron D, Cheon HG, Taylor WG, Fortney E, Sakata H, Finch PW, LaRochelle WJ. Keratinocyte growth factor. Cell Biol Int 1995; 19:399–411.[CrossRef][Medline]
  10. Beer HD, Florence C, Dammeier J, McGuire L, Werner S, Duan DR. Mouse fibroblast growth factor 10: cDNA cloning, protein characterization, and regulation of mRNA expression. Oncogene 1997; 15:2211–2218.[CrossRef][Medline]
  11. Zarnegar R, Michalopoulos GK. The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J Cell Biol 1995; 129:1177–1180.[Free Full Text]
  12. Finch PW, Rubin JS, Miki T, Ron D, Aaronson SA. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science 1989; 245:752–755.[Abstract/Free Full Text]
  13. Parrott JA, Skinner MK. Developmental and hormonal regulation of keratinocyte growth factor expression and action in the ovarian follicle. Endocrinology 1998; 139:228–235.[Abstract/Free Full Text]
  14. Yan G, Fukabori Y, Nikolaropoulos S, Wang F, McKeehan WL. Heparin-binding keratinocyte growth factor is a candidate stromal to epithelial cell andromedin. Mol Endocrinol 1992; 6:2123–2128.[Abstract]
  15. Pekonen F, Nyman T, Rutanen E-M. Differential expression of keratinocyte growth factor and its receptor in the human uterus. Mol Cell Endocrinol 1993; 95:43–49.[CrossRef][Medline]
  16. Koji T, Chedid M, Rubin JS, Slayden OD, Csaky KG, Aaronson SA, Brenner RM. Progesterone-dependent expression of keratinocyte growth factor mRNA in stromal cells of the primate endometrium: keratinocyte growth factor as a progestomedin. J Cell Biol 1994; 125:393–401.[Abstract/Free Full Text]
  17. Hines MD, Allen-Hoffmann BL. Keratinocyte growth factor inhibits cross-linked envelope formation and nucleosomal fragmentation in cultured human keratinocytes. J Biol Chem 1996; 271:6245–6251.[Abstract/Free Full Text]
  18. Buckley S, Barsky L, Driscoll B, Weinberg K, Anderson KD, Warburton D. Apoptosis and DNA damage in type 2 alveolar epithelial cells cultured from hyperoxic rats. Am J Physiol 1998; 274:L714-L720.
  19. Senaldi G, Shaklee CL, Simon B, Rowan CG, Lacey DL, Hartung T. Keratinocyte growth factor protects murine hepatocytes from tumor necrosis factor-induced apoptosis in vivo and in vitro. Hepatology 1998; 27:1584–1591.[CrossRef][Medline]
  20. Panos RJ, Bak PM, Simonet WS, Rubin JS, Smith LJ. Intratracheal instillation of keratinocyte growth factor decreases hyperoxia-induces mortality in rats. J Clin Invest 1995; 96:2026–2033.
  21. Miki T, Bottaro DP, Fleming TP, Smith CL, Burgess WH, Chan AML, Aaronson SA. Determination ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. Proc Natl Acad Sci USA 1992; 89:246–250.[Abstract/Free Full Text]
  22. Bottaro DP, Rubin JS, Ron D, Finch PW, Florio C, Aaronson SA. Characterization of the receptor for keratinocyte growth factor. Evidence for multiple fibroblast growth factor receptors. J Biol Chem 1990; 265:12767–12770.[Abstract/Free Full Text]
  23. Dionne CA, Jaye M, Schlessinger J. Structural diversity and binding of FGF receptors. Ann NY Acad Sci 1991; 638:161–166.[Medline]
  24. Miki T, Fleming TP, Bottaro DP, Rubin JS, Ron D, Aaronson SA. Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop. Science 1991; 251:72–75.[Abstract/Free Full Text]
  25. Igarashi M, Finch PW, Aaronson SA. Characterization of recombinant human fibroblast growth factor (FGF)-10 reveals functional similarities with keratinocyte growth factor (FGF-7). J Biol Chem 1998; 273:13230–13235.[Abstract/Free Full Text]
  26. Marchese C, Chedid M, Dirsch OR, Csaky KG, Santanelli F, Latini C, LaRochelle WJ, Torrisi MR, Aaronson SA. Modulation of keratinocyte growth factor and its receptor in reepithelializing human skin. J Exp Med 1995; 182:1369–1376.[Abstract/Free Full Text]
  27. Spencer TE, Ing NH, Ott TL, Mayes JS, Becker WC, Watson GH, Mirando MA, Bazer FW. Intrauterine injection of ovine interferon-{tau} alters oestrogen receptor and oxytocin receptor expression in the endometrium of cyclic ewes. J Mol Endocrinol 1995; 15:203–220.[Abstract]
  28. SAS Institute. SAS User's Guide: Statistics, Version 6. Cary, NC: Statistical Analysis System Institute, Inc.; 1990.
  29. Hattori Y, Odagiri H, Nakatani H, Miyagawa K, Naito K, Sakamoto K, Katoh O, Yoshida T, Sugimura T, Terada M. K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes. Proc Natl Acad Sci USA 1990; 87:5983–5987.[Abstract/Free Full Text]
  30. Rubin JS, Osada H, Finch PW, Taylor WG, Rudikoff S, Aaronson SA. Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci USA 1989; 86:802–806.[Abstract/Free Full Text]
  31. Geisert RD, Renegar RH, Thatcher WW, Roberts RM, Bazer FW. Establishment of pregnancy in the pig: I. Interrelationships between preimplantation development of the pig blastocyst and uterine endometrial secretions. Biol Reprod 1982; 27:925–939.[CrossRef][Medline]
  32. Tuo W, Harney JP, Bazer FW. Developmentally regulated expression of interleukin-1ß by peri-implantation conceptuses in swine. J Reprod Immunol 1996; 31:185–198.[CrossRef][Medline]
  33. Chedid M, Rubin JS, Csaky KG, Aaronson SA. Regulation of keratinocyte growth factor gene expression by interleukin 1. J Biol Chem 1994; 269:10753–10757.[Abstract/Free Full Text]
  34. Li D-Q, Tseng SCG. Differential regulation of keratinocyte growth factor and hepatocyte growth factor/scatter factor by different cytokines in human corneal and limbal fibroblasts. J Cell Physiol 1997; 172:361–372.[CrossRef][Medline]
  35. Stone BA, Seamark RF. Steroid hormones in uterine washings and in plasma of gilts between days 9 and 15 after oestrous and between days 9 and 15 after coitus. J Reprod Fertil 1985; 75:209–221.[Abstract]
  36. Fasciana C, van der Made AC, Faber PW, Trapman J. Androgen regulation of the rat keratinocyte growth factor (KGF/FGF7) promoter. Biochem Biophys Res Commun 1996; 220:858–863.[CrossRef][Medline]
  37. Adesanya-Famuyiwa OO, Zhou J, Wu G, Bondy C. Localization and sex steroid regulation of androgen receptor gene expression in rhesus monkey uterus. Obstet Gynecol 1999; 93:265–270.[Abstract/Free Full Text]
  38. Hackenberg R, Schulz KD. Androgen receptor mediated growth control of breast cancer and endometrial cancer modulated by antiandrogen- and androgen-like steroids. J Steroid Biochem Mol Biol 1996; 56:113–117.[CrossRef][Medline]
  39. Chen C, Spencer TE, Bazer FW. Identification of stromal mediators of epithelial function in the ovine uterus. Biol Reprod 1999; 60(suppl 1):204 (abstract 358).
  40. Roberts RM, Bazer FW. The functions of uterine secretions. J Reprod Fertil 1988; 82:875–892.[Abstract]
  41. Carson DD, DeSouza MM, Regisford EGC. Mucin and proteoglycan functions in embryo implantation. Bioessays 1998; 20:577–583.[CrossRef][Medline]
  42. Carson DD, Tang JP, Julian J, Glasser SR. Vectorial secretion of proteoglycans by polarized rat uterine epithelial cells. J Cell Biol 1988; 107:2425–2435.[Abstract/Free Full Text]
  43. McKeehan WL, Wang F, Kan M. The heparan sulfate-fibroblast growth factor family: diversity of structure and function. Prog Nucleic Acid Res Mol Biol 1998; 59:135–176.[Medline]
  44. Dlugosz AA, Cheng C, Denning MF, Dempsey PJ, Coffey RJ, Yuspa SH. Keratinocyte growth factor receptor ligands induce transforming growth factor {alpha} expression and activate the epidermal growth factor receptor signaling pathway in cultured epidermal keratinocytes. Cell Growth Differ 1994; 5:1283–1292.[Abstract]
  45. Vaughan TJ, James PS, Pascall JC, Brown KD. Expression of the genes for TGF alpha, EGF and the EGF receptor during early pig development. Development 1992; 116:663–669.[Abstract]
  46. Chia CM, Winston RML, Handyside AH. EGF, TGF-{alpha} and EGFR expression in human preimplantation embryos. Development 1995; 121:299–307.[Abstract]
  47. Rappolee DA, Brenner CA, Schultz R, Mark D, Werb Z. Developmental expression of PDGF, TGF-alpha, and TGF-beta genes in preimplantation mouse embryos. Science 1988; 241:1823–1825.[Abstract/Free Full Text]
  48. Maatta A, Jaakkola P, Jalkanen M. Extracellular matrix-dependent activation of syndecan-1 expression in keratinocyte growth factor-treated keratinocytes. J Biol Chem 1999; 274:9891–9898.[Abstract/Free Full Text]
  49. Munz B, Frank S, Hubner G, Olson E, Werner S. A novel type of glutathione peroxidase: expression and regulation during wound repair. Biochem J 1997; 326:579–585.



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