Skip to main content
PMC home page
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1994 Apr 2;125(2):393–401. doi: 10.1083/jcb.125.2.393

Progesterone-dependent expression of keratinocyte growth factor mRNA in stromal cells of the primate endometrium: keratinocyte growth factor as a progestomedin

PMCID: PMC2120039  PMID: 8163555

Abstract

In vitro studies have shown that keratinocyte growth factor (KGF, also known as FGF-7) is secreted by fibroblasts and is mitogenic specifically for epithelial cells. Therefore, KGF may be an important paracrine mediator of epithelial cell proliferation in vivo. Because stromal cells are thought to influence glandular proliferation in the primate endometrium, we investigated the hormonal regulation and cellular localization of KGF mRNA expression in the rhesus monkey uterus. Tissues were obtained both from naturally cycling monkeys in the follicular and luteal phases of the cycle, and from spayed monkeys that were either untreated or treated with estradiol (E2) alone, E2 followed by progesterone (P), E2 plus P, or E2 plus P plus an antiprogestin (RU 486). Northern blot analysis of total RNA with 32P- labeled probes revealed that the level of KGF mRNA in the endometrium was 70-100-fold greater in the luteal phase or after P treatment than in untreated, E2-treated, or follicular phase animals. Northern analysis also showed that KGF mRNA was present in the myometrium but was unaffected by hormonal state. RU 486 treatment prevented the P- induced elevation of endometrial KGF mRNA. P-dependent elevation of endometrial KGF expression was confirmed by measurement of KGF protein in tissue extracts using a two-site enzyme-linked immunosorbent assay. In situ hybridization with nonradioactive digoxigenin-labeled cDNA probes revealed that the KGF mRNA signal, which was present only in stromal and smooth muscle cells, was substantially increased by P primarily in the stromal cells located in the basalis region. Smooth muscle cells in the myometrium and the walls of the spiral arteries also expressed KGF mRNA, but the degree of this expression did not differ with hormonal state. P treatment led to increased proliferation in the glandular epithelium of the basalis region and to extensive growth of the spiral arteries. We conclude that the P-dependent increase in endometrial KGF resulted from a dual action of P: (a) a P- dependent induction of KGF expression in stromal cells, especially those in the basalis (zones III and IV), and (b) a P-dependent increase in the number of KGF-positive vascular smooth muscle cells caused by the proliferation of the spiral arteries. KGF is one of the first examples in primates of a P-induced, stromally derived growth factor that might function as a progestomedin.

Full Text

The Full Text of this article is available as a PDF (2.9 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alarid E. T., Rubin J. S., Young P., Chedid M., Ron D., Aaronson S. A., Cunha G. R. Keratinocyte growth factor functions in epithelial induction during seminal vesicle development. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1074–1078. doi: 10.1073/pnas.91.3.1074. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bottaro D. P., Fortney E., Rubin J. S., Aaronson S. A. A keratinocyte growth factor receptor-derived peptide antagonist identifies part of the ligand binding site. J Biol Chem. 1993 May 5;268(13):9180–9183. [PubMed] [Google Scholar]
  3. Brenner R. M., Carlisle K. S., Hess D. L., Sandow B. A., West N. B. Morphology of the oviducts and endometria of cynomolgus macaques during the menstrual cycle. Biol Reprod. 1983 Dec;29(5):1289–1302. doi: 10.1095/biolreprod29.5.1289. [DOI] [PubMed] [Google Scholar]
  4. Brenner R. M., McClellan M. C., West N. B., Novy M. J., Haluska G. J., Sternfeld M. D. Estrogen and progestin receptors in the macaque endometrium. Ann N Y Acad Sci. 1991;622:149–166. doi: 10.1111/j.1749-6632.1991.tb37859.x. [DOI] [PubMed] [Google Scholar]
  5. Clarke C. L., Sutherland R. L. Progestin regulation of cellular proliferation. Endocr Rev. 1990 May;11(2):266–301. doi: 10.1210/edrv-11-2-266. [DOI] [PubMed] [Google Scholar]
  6. Cunha G. R., Chung L. W., Shannon J. M., Taguchi O., Fujii H. Hormone-induced morphogenesis and growth: role of mesenchymal-epithelial interactions. Recent Prog Horm Res. 1983;39:559–598. doi: 10.1016/b978-0-12-571139-5.50018-5. [DOI] [PubMed] [Google Scholar]
  7. Cunha G. R. Epithelial-stromal interactions in development of the urogenital tract. Int Rev Cytol. 1976;47:137–194. doi: 10.1016/s0074-7696(08)60088-1. [DOI] [PubMed] [Google Scholar]
  8. Enders A. C., King B. F. Early stages of trophoblastic invasion of the maternal vascular system during implantation in the macaque and baboon. Am J Anat. 1991 Dec;192(4):329–346. doi: 10.1002/aja.1001920403. [DOI] [PubMed] [Google Scholar]
  9. Finch P. W., Rubin J. S., Miki T., Ron D., Aaronson S. A. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science. 1989 Aug 18;245(4919):752–755. doi: 10.1126/science.2475908. [DOI] [PubMed] [Google Scholar]
  10. Gerdes J., Lemke H., Baisch H., Wacker H. H., Schwab U., Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984 Oct;133(4):1710–1715. [PubMed] [Google Scholar]
  11. Ghahary A., Chakrabarti S., Murphy L. J. Localization of the sites of synthesis and action of insulin-like growth factor-I in the rat uterus. Mol Endocrinol. 1990 Feb;4(2):191–195. doi: 10.1210/mend-4-2-191. [DOI] [PubMed] [Google Scholar]
  12. Ghosh D., De P., Sengupta J. Effect of RU 486 on the endometrial response to deciduogenic stimulus in ovariectomized rhesus monkeys treated with oestrogen and progesterone. Hum Reprod. 1992 Sep;7(8):1048–1060. doi: 10.1093/oxfordjournals.humrep.a137792. [DOI] [PubMed] [Google Scholar]
  13. Ghosh D., Sengupta J. Endometrial responses to a deciduogenic stimulus in ovariectomized rhesus monkeys treated with oestrogen and progesterone. J Endocrinol. 1989 Jan;120(1):51–58. doi: 10.1677/joe.0.1200051. [DOI] [PubMed] [Google Scholar]
  14. Giudice L. C., Lamson G., Rosenfeld R. G., Irwin J. C. Insulin-like growth factor-II (IGF-II) and IGF binding proteins in human endometrium. Ann N Y Acad Sci. 1991;626:295–307. doi: 10.1111/j.1749-6632.1991.tb37924.x. [DOI] [PubMed] [Google Scholar]
  15. Giudice L. C., Milkowski D. A., Lamson G., Rosenfeld R. G., Irwin J. C. Insulin-like growth factor binding proteins in human endometrium: steroid-dependent messenger ribonucleic acid expression and protein synthesis. J Clin Endocrinol Metab. 1991 Apr;72(4):779–787. doi: 10.1210/jcem-72-4-779. [DOI] [PubMed] [Google Scholar]
  16. Halaban R., Funasaka Y., Lee P., Rubin J., Ron D., Birnbaum D. Fibroblast growth factors in normal and malignant melanocytes. Ann N Y Acad Sci. 1991;638:232–243. doi: 10.1111/j.1749-6632.1991.tb49034.x. [DOI] [PubMed] [Google Scholar]
  17. Henderson G. S., Conary J. T., Davidson J. M., Stewart S. J., House F. S., McCurley T. L. A reliable method for northern blot analysis using synthetic oligonucleotide probes. Biotechniques. 1991 Feb;10(2):190–197. [PubMed] [Google Scholar]
  18. Hild-Petito S., Verhage H. G., Fazleabas A. T. Immunocytochemical localization of estrogen and progestin receptors in the baboon (Papio anubis) uterus during implantation and pregnancy. Endocrinology. 1992 Apr;130(4):2343–2353. doi: 10.1210/endo.130.4.1372241. [DOI] [PubMed] [Google Scholar]
  19. Huet-Hudson Y. M., Chakraborty C., De S. K., Suzuki Y., Andrews G. K., Dey S. K. Estrogen regulates the synthesis of epidermal growth factor in mouse uterine epithelial cells. Mol Endocrinol. 1990 Mar;4(3):510–523. doi: 10.1210/mend-4-3-510. [DOI] [PubMed] [Google Scholar]
  20. Kelley M. J., Pech M., Seuanez H. N., Rubin J. S., O'Brien S. J., Aaronson S. A. Emergence of the keratinocyte growth factor multigene family during the great ape radiation. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9287–9291. doi: 10.1073/pnas.89.19.9287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Koji T., Brenner R. M. Localization of estrogen receptor messenger ribonucleic acid in rhesus monkey uterus by nonradioactive in situ hybridization with digoxigenin-labeled oligodeoxynucleotides. Endocrinology. 1993 Jan;132(1):382–392. doi: 10.1210/endo.132.1.8419136. [DOI] [PubMed] [Google Scholar]
  22. Lewis S. A., Balcarek J. M., Krek V., Shelanski M., Cowan N. J. Sequence of a cDNA clone encoding mouse glial fibrillary acidic protein: structural conservation of intermediate filaments. Proc Natl Acad Sci U S A. 1984 May;81(9):2743–2746. doi: 10.1073/pnas.81.9.2743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. McClellan M. C., Rankin S., West N. B., Brenner R. M. Estrogen receptors, progestin receptors and DNA synthesis in the macaque endometrium during the luteal-follicular transition. J Steroid Biochem Mol Biol. 1990 Dec 10;37(5):631–641. doi: 10.1016/0960-0760(90)90345-l. [DOI] [PubMed] [Google Scholar]
  24. Miki T., Bottaro D. P., Fleming T. P., Smith C. L., Burgess W. H., Chan A. M., Aaronson S. A. Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):246–250. doi: 10.1073/pnas.89.1.246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Miki T., Fleming T. P., Bottaro D. P., Rubin J. S., Ron D., Aaronson S. A. Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop. Science. 1991 Jan 4;251(4989):72–75. doi: 10.1126/science.1846048. [DOI] [PubMed] [Google Scholar]
  26. Murphy L. J., Murphy L. C., Friesen H. G. Estrogen induces insulin-like growth factor-I expression in the rat uterus. Mol Endocrinol. 1987 Jul;1(7):445–450. doi: 10.1210/mend-1-7-445. [DOI] [PubMed] [Google Scholar]
  27. Nelson K. G., Takahashi T., Bossert N. L., Walmer D. K., McLachlan J. A. Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):21–25. doi: 10.1073/pnas.88.1.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nelson K. G., Takahashi T., Lee D. C., Luetteke N. C., Bossert N. L., Ross K., Eitzman B. E., McLachlan J. A. Transforming growth factor-alpha is a potential mediator of estrogen action in the mouse uterus. Endocrinology. 1992 Oct;131(4):1657–1664. doi: 10.1210/endo.131.4.1396310. [DOI] [PubMed] [Google Scholar]
  29. Okulicz W. C., Balsamo M., Tast J. Progesterone regulation of endometrial estrogen receptor and cell proliferation during the late proliferative and secretory phase in artificial menstrual cycles in the rhesus monkey. Biol Reprod. 1993 Jul;49(1):24–32. doi: 10.1095/biolreprod49.1.24. [DOI] [PubMed] [Google Scholar]
  30. Okulicz W. C., Savasta A. M., Hoberg L. M., Longcope C. Biochemical and immunohistochemical analyses of estrogen and progesterone receptors in the rhesus monkey uterus during the proliferative and secretory phases of artificial menstrual cycles. Fertil Steril. 1990 May;53(5):913–920. doi: 10.1016/s0015-0282(16)53531-6. [DOI] [PubMed] [Google Scholar]
  31. Padykula H. A., Coles L. G., Okulicz W. C., Rapaport S. I., McCracken J. A., King N. W., Jr, Longcope C., Kaiserman-Abramof I. R. The basalis of the primate endometrium: a bifunctional germinal compartment. Biol Reprod. 1989 Mar;40(3):681–690. doi: 10.1095/biolreprod40.3.681. [DOI] [PubMed] [Google Scholar]
  32. Pekonen F., Nyman T., Rutanen E. M. Differential expression of keratinocyte growth factor and its receptor in the human uterus. Mol Cell Endocrinol. 1993 Sep;95(1-2):43–49. doi: 10.1016/0303-7207(93)90027-h. [DOI] [PubMed] [Google Scholar]
  33. Ron D., Bottaro D. P., Finch P. W., Morris D., Rubin J. S., Aaronson S. A. Expression of biologically active recombinant keratinocyte growth factor. Structure/function analysis of amino-terminal truncation mutants. J Biol Chem. 1993 Feb 5;268(4):2984–2988. [PubMed] [Google Scholar]
  34. Rubin J. S., Osada H., Finch P. W., Taylor W. G., Rudikoff S., Aaronson S. A. Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci U S A. 1989 Feb;86(3):802–806. doi: 10.1073/pnas.86.3.802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Slayden O. D., Hirst J. J., Brenner R. M. Estrogen action in the reproductive tract of rhesus monkeys during antiprogestin treatment. Endocrinology. 1993 Apr;132(4):1845–1856. doi: 10.1210/endo.132.4.8462480. [DOI] [PubMed] [Google Scholar]
  36. Staiano-Coico L., Krueger J. G., Rubin J. S., D'limi S., Vallat V. P., Valentino L., Fahey T., 3rd, Hawes A., Kingston G., Madden M. R. Human keratinocyte growth factor effects in a porcine model of epidermal wound healing. J Exp Med. 1993 Sep 1;178(3):865–878. doi: 10.1084/jem.178.3.865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Stampfer M. R., Bartley J. C. Induction of transformation and continuous cell lines from normal human mammary epithelial cells after exposure to benzo[a]pyrene. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2394–2398. doi: 10.1073/pnas.82.8.2394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Tso J. Y., Sun X. H., Kao T. H., Reece K. S., Wu R. Isolation and characterization of rat and human glyceraldehyde-3-phosphate dehydrogenase cDNAs: genomic complexity and molecular evolution of the gene. Nucleic Acids Res. 1985 Apr 11;13(7):2485–2502. doi: 10.1093/nar/13.7.2485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Werner S., Peters K. G., Longaker M. T., Fuller-Pace F., Banda M. J., Williams L. T. Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6896–6900. doi: 10.1073/pnas.89.15.6896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. West N. B., McClellan M. C., Sternfeld M. D., Brenner R. M. Immunocytochemistry versus binding assays of the estrogen receptor in the reproductive tract of spayed and hormone-treated macaques. Endocrinology. 1987 Nov;121(5):1789–1800. doi: 10.1210/endo-121-5-1789. [DOI] [PubMed] [Google Scholar]
  41. Yan G., Fukabori Y., Nikolaropoulos S., Wang F., McKeehan W. L. Heparin-binding keratinocyte growth factor is a candidate stromal-to-epithelial-cell andromedin. Mol Endocrinol. 1992 Dec;6(12):2123–2128. doi: 10.1210/mend.6.12.1491693. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES