Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2002 Oct 1;367(Pt 1):271–277. doi: 10.1042/BJ20020026

High expression in involuting reproductive tissues of uterocalin/24p3, a lipocalin and acute phase protein.

Joel Ryon 1, Lee Bendickson 1, Marit Nilsen-Hamilton 1
PMCID: PMC1222854  PMID: 12067275

Abstract

During reproduction the mass and number of cells in the uterus and the mammary gland increase rapidly and then diminish more rapidly after their reproductive functions are completed. The diminishment of tissue mass, known as involution, involves an ordered series of events that includes apoptosis of resident cells, neutrophil invasion, the release of degradative enzymes and phagocytosis of cellular debris. Local signals are believed to regulate the progression of involution in each tissue. Here we show that the mammary gland and uterus express high levels of uterocalin, a protein that specifically induces apoptosis in neutrophils and other leucocytes. In the mammary gland, uterocalin expression is induced by weaning. In both tissues, uterocalin is expressed at extremely high levels such that it constitutes an average of 0.2-0.5% of the total extractable protein at its peak. Epithelial cells in the uterus and mammary gland produce uterocalin. In each case, the protein is secreted into the tissue lumen, with mammary-derived uterocalin being found in the milk. The period of highest uterocalin expression in vivo is consistent with the hypothesis that one of its physiological roles is to induce apoptosis of infiltrating neutrophils and thereby delay the entry of neutrophils into the tissue. It is proposed that the role of uterocalin during involution is to provide a window of time during which resident cells are protected from the degradative enzymes, free radicals and other secreted products of activated phagocytes to allow these cells to prepare to survive the processes of involution.

Full Text

The Full Text of this article is available as a PDF (222.0 KB).

Selected References

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

  1. Ball R. K., Friis R. R., Schoenenberger C. A., Doppler W., Groner B. Prolactin regulation of beta-casein gene expression and of a cytosolic 120-kd protein in a cloned mouse mammary epithelial cell line. EMBO J. 1988 Jul;7(7):2089–2095. doi: 10.1002/j.1460-2075.1988.tb03048.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Cancedda F. D., Malpeli M., Gentili C., Di Marzo V., Bet P., Carlevaro M., Cermelli S., Cancedda R. The developmentally regulated avian Ch21 lipocalin is an extracellular fatty acid-binding protein. J Biol Chem. 1996 Aug 16;271(33):20163–20169. doi: 10.1074/jbc.271.33.20163. [DOI] [PubMed] [Google Scholar]
  3. Chu S. T., Huang H. L., Chen J. M., Chen Y. H. Demonstration of a glycoprotein derived from the 24p3 gene in mouse uterine luminal fluid. Biochem J. 1996 Jun 1;316(Pt 2):545–550. doi: 10.1042/bj3160545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chu S. T., Lin H. J., Huang H. L., Chen Y. H. The hydrophobic pocket of 24p3 protein from mouse uterine luminal fluid: fatty acid and retinol binding activity and predicted structural similarity to lipocalins. J Pept Res. 1998 Nov;52(5):390–397. doi: 10.1111/j.1399-3011.1998.tb00663.x. [DOI] [PubMed] [Google Scholar]
  5. Collard M. W., Griswold M. D. Biosynthesis and molecular cloning of sulfated glycoprotein 2 secreted by rat Sertoli cells. Biochemistry. 1987 Jun 16;26(12):3297–3303. doi: 10.1021/bi00386a008. [DOI] [PubMed] [Google Scholar]
  6. Cowland J. B., Borregaard N. Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. Genomics. 1997 Oct 1;45(1):17–23. doi: 10.1006/geno.1997.4896. [DOI] [PubMed] [Google Scholar]
  7. Davis T. R., Tabatabai L., Bruns K., Hamilton R. T., Nilsen-Hamilton M. Basic fibroblast growth factor induces 3T3 fibroblasts to synthesize and secrete a cyclophilin-like protein and beta 2-microglobulin. Biochim Biophys Acta. 1991 Oct 26;1095(2):145–152. doi: 10.1016/0167-4889(91)90077-b. [DOI] [PubMed] [Google Scholar]
  8. Devireddy L. R., Teodoro J. G., Richard F. A., Green M. R. Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation. Science. 2001 Aug 3;293(5531):829–834. doi: 10.1126/science.1061075. [DOI] [PubMed] [Google Scholar]
  9. Fang Y., Lepont P., Fassett J. T., Ford S. P., Mubaidin A., Hamilton R. T., Nilsen-Hamilton M. Signaling between the placenta and the uterus involving the mitogen-regulated protein/proliferins. Endocrinology. 1999 Nov;140(11):5239–5249. doi: 10.1210/endo.140.11.7142. [DOI] [PubMed] [Google Scholar]
  10. Feng Z., Marti A., Jehn B., Altermatt H. J., Chicaiza G., Jaggi R. Glucocorticoid and progesterone inhibit involution and programmed cell death in the mouse mammary gland. J Cell Biol. 1995 Nov;131(4):1095–1103. doi: 10.1083/jcb.131.4.1095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Flower D. R., North A. C., Attwood T. K. Mouse oncogene protein 24p3 is a member of the lipocalin protein family. Biochem Biophys Res Commun. 1991 Oct 15;180(1):69–74. doi: 10.1016/s0006-291x(05)81256-2. [DOI] [PubMed] [Google Scholar]
  12. Flower D. R. The lipocalin protein family: structure and function. Biochem J. 1996 Aug 15;318(Pt 1):1–14. doi: 10.1042/bj3180001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fort P., Marty L., Piechaczyk M., el Sabrouty S., Dani C., Jeanteur P., Blanchard J. M. Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res. 1985 Mar 11;13(5):1431–1442. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Garay-Rojas E., Harper M., Hraba-Renevey S., Kress M. An apparent autocrine mechanism amplifies the dexamethasone- and retinoic acid-induced expression of mouse lipocalin-encoding gene 24p3. Gene. 1996 May 8;170(2):173–180. doi: 10.1016/0378-1119(95)00896-9. [DOI] [PubMed] [Google Scholar]
  15. Gobé G. C., Buttyan R., Wyburn K. R., Etheridge M. R., Smith P. J. Clusterin expression and apoptosis in tissue remodeling associated with renal regeneration. Kidney Int. 1995 Feb;47(2):411–420. doi: 10.1038/ki.1995.54. [DOI] [PubMed] [Google Scholar]
  16. Green M. R., Pastewka J. V. Characterization of major milk proteins from BALB/c and C3H mice. J Dairy Sci. 1976 Feb;59(2):207–215. doi: 10.3168/jds.S0022-0302(76)84186-0. [DOI] [PubMed] [Google Scholar]
  17. Hennighausen L., Robinson G. W. Think globally, act locally: the making of a mouse mammary gland. Genes Dev. 1998 Feb 15;12(4):449–455. doi: 10.1101/gad.12.4.449. [DOI] [PubMed] [Google Scholar]
  18. Hraba-Renevey S., Türler H., Kress M., Salomon C., Weil R. SV40-induced expression of mouse gene 24p3 involves a post-transcriptional mechanism. Oncogene. 1989 May;4(5):601–608. [PubMed] [Google Scholar]
  19. Humphreys D. T., Carver J. A., Easterbrook-Smith S. B., Wilson M. R. Clusterin has chaperone-like activity similar to that of small heat shock proteins. J Biol Chem. 1999 Mar 12;274(11):6875–6881. doi: 10.1074/jbc.274.11.6875. [DOI] [PubMed] [Google Scholar]
  20. Kasik J. W., Rice E. J. An increase in expression of the lipocalin 24p3 is found in mouse uterus coincident with birth. Am J Obstet Gynecol. 1995 Aug;173(2):613–617. doi: 10.1016/0002-9378(95)90291-0. [DOI] [PubMed] [Google Scholar]
  21. Li M., Liu X., Robinson G., Bar-Peled U., Wagner K. U., Young W. S., Hennighausen L., Furth P. A. Mammary-derived signals activate programmed cell death during the first stage of mammary gland involution. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3425–3430. doi: 10.1073/pnas.94.7.3425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Liu Q., Nilsen-Hamilton M. Identification of a new acute phase protein. J Biol Chem. 1995 Sep 22;270(38):22565–22570. doi: 10.1074/jbc.270.38.22565. [DOI] [PubMed] [Google Scholar]
  23. Liu Q., Ryon J., Nilsen-Hamilton M. Uterocalin: a mouse acute phase protein expressed in the uterus around birth. Mol Reprod Dev. 1997 Apr;46(4):507–514. doi: 10.1002/(SICI)1098-2795(199704)46:4<507::AID-MRD9>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
  24. Lund L. R., Rømer J., Thomasset N., Solberg H., Pyke C., Bissell M. J., Danø K., Werb Z. Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways. Development. 1996 Jan;122(1):181–193. doi: 10.1242/dev.122.1.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Marti A., Feng Z., Altermatt H. J., Jaggi R. Milk accumulation triggers apoptosis of mammary epithelial cells. Eur J Cell Biol. 1997 Jun;73(2):158–165. [PubMed] [Google Scholar]
  26. Matrisian L. M., Bowden G. T., Krieg P., Fürstenberger G., Briand J. P., Leroy P., Breathnach R. The mRNA coding for the secreted protease transin is expressed more abundantly in malignant than in benign tumors. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9413–9417. doi: 10.1073/pnas.83.24.9413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Miyake H., Nelson C., Rennie P. S., Gleave M. E. Acquisition of chemoresistant phenotype by overexpression of the antiapoptotic gene testosterone-repressed prostate message-2 in prostate cancer xenograft models. Cancer Res. 2000 May 1;60(9):2547–2554. [PubMed] [Google Scholar]
  28. Nilsen-Hamilton M., Hamilton R. T., Adams G. A. Rapid selective stimulation by growth factors of the incorporation by BALB/C 3T3 cells of [35S]methionine into a glycoprotein and five superinducible proteins. Biochem Biophys Res Commun. 1982 Sep 16;108(1):158–166. doi: 10.1016/0006-291x(82)91845-9. [DOI] [PubMed] [Google Scholar]
  29. Piotte C. P., Hunter A. K., Marshall C. J., Grigor M. R. Phylogenetic analysis of three lipocalin-like proteins present in the milk of Trichosurus vulpecula (Phalangeridae, Marsupialia). J Mol Evol. 1998 Mar;46(3):361–369. doi: 10.1007/pl00006313. [DOI] [PubMed] [Google Scholar]
  30. Strange R., Li F., Saurer S., Burkhardt A., Friis R. R. Apoptotic cell death and tissue remodelling during mouse mammary gland involution. Development. 1992 May;115(1):49–58. doi: 10.1242/dev.115.1.49. [DOI] [PubMed] [Google Scholar]
  31. Viard I., Wehrli P., Jornot L., Bullani R., Vechietti J. L., Schifferli J. A., Tschopp J., French L. E. Clusterin gene expression mediates resistance to apoptotic cell death induced by heat shock and oxidative stress. J Invest Dermatol. 1999 Mar;112(3):290–296. doi: 10.1046/j.1523-1747.1999.00531.x. [DOI] [PubMed] [Google Scholar]
  32. Walker N. I., Bennett R. E., Kerr J. F. Cell death by apoptosis during involution of the lactating breast in mice and rats. Am J Anat. 1989 May;185(1):19–32. doi: 10.1002/aja.1001850104. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES