Abstract
Purpose
Recent studies have shown that proliferation and differentiation of various cell types is regulated by cell-cycle-related proteins, such as protein p53 and retinoblastoma protein pRb.
Methods
Three monoclonal antibodies to p53 (PAb240, PAb421, and PAb1801) and 3H9 monoclonal antibody to pRb were utilized for localization of proteins by peroxidase immunohistochemistry in frozen tissue sections.
Results
Nuclear and nucleolar p53 expression was detected in nondividing and relatively stable cells, e.g., oocytes in primordial follicles and granulosa lutein cells. On the other hand, strong cytoplasmic p53 expression was detected in proliferating and low differentiated epithelial cells of the ovarian surface epithelium, amnion, endocervix and ectocervix, indicating enhanced p53 synthesis. Not all three p53 antibodies reacted with each tissue, perhaps due to structural and conformational changes in the p53 molecule, accompanying p53 association with other proteins, e.g., tissue specific transcription factor interactions. pRb expression was usually restricted to the cell nuclei and nucleoli. However, glandular cells of the female reproductive tract showed cytoplasmic pRb expression in juxtaluminal (secretory) segments of cells, a feature not previously described in any cell type. p53 and pRb immunoreactivities declined with advanced differentiation of cells. No p53 or pRb was detected in placental syncytiotrophoblast or terminally differentiated squamous epithelial cells.
Conclusion
Our data indicate that large quantities of p53 are synthesized in cells leaving the cell cycle and entering differentiation. Except in glandular cells, the pRb expression is confined to the cell nuclei and nucleoli. A unique cytoplasmic expression of pRb in juxtaluminal segments of glandular cells suggests a role for pRb in human female fertility and conception.
Similar content being viewed by others
References
Zambetti GP, Levine AJ: A comparison of the biological activities of wild-type and mutant p53. FASEB J 1993;7:855–865
Clore GM, Omichinski JG, Sakaguchi K, Zambrano N, Sakamoto H, Appella E, Gronenborn AM: High-resolution structure of the oligomerization domain of p53 by multidimensional NMR. Science 1994;265:386–391
Goodrich DW, Lee WH: Molecular characterization of the retinoblastoma susceptibility gene. Biochim Biophys Acta 1993;1155:43–61
Ewen ME: The cell cycle and the retinoblastoma protein family. Cancer Metastasis Rev 1994;13:45–66
Mancini MA, Shan B, Nickerson JA, Penman S, Lee WH: The retinoblastoma gene product is a cell cycle-dependent, nuclear matrix-associated protein. Proc Natl Acad Sci USA 1994;91:418–422
Shay JW, Pereira Smith OM, Wright WE: A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res 1991;196:33–39
Vousden K: Interactions of human papillomavirus transforming proteins with the products of tumor suppressor genes. FASEB J 1993;7:872–879
Ali AA, Marcus JN, Harvey JP, Roll R, Hodgson CP, Wildrick DM, Chakraborty A, Boman BM: RB1 protein in normal and malignant human colorectal tissue and colon cancer cell lines. FASEB J 1993;7:931–937
Rogalsky V, Todorov G, Moran D: Translocation of retinoblastoma protein associated with tumor cell growth inhibition. Biochem Biophys Res Commun 1993;192:1139–1146
Woodworth CD, Wang H, Simpson S, Alvarez Salas LM, Notario V: Overexpression of wild-type p53 alters growth and differentiation of normal human keratinocytes but not human papillomavirus-expressing cell lines. Cell Growth Differ 1993;4:367–376
Evans HJ, Presser J: Tumor-suppressor genes: cardinal factors in inherited predisposition to human cancers. Environ Health Perspect 1992;98:25–37
Sherr CJ: The ins and outs of RB: coupling gene expression to the cell cycle clock. Trends Cell Biol 1994;4:15–18
Berchuck A, Kohler MF, Marks JR, Wiseman R, Boyd J, Bast RC Jr: The p53 tumor suppressor gene frequently is altered in gynecologic cancers. Am J Obstet Gynecol 1994;170:246–252
Gu W, Schneider JW, Condorelli G, Kaushal S, Mahdavi V, Nadal Girnard B: Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation. Cell 1993;72:309–324
Bukovsky A, Caudle MR, Keenan JA, Wimalasena J, Foster JS, Van Meter SE: Quantitative evaluation of the cell cyclerelated protein (pRb) and localization of Thy-1 differentiation protein and macrophages during follicular development and atresia and in human corpora lutea. Biol Reprod 1995;52:776–792
Dallenbach Hellweg G: Histopathology of the Endometrium. Berlin, Springer-Verlag, 1971, pp 20–76
Corner GW Jr: The histological dating of the human corpus luteum of menstruation. Am J Anat 1956;98:377–392
Bukovsky A, Presl J, Zidovsky J, Mancal P: The localization of Thy-1.1, MRC OX 2 and Ia antigens in the rat ovary and fallopian tube. Immunology 1983;48:587–596
Bukovsky A, Chen TT, Wimalasena J, Caudle MR: Cellular localization of luteinizing hormone receptor immunoreactivity in the ovaries of immature, gonadotropin-primed and normal cycling rats. Biol Reprod 1993;48:1367–1382
Chang K, Ding I, Kern FG, Willingham MC: Immunohistochemical analysis of p53 and HER-2/neu proteins in human tumors. J Histochem Cytochem 1991;39:1281–1287
Weinberg RA: Tumor suppressor genes. Science 1991;254:1138–1146
Motta PM, Van Blerkom J, Makabe S: Changes in the surface morphology of ovarian ‘germinal’ epithelium during the reproductive cycle and in some pathological conditions. J Submicrosc Cytol 1980;12:407–425
Papadaki L, Beilby JOW: The fine structure of the surface epithelium of the human ovary. J Cell Sci 1971;8:445–465
Bukovsky A, Keenan JA, Caudle MR, Wimalasena J, Upadhyaya N, Van Meter SE: Immunohistochemical studies of the adult human ovary: possible contribution of immune and epithelial factors to folliculogenesis. Am J Reprod Immunol 1995 (in press)
Cordon Cardo C, Richon VM: Expression of the retinoblastoma protein is regulated in normal human tissues. Am J Pathol 1994;144:500–510
Lane DP, Midgley C, Hupp T: Tumour suppressor genes and molecular chaperones. Philos Trans R Soc Lond Biol 1993;339:369–372
Kastan MB, Onyewkere O, Sidransky D, Vogelstein B, Craig RW: Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991;51:6304–6311
Endo T, Goto S: Retinoblastoma gene product Rb accumulates during myogenic differentiation and is deinduced by the expression of SV40 large T antigen. J Biochem Tokyo 1992; 112:427–430
Richon VM, Rifkind RA, Marks PA: Expression and phosphorylation of the retinoblastoma protein during induced differentiation of murine erythroleukemia cells. Cell Growth Differ 1992;3:413–420
Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD: Molecular Biology of the Cell. New York, Garland, 1989
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bukovsky, A., Caudle, M.R., Keenan, J.A. et al. Expression of cell cycle regulatory proteins (p53, pRB) in the human female genital tract. J Assist Reprod Genet 12, 123–131 (1995). https://doi.org/10.1007/BF02211381
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02211381