Abstract
Intrauterine growth restriction (IUGR) affects 3–8% of pregnancies and is associated with altered cell turnover in the villous trophoblast, an essential functional cell type of the human placenta. The intrinsic pathway of apoptosis, particularly p53, is important in regulating placental cell turnover in response to damage. We hypothesised that expression of proteins in the p53 pathway in placental tissue would be altered in IUGR. Expression of constituents of the p53 pathway was assessed using real-time PCR, Western blotting and immunohistochemistry. p53 mRNA and protein expression was increased in IUGR, which localised to the syncytiotrophoblast. Similar changes were noted in p21 and Bax expression. There was no change in the expression of Mdm2, Bak and Bcl-2. The association between altered trophoblast cell turnover in IUGR and increased p53 expression is reminiscent of that following exposure to hypoxia. These observations provide further insight into the potential pathogenesis of IUGR. Further research is required to elicit the role and interactions of p53 and its place in the pathogenesis of IUGR.
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References
Huppertz B, Kingdom JC (2004) Apoptosis in the trophoblast-role of apoptosis in placental morphogenesis. J Soc Gynecol Investig 11(6):353–362
Mayhew TM et al (2007) The placenta in pre-eclampsia and intrauterine growth restriction: studies on exchange surface areas, diffusion distances and villous membrane diffusive conductances. Placenta 28(2–3):233–238
Hitschold TP (1998) Doppler flow velocity waveforms of the umbilical arteries correlate with intravillous blood volume. Am J Obstet Gynecol 179(2):540–543
Krebs C et al (1996) Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree. Am J Obstet Gynecol 175(6):1534–1542
Levy R et al (2002) Trophoblast apoptosis from pregnancies complicated by fetal growth restriction is associated with enhanced p53 expression. Am J Obstet Gynecol 186(5):1056–1061
Smith SC, Baker PN, Symonds EM (1997) Increased placental apoptosis in intrauterine growth restriction. Am J Obstet Gynecol 177(6):1395–1401
Macara L et al (1996) Structural analysis of placental terminal villi from growth-restricted pregnancies with abnormal umbilical artery Doppler waveforms. Placenta 17(1):37–48
Heazell AE et al (2007) Formation of syncytial knots is increased by hyperoxia, hypoxia and reactive oxygen species. Placenta 28(Suppl 1):S33–S40
Scifres CM, Nelson DM (2009) Intrauterine growth restriction, human placental development and trophoblast cell death. J Physiol 587(Pt 14):3453–3458
Oren M, Maltzman W, Levine AJ (1981) Post-translational regulation of the 54K cellular tumor antigen in normal and transformed cells. Mol Cell Biol 1(2):101–110
Maltzman W, Czyzyk L (1984) UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol Cell Biol 4(9):1689–1694
Gartel AL, Tyner AL (1999) Transcriptional regulation of the p21((WAF1/CIP1)) gene. Exp Cell Res 246(2):280–289
Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80(2):293–299
Nakano K, Vousden KH, MA PU (2001) a novel proapoptotic gene, is induced by p53. Mol Cell 7(3):683–694
Moroni MC et al (2001) Apaf-1 is a transcriptional target for E2F and p53. Nat Cell Biol 3(6):552–558
Haupt Y et al (1997) Mdm2 promotes the rapid degradation of p53. Nature 387(6630):296–299
Moll UM et al (2005) Transcription-independent pro-apoptotic functions of p53. Curr Opin Cell Biol 17(6):631–636
Heazell AE, Crocker IP (2008) Live and let die—regulation of villous trophoblast apoptosis in normal and abnormal pregnancies. Placenta 29(9):772–783
Jeschke U et al (2006) Expression of the proliferation marker Ki-67 and of p53 tumor protein in trophoblastic tissue of preeclamptic, HELLP, and intrauterine growth-restricted pregnancies. Int J Gynecol Pathol 25(4):354–360
Heazell AE et al (2008) Altered expression of regulators of caspase activity within trophoblast of normal pregnancies and pregnancies complicated by pre-eclampsia. Reprod Sci 15(10):1034–1043
Crocker IP, Daayana SL, Baker PN (2004) An image analysis technique for the investigation of human placental morphology in pre-eclampsia and intrauterine growth restriction. J Soc Gynecol Investig 11(2 Suppl):347A
Cheung AN et al (1994) Assessment of cell proliferation in hydatidiform mole using monoclonal antibody MIB1 to Ki-67 antigen. J Clin Pathol 47(7):601–604
Lacey HA et al (2005) Gestational profile of Na+/H+ exchanger and Cl-/HCO3-anion exchanger mRNA expression in placenta using real-time QPCR. Placenta 26(1):93–98
Jones CJ et al (1987) Elimination of the non-specific binding of avidin to tissue sections. Histochem J 19(5):264–268
Ishihara N et al (2002) Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation. Am J Obstet Gynecol 186(1):158–166
Endo H et al (2005) Frequent apoptosis in placental villi from pregnancies complicated with intrauterine growth restriction and without maternal symptoms. Int J Mol Med 16(1):79–84
Crocker IP, Daayana SL, Baker PN (2004) An image analysis technique for the investigation of human placental morphology in pre-eclampsia and intrauterine growth restriction. J Soc Gynecol Investig 11(8):545–552
Huppertz B et al (1998) Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta. Histochem Cell Biol 110(5):495–508
Feng Y et al (2005) Subcellular localization of caspase-3 activation correlates with changes in apoptotic morphology in MOLT-4 leukemia cells exposed to X-ray irradiation. Int J Oncol 27(3):699–704
Glamoclija V et al (2005) Apoptosis and active caspase-3 expression in human granulosa cells. Fertil Steril 83(2):426–431
Marzusch K et al (1995) Expression of the p53 tumour suppressor gene in human placenta: an immunohistochemical study. Placenta 16:101–114
Yan Y et al (1997) Inhibition of protein phosphatase activity induces p53-dependent apoptosis in the absence of p53 transactivation. J Biol Chem 272(24):15220–15226
Mihara M et al (2003) p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11(3):577–590
Erster S, Moll UM (2005) Stress-induced p53 runs a transcription-independent death program. Biochem Biophys Res Commun 331(3):843–850
Chen B et al (2010) Hypoxia down-regulates p53 but induces apoptosis and enhances expression of BAD in cultures of human syncytiotrophoblasts. Am J Physiol Cell Physiol. doi:10.1152/ajpcell.00154.2010
Heazell AE et al (2008) Effects of oxygen on cell turnover and expression of regulators of apoptosis in human placental trophoblast. Placenta 29(2):175–186
Barak Y et al (1993) mdm2 expression is induced by wild type p53 activity. EMBO J 12(2):461–468
Cheung AN et al (1999) Immunohistochemical and mutational analysis of p53 tumor suppressor gene in gestational trophoblastic disease: correlation with mdm2, proliferation index, and clinicopathologic parameters. Int J Gynecol Cancer 9(2):123–130
Heazell AE et al (2009) Does altered oxygenation or reactive oxygen species alter cell turnover of BeWo choriocarcinoma cells? Reprod Biomed 18(1):111–119
Nieminen AL et al (2005) mdm2 and HIF-1alpha interaction in tumor cells during hypoxia. J Cell Physiol 204(2):364–369
Ratts VS et al (2000) Expression of BCL-2, BAX and BAK in the trophoblast layer of the term human placenta: a unique model of apoptosis within a syncytium. Placenta 21(4):361–366
Qiao S et al (1998) p53, Bax and Bcl-2 expression, and apoptosis in gestational trophoblast of complete hydatidiform mole. Placenta 19(5–6):361–369
Yusuf K et al (2001) Thromboxane A(2) limits differentiation and enhances apoptosis of cultured human trophoblasts. Pediatr Res 50(2):203–209
Levy R et al (2000) Apoptosis in human cultured trophoblasts is enhanced by hypoxia and diminished by epidermal growth factor. Am J Physiol Cell Physiol 278(5):C982–C988
Quenby S et al (1998) Oncogene and tumour suppressor gene products during trophoblast differentiation in the first trimester. Mol Hum Reprod 4(5):477–481
Adler V et al (1997) Conformation-dependent phosphorylation of p53. Proc Natl Acad Sci USA 94(5):1686–1691
Gu W, Roeder RG (1997) Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90(4):595–606
Shaw P et al (1996) Regulation of specific DNA binding by p53: evidence for a role for O-glycosylation and charged residues at the carboxy-terminus. Oncogene 12(4):921–930
Acknowledgments
This work was financially supported by Tommy’s—The Baby Charity, The Peel Medical Research Trust and The Castang Foundation. We would like to thank Ms Jemma Corcoran for her technical assistance.
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Heazell, A.E.P., Sharp, A.N., Baker, P.N. et al. Intra-uterine growth restriction is associated with increased apoptosis and altered expression of proteins in the p53 pathway in villous trophoblast. Apoptosis 16, 135–144 (2011). https://doi.org/10.1007/s10495-010-0551-3
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DOI: https://doi.org/10.1007/s10495-010-0551-3