Increased immortalization‐upregulated protein 2 (IMUP‐2) by hypoxia induces apoptosis of the trophoblast and pre‐eclampsia

Abstract

In regulation of the developmental process, the balance between cellular proliferation and cell death is critical. Placental development tightly controls this mechanism, and increased apoptosis of placental trophoblasts can cause a variety of gynecological diseases. Members of the immortalization-upregulated protein (IMUP) family are nuclear proteins implicated in SV40-mediated immortalization and cellular proliferation; however, the mechanisms by which their expression is regulated in placental development are still unknown. We compared IMUP-2 expression in normal and pre-eclamptic placental tissues and evaluated the function of IMUP-2 in HTR-8/SVneo trophoblast cells under hypoxic conditions. IMUP-2 was expressed in syncytiotrophoblasts and syncytial knots of the placental villi. IMUP-2 expression was significantly higher in preterm pre-eclampsia patients than in patients who went to term (P < 0.001); however, we observed no differences in IMUP-2 expression between normal term patients with and without pre-eclampsia. Hypoxic conditions increased apoptosis of HTR8/SVneo trophoblast cells and induced IMUP-2 expression. Also, apoptosis of HTR-8/SVneo trophoblast cells was increased after IMUP-2 gene transfection. These results suggest that IMUP-2 expression is specifically elevated in preterm pre-eclampsia and under hypoxic conditions, and that IMUP-2 induces apoptosis of the trophoblast. Therefore, IMUP-2 might have functional involvement in placental development and gynecological diseases such as pre-eclampsia.

Dynamic alterations in integrin α4 expression by hypoxia are involved in trophoblast invasion during early implantation

“…In particular, low O 2 tension is a critical determinant of trophoblast fate and function, and of the expression of several genes during placentation [Wyatt et al, 2005;Huppertz et al, 2009]. Furthermore, we reported that increased immortalizationupregulated protein 2 (IMUP-2), a novel protein found in trophoblasts under hypoxic conditions, induces preeclampsia and apoptosis in trophoblasts [Jeon et al, 2010]. Therefore, hypoxic conditions during implantation and early pregnancy are one of the most important environmental factors dynamically regulating gene expression.…”

Only humans have human placentas: molecular differences between mice and humans

“…It is important to note that glycodelin itself is a primate-specific protein (Soni and Karande, 2010). Jeon et al (2010) report on a human-specific protein isoform with a potential role in the placenta, the splice variant IMUP-2 (immortalization-upregulated protein-2), which is involved in pathophysiological processes in preeclampsia. It is expressed significantly more highly in placental tissues of patients with preterm preeclampsia compared with those from women with preeclampsia who went to term.…”

Effect of Immortalization-Upregulated Protein-2 (IMUP-2) on Cell Death of Trophoblast

“…However, increased IMUP-2 by hypoxia induced apoptosis in trophoblasts of placenta. In previous reports, we demonstrated that IMUP-2 mRNA was expressed in syncytiotrophoblasts, syncytial knots, and decidual cells of the placental villi, however, IMUP-2 mRNA expression was strong in syncytiotrophoblasts and syncytial knots within pre-eclamptic placentas, which induced apoptosis of the trophoblast ( Jeon et al, 2010 ). Syncytial fusion by caspase 8, 9, and 10 activities in cytotrophoblasts and the formation of syncytial knots in syncytiontrophoblasts has been reported to induce apoptosis of trophoblasts ( Huppertz et al, 1998 ; Huppertz et al, 1999 ).…”

“…Although IMUPs are known for their cellular proliferation and cell death, however, trophoblastic effectiveness is not well known. A recent study showed placentas with an obstetrical disease, such as pre-eclampsia, have an excess of IMUPs compared with normal placentas and the excess IMUPs can cause cell death ( Jeon et al, 2010 ).…”