Immunohistochemical Expression of Cell Cycle Proteins E2F-1, Cdk-2, Cyclin E, p27kip1, and Ki-67 in Normal Placenta and Gestational Trophoblastic Disease

Olvera, Maria; Harris, Selena; Amezcua, Charles A.; McCourty, Althea; Rezk, Sherif; Koo, Charles; Felix, Janine F.; Brynes, Russell K.

doi:10.1038/modpathol.3880432

Cited by 44 publications

(23 citation statements)

References 36 publications

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“…PRb expression was inversely correlated with MIB-1 proliferative activity in tumor cells. 34,35 There was a positive correlation between the MIB-1 and E2F-1 indices, [36][37][38] and an increase in these two proliferative indices could be interpreted as consistent with an inverse correlation with pRb function. There were some reports about correlation between E2F-1 and clinicopathological prognostic factors.…”

Section: Discussionmentioning

confidence: 90%

Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma

et al. 2004

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Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in children. Some reports have discussed the altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma; however, variable frequencies of occurrence have been noted. In the current study, among 72 cases of rhabdomyosarcoma, the authors evaluated for the expression of p53, MDM2, p16, p21/WAF1, p27, cyclin D1, cyclin E, pRb and E2F-1 protein immunohistochemically and assessed for proliferative activities using MIB-1. We also analyzed the mutation of the p53 gene in 45 cases, the amplification of the MDM2 gene in 18 cases and the mutation of the H-ras gene in 29 cases, using formalin-fixed paraffin-embedded materials. Furthermore, we assessed the correlation between clinicopathologic factors and the results of both immunohistochemical and molecular analyses. Alveolar type affected older patients, and it had a significantly higher mitotic rate compared with the embryonal type (P ¼ 0.0226). p53 overexpression was detected in 22 (30.6%) of 72 cases, and 10 (22.2%) of 45 cases had p53 gene abnormalities. As for MDM2, its overexpression was found in nine (12.5%) of 72 cases, and three (16.7%) of 18 cases showed MDM2 amplification. A statistically significant association was observed between immunoreaction for MDM2 and p53 overexpression (P ¼ 0.0002), and p53 and MDM2 overexpression was significantly correlated with high MIB-1 labeling indices. E2F-1 labeling indices showed a significantly higher score in alveolar type compared with that seen in embryonal type (P ¼ 0.0334), but MIB-1 did not. In conclusion, our study suggests that p53 overexpression may be related to tumor progression because tumors with p53 overexpression have a high proliferative activity in the current study. Alveolar type had a significantly higher both mitotic rate and E2F-1 labeling indices when compared with the embryonal type. The current study is the first report of the correlation of E2F-1 with alveolar rhabdomyosarcoma.

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Section: Discussionmentioning

confidence: 90%

Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma

et al. 2004

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“…Recent studies suggest that also cyclin E/ CDK2 complex acts to regulate cell cycle proliferation in human placenta phosphorylating/inactivating pRB. Particularly, it has been demonstrated that also cyclin E was expressed at moderate levels in the villous cytotrophoblast basal layer during gestation and that also this protein was correlated with proliferation (McKenzie et al 1998;Bamberger et al 1999;Olvera et al 2001). …”

Section: Discussionmentioning

confidence: 99%

Pattern of expression of cyclin D1/CDK4 complex in human placenta during gestation

et al. 2004

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Progression through the cell cycle in eukaryotic cells is controlled by a family of protein kinases, termed cyclin-dependent kinases (CDKs), and their specific partners, the cyclins. In particular, the control of mammalian cell proliferation occurs largely during the G1 phase of the cell cycle. Five mammalian G1 cyclins have been enumerated to date: cyclins D1, D2, and D3 (D-type cyclins), and cyclins E and E2. By the use of immunohistochemistry and immunoelectron microscopy, we observed that in the first trimester of gestation of human placenta, cyclin D1 was distributed in the nuclei of the cytotrophoblast compartment together with a weak positivity of endothelial cells surrounding blood vessels. The endothelial positivity of cyclin D1 strongly increased in the third trimester of gestation. Moreover, we observed the subcellular localization of cyclin D1 that was present both in the stroma of placental villi and in the nuclei of syncytiotrophoblast cells. Therefore, we observed that CDK4 was localized in the nuclei of the cytotrophoblast compartment during the first and third trimesters and it also had a nuclear positivity in the endothelial cells of blood vessels at the end of the third trimester of gestation. In conclusion we may hypothesize that cyclin D1/CDK4 complex functions to regulate the cell cycle progression in the proliferative compartment of human placenta, the cytotrophoblast, during the first trimester through interaction with p107 and p130. Therefore, cyclin D1 and CDK4 seem to be involved in the control of placental angiogenesis during the third trimester of gestation.

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“…Double immunohistochemical labelling with cytokeratin 7 allowed clear identification of the EVT and their expression of the cell cycle regulators, thus ruling out any confusion with the large leucocyte population present in the decidua at early stages in gestation. Other studies on cell cycle regulators have either not reported on the EVT or not distinguished between proximal and distal cells of the cell columns (Deloia et al 1997;Bamberger et al 1999;Olvera et al 2001;De Falco et al 2004). The set of cell cycle regulators present in the cell column strongly suggests that the cells in both the proximal and distal parts do not acutely proliferate.…”

Section: Cip/kip Cell Cycle Inhibitorsmentioning

confidence: 97%

“…They may become active in some situations characterized by a concomitant downregulation of p27 or p57, thus releasing the inhibition and allowing the cells to progress through the cell cycle. Indeed EVT p27 expression is lost in gestational trophoblastic disease such as complete hydatidiform moles and choriocarcinoma (Olvera et al 2001). In contrast to the cells that have superficially invaded the deciduas, EVT deep in the decidua have lost any proliferative potential similar to the syncytiotrophoblast.…”

Section: Cell Cycle Exit Of Evt In Deep Deciduasmentioning

confidence: 99%

Location of cell cycle regulators cyclin B1, cyclin A, PCNA, Ki67 and cell cycle inhibitors p21, p27 and p57 in human first trimester placenta and deciduas

Korgun

Çelik-Özenci

Acar

et al. 2006

Histochem Cell Biol

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Although placental development and implantation depend on the coordination of trophoblast proliferation, differentiation and invasion, little is known about the cell cycle regulators that govern the control of these events. The hypothesis that the coordinated expression of cell cycle progression and inhibition factors will determine whether cytotrophoblasts proliferate or undergo cell cycle arrest or cell cycle exit allowing subsequent differentiation was tested. The cell cycle promotors cyclin A, cyclin B1, PCNA, Ki67 and the cell cycle inhibitors p21, p27 and p57 were immunolocalized in tissue sections of first trimester pregnancies (weeks 6 and 9-12). Double staining with cytokeratin 7 allowed unambiguous identification of extravillous cytotrophoblast (EVT) in the decidua. Villous cytotrophoblasts were immunolabelled for Ki67 and cyclin A but only few were stained with anti-cyclin B1. The syncytiotrophoblast was devoid of immunoreactivity for any of the cell cycle progression factors. It expressed especially p21, whereas p27 and p57 were predominantly found in villous cytotrophoblasts. PCNA, Ki67, cyclin A and cyclin B1 were immunolocalized in proximal and distal EVTs of anchoring villi and in EVT which had invaded the upper decidual segments. All EVTs strongly expressed p27 and p57, but not p21. These data clearly suggest different functions for p21, p27 and p57 in placental development with distinct roles for p21 and p57 in syncytiotrophoblast and EVT differentiation, respectively. p27 appears to be involved in both the processes. The results may also challenge the concept of differential mitotic activity in the proximal and distal parts of the first trimester cytotrophoblast cell column, but more functional studies are clearly needed. The presence of p27 and p57 in EVT cells, which invade the deciduas deeply, may account for the loss of mitogenic potential of these cells.

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Immunohistochemical Expression of Cell Cycle Proteins E2F-1, Cdk-2, Cyclin E, p27kip1, and Ki-67 in Normal Placenta and Gestational Trophoblastic Disease

Cited by 44 publications

References 36 publications

Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma

Altered expression and molecular abnormalities of cell-cycle-regulatory proteins in rhabdomyosarcoma

Pattern of expression of cyclin D1/CDK4 complex in human placenta during gestation

Location of cell cycle regulators cyclin B1, cyclin A, PCNA, Ki67 and cell cycle inhibitors p21, p27 and p57 in human first trimester placenta and deciduas

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