scholarly journals Maternal Obesity Alters Placental Cell Cycle Regulators in the First Trimester of Human Pregnancy: New Insights for BRCA1

2020 ◽  
Vol 21 (2) ◽  
pp. 468 ◽  
Author(s):  
Denise Hoch ◽  
Martina Bachbauer ◽  
Caroline Pöchlauer ◽  
Francisco Algaba-Chueca ◽  
Veronika Tandl ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Maternal Obesity ◽  
First Trimester ◽  
Cell Cycle Regulators ◽  
Placental Development ◽  
Cell Cycle Protein ◽  
Short Term Treatment ◽  
Placental Cell ◽  
Human Pregnancy ◽  
Wide Range

In the first trimester of pregnancy, placental development involves a wide range of cellular processes. These include trophoblast proliferation, fusion, and differentiation, which are dependent on tight cell cycle control. The intrauterine environment affects placental development, which also includes the trophoblast cell cycle. In this work, we focus on maternal obesity to assess whether an altered intrauterine milieu modulates expression and protein levels of placental cell cycle regulators in early human pregnancy. For this purpose, we use first trimester placental tissue from lean and obese women (gestational week 5+0–11+6, n = 58). Using a PCR panel, a cell cycle protein array, and STRING database analysis, we identify a network of cell cycle regulators increased by maternal obesity in which breast cancer 1 (BRCA1) is a central player. Immunostaining localizes BRCA1 predominantly to the villous and the extravillous cytotrophoblast. Obesity-driven BRCA1 upregulation is not able to be explained by DNA methylation (EPIC array) or by short-term treatment of chorionic villous explants at 2.5% oxygen with tumor necrosis factor α (TNF-α) (50 mg/mL), leptin (100 mg/mL), interleukin 6 (IL-6) (100 mg/mL), or high glucose (25 nM). Oxygen tension rises during the first trimester, but this change in vitro has no effect on BRCA1 (2.5% and 6.5% O2). We conclude that maternal obesity affects placental cell cycle regulation and speculate this may alter placental development.

scholarly journals Loss of CIC promotes mitotic dysregulation and chromosome segregation defects

2019 ◽  
Author(s):  
Suganthi Chittaranjan ◽  
Jungeun Song ◽  
Susanna Y. Chan ◽  
Stephen Dongsoo Lee ◽  
Shiekh Tanveer Ahmad ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromosome Segregation ◽  
Mammalian Cells ◽  
Chromosomal Instability ◽  
Spindle Assembly Checkpoint ◽  
Tumour Suppressor ◽  
Cell Cycle Regulators ◽  
Loss Of Function ◽  
Wide Range ◽  
Cancer Types

AbstractBackgroundCIC is a transcriptional repressor inactivated by loss-of-function mutations in several cancer types, including gliomas, lung cancers, and gastric adenocarcinomas. CIC alterations and/or loss of CIC activity have been associated with poorer outcomes and more aggressive phenotypes across cancer types, which is consistent with the notion that CIC functions as a tumour suppressor across a wide range of contexts.ResultsUsing mammalian cells lacking functional CIC, we found that CIC deficiency was associated with chromosome segregation (CS) defects, resulting in chromosomal instability and aneuploidy. These CS defects were associated with transcriptional dysregulation of spindle assembly checkpoint and cell cycle regulators. We also identified novel CIC interacting proteins, including core members of the SWI/SNF complex, and showed that they cooperatively regulated the expression of genes involved in cell cycle regulation. Finally, we showed that loss of CIC and ARID1A cooperatively increased CS defects and reduced cell viability.ConclusionsOur study ascribes a novel role to CIC as an important regulator of the cell cycle and demonstrates that loss of CIC can lead to chromosomal instability and aneuploidy in human and murine cells through defects in CS, providing insight into the underlying mechanisms of CIC’s increasingly apparent role as a “pan-cancer” tumour suppressor.

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

2006 ◽  
Vol 125 (6) ◽  
pp. 615-624 ◽  
Author(s):  
Emin Türkay Korgun ◽  
Ciler Celik-Ozenci ◽  
Nuray Acar ◽  
Sevil Cayli ◽  
Gernot Desoye ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin A ◽  
First Trimester ◽  
Cyclin B1 ◽  
Cell Cycle Regulators ◽  
Cell Cycle Inhibitors

scholarly journals Temperature-Induced Uncoupling of Cell Cycle Regulators

2020 ◽  
Author(s):  
Hanieh Falahati ◽  
Woonyung Hur ◽  
Stefano Di Talia ◽  
Eric F. Wieschaus
Keyword(s):  
Cell Cycle ◽  
Perturbation Method ◽  
Chromosome Condensation ◽  
Feedback Loops ◽  
Differential Sensitivity ◽  
Cell Cycle Regulators ◽  
Signaling Systems ◽  
Wide Range ◽  
Rate Limiting

AbstractWhile feedback loops are essential for robustness in signaling systems, they make discerning the role of individual components challenging. Here we introduce temperature as a powerful perturbation method for uncoupling enzymatic processes, by exposing the differential sensitivity of limiting reactions to temperature due to their activation energies. Using this method, we study the sensitivity to temperature of different cell cycle events of early fly embryos. While the subdivision of cell cycle steps is conserved across a wide range of temperatures (5-35°C), the transition into prometaphase exhibits the most sensitivity, arguing that it has a different mechanism of regulation. Using a biosensor, we quantify the activity of Cdk1 and show that the activation of Cdk1 drives entry into prometaphase but is not required for earlier events. In fact, chromosome condensation can still occur when Cdk1 is inhibited pharmacologically. These results demonstrate that different kinases are rate-limiting for different steps of mitosis.

scholarly journals The insulin receptor adaptor IRS2 is an APC/C substrate that promotes cell cycle protein expression and a robust spindle assembly checkpoint

2019 ◽  
Author(s):  
Sandhya Manohar ◽  
Qing Yu ◽  
Steven P. Gygi ◽  
Randall W. King
Keyword(s):  
Cell Cycle ◽  
Insulin Receptor ◽  
Tyrosine Kinases ◽  
Cell Cycle Progression ◽  
Spindle Assembly Checkpoint ◽  
Cell Cycle Control ◽  
Spindle Assembly ◽  
Cell Cycle Regulators ◽  
Cell Cycle Protein ◽  
Proteomic Screen

AbstractInsulin receptor substrate 2 (IRS2) is an essential adaptor that mediates signaling downstream of the insulin receptor and other receptor tyrosine kinases. Transduction through IRS2-dependent pathways is important for coordinating metabolic homeostasis, and dysregulation of IRS2 causes systemic insulin signaling defects. Despite the importance of maintaining proper IRS2 abundance, little is known about what factors mediate its protein stability. We conducted an unbiased proteomic screen to uncover novel substrates of the Anaphase Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that controls the abundance of key cell cycle regulators. We found that IRS2 levels are regulated by APC/C activity and that IRS2 is a direct APC/C target in G1. Consistent with the APC/C’s role in degrading cell cycle regulators, quantitative proteomic analysis of IRS2-null cells revealed a deficiency in proteins involved in cell cycle progression. We further show that cells lacking IRS2 display a weakened spindle assembly checkpoint in cells treated with microtubule inhibitors. Together, these findings reveal a new pathway for IRS2 turnover and indicate that IRS2 is a component of the cell cycle control system in addition to acting as an essential metabolic regulator.

scholarly journals Knockdown of Splicing Complex Protein PCBP2 Reduces Extravillous Trophoblast Differentiation Through Transcript Switching

2021 ◽  
Vol 9 ◽  
Author(s):  
Danai Georgiadou ◽  
Souad Boussata ◽  
Remco Keijser ◽  
Dianta A. M. Janssen ◽  
Gijs B. Afink ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Hellp Syndrome ◽  
Rna Splicing ◽  
Ex Vivo ◽  
First Trimester ◽  
Cellular Growth ◽  
Extravillous Trophoblast ◽  
Placental Development ◽  
Alternative Mrna Splicing

Mutations in the LINC-HELLP non-coding RNA (HELLPAR) have been associated with familial forms of the pregnancy-specific HELLP syndrome. These mutations negatively affect extravillous trophoblast (EVT) differentiation from a proliferative to an invasive state and disturb the binding of RNA splicing complex proteins PCBP1, PCBP2, and YBX1 to LINC-HELLP. In this study, by using both in vitro and ex vivo experiments, we investigate if these proteins are involved in the regulation of EVT invasion during placentation. Additionally, we study if this regulation is due to alternative mRNA splicing. HTR-8/SVneo extravillous trophoblasts and human first trimester placental explants were used to investigate the effect of siRNA-mediated downregulation of PCBP1, PCBP2, and YBX1 genes on the differentiation of EVTs. Transwell invasion assays and proliferation assays indicated that upon knockdown of PCBP2 and, to a lesser extent, YBX1 and PCBP1, EVTs fail to differentiate toward an invasive phenotype. The same pattern was observed in placental explants where PCBP2 knockdown led to approximately 80% reduction in the number of explants showing any EVT outgrowth. Of the ones that still did show EVT outgrowth, the percentage of proliferating EVTs was significantly higher compared to explants transfected with non-targeting control siRNAs. To further investigate this effect of PCBP2 silencing on EVTs, we performed whole transcriptome sequencing (RNA-seq) on HTR-8/SVneo cells after PCBP2 knockdown. PCBP2 knockdown was found to have minimal effect on mRNA expression levels. In contrast, PCBP2 silencing led to a switch in splicing for a large number of genes with predominant functions in cellular assembly and organization, cellular function and maintenance, and cellular growth and proliferation and the cell cycle. EVTs, upon differentiation, alter their function to be able to invade the decidua of the mother by changing their cellular assembly and their proliferative activity by exiting the cell cycle. PCBP2 appears to be a paramount regulator of these differentiation mechanisms, where its disturbed binding to LINC-HELLP could contribute to dysfunctional placental development as seen in the HELLP syndrome.

scholarly journals Changes in cell cycle and extracellular matrix gene expression during placental development in deer mouse (Peromyscus) hybrids

2007 ◽  
Vol 19 (5) ◽  
pp. 695 ◽  
Author(s):  
Amanda R. Duselis ◽  
Craig Obergfell ◽  
Jennifer A. Mack ◽  
Michael J. O'Neill ◽  
Quang K. Nguyen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Extracellular Matrix ◽  
Deer Mouse ◽  
Cell Cycle Regulators ◽  
Placental Development ◽  
Altered Expression ◽  
Matrix Gene ◽  
Proliferation And Differentiation ◽  
Cycle Regulation

Crosses between two species of the rodent genus Peromyscus produce defects in both growth and development. The defects are pronounced in the hybrid placentas. Peromyscuys maniculatus (strain BW) females mated to P. polionotus (strain PO) males produce placentas half the size of the parental species, as well as growth-retarded embryos. In contrast, PO females mated to BW males result in defective conceptuses that display embryonic and placental overgrowth. These ‘parent-of-origin’-dependent phenotypes are consistent with previous studies that demonstrated altered expression of imprinted genes and genetic linkage of the overgrowth phenotypes to imprinted domains. In the present study, we take a broader approach in assessing perturbations in hybrid placental gene expression through the use of Mus musculus cDNA microarrays. In verifying classes of genes identified in microarray screens differentially regulated during hybrid placental development, we focused on those influencing the cell cycle and extracellular matrix (ECM). Our work suggests that cell cycle regulators at the G1/S phase check-point are downregulated in the large hybrid placenta, whereas the small hybrid placenta is more variable. The ECM genes are typically downstream targets of cell cycle regulation and their misregulation is consistent with many of the dysmorphic phenotypes. Thus, these data suggest imbalances in proliferation and differentiation in hybrid placentation.

scholarly journals Functional Analysis of p21Cip1/CDKN1A and Its Family Members in Trophoblastic Cells of the Placenta and Its Roles in Preeclampsia

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2214
Author(s):  
Nina-Naomi Kreis ◽  
Alexandra Friemel ◽  
Lukas Jennewein ◽  
Samira Catharina Hoock ◽  
Anna Elisabeth Hentrich ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Signaling Pathways ◽  
Early Onset ◽  
Family Members ◽  
Delivery Mode ◽  
Cell Cycle Regulators ◽  
Placental Development ◽  
Trophoblastic Cells ◽  
Elevated Liver Enzymes

Preeclampsia (PE), a gestational hypertensive disease originating from the placenta, is characterized by an imbalance of various cellular processes. The cell cycle regulator p21Cip1/CDKN1A (p21) and its family members p27 and p57 regulate signaling pathways fundamental to placental development. The aim of the present study was to enlighten the individual roles of these cell cycle regulators in placental development and their molecular involvement in the pathogenesis of PE. The expression and localization of p21, phospho-p21 (Thr-145), p27, and p57 was immunohistochemically analyzed in placental tissues from patients with early-onset PE, early-onset PE complicated by the HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome as well as late-onset PE compared to their corresponding control tissues from well-matched women undergoing caesarean sections. The gene level was evaluated using real-time quantitative PCR. We demonstrate that the delivery mode strongly influenced placental gene expression, especially for CDKN1A (p21) and CDKN1B (p27), which were significantly upregulated in response to labor. Cell cycle regulators were highly expressed in first trimester placentas and impacted by hypoxic conditions. In support of these observations, p21 protein was abundant in trophoblast organoids and hypoxia reduced its gene expression. Microarray analysis of the trophoblastic BeWo cell line depleted of p21 revealed various interesting candidate genes and signaling pathways for the fusion process. The level of p21 was reduced in fusing cytotrophoblasts in early-onset PE placentas and depletion of p21 led to reduced expression of fusion-related genes such as syncytin-2 and human chorionic gonadotropin (β-hCG), which adversely affected the fusion capability of trophoblastic cells. These data highlight that cell cycle regulators are important for the development of the placenta. Interfering with p21 influences multiple pathways related to the pathogenesis of PE.

scholarly journals 6′-Sialyllactose Ameliorates in Vivo and in Vitro Benign Prostatic Hyperplasia by Regulating the E2F1/pRb–AR Pathway

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2203 ◽  
Author(s):  
Jin ◽  
Kim ◽  
Kim ◽  
Chung ◽  
Ha ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Benign Prostatic Hyperplasia ◽  
Specific Antigen ◽  
Prostatic Hyperplasia ◽  
Control Group ◽  
Therapeutic Effects ◽  
Cell Cycle Protein ◽  
Wide Range

Abstract: Background: 6′-Sialyllactose (6SL) displays a wide range of the bioactive benefits, such as anti-proliferative and anti-angiogenic activities. However, the therapeutic effects of 6SL on benign prostatic hyperplasia (BPH) remain unknown. Methods: Six-week-old male Wistar rats (n = 40) were used for in vivo experiments. All rats were castrated and experimental BPH was induced in castrated rats by intramuscular injection of testosterone, with the exception of those in the control group. Rats with BPH were administrated finasteride and 0.5 or 1.0 mg/kg 6SL. Furthermore, the inhibitory effects of 6SL on human epithelial BPH cell line (BPH-1) cells were determined in vitro. Results: Rats with BPH exhibited outstanding BPH manifestations, including prostate enlargement, histological alterations, and increased prostate-specific antigen (PSA) levels. Compared to those in the BPH group, rats in the 6SL group showed fewer pathological changes and normal androgen events, followed by restoration of retinoblastoma protein (pRb) and cell cycle-related proteins. In BPH-1 cells, treatment with 6SL significantly suppressed the effects on the androgen receptor (AR), PSA, and E2F transcription factor 1 (E2F1)-dependent cell cycle protein expression. Conclusions: 6SL demonstrated anti-proliferative effects in a testosterone-induced BPH rat model and on BPH-1 cells by regulating the pRB/E2F1–AR pathway. According to our results, we suggest that 6SL may be considered a potential agent for the treatment of BPH.

scholarly journals Type 1 Diabetes Mellitus and the First Trimester Placenta: Hyperglycemia-Induced Effects on Trophoblast Proliferation, Cell Cycle Regulators, and Invasion

2021 ◽  
Vol 22 (20) ◽  
pp. 10989
Author(s):  
Alejandro Majali-Martinez ◽  
Ursula Weiss-Fuchs ◽  
Heidi Miedl ◽  
Desiree Forstner ◽  
Julia Bandres-Meriz ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cell Cycle ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
First Trimester ◽  
Trophoblast Invasion ◽  
Cell Cycle Distribution ◽  
Cell Cycle Regulators ◽  
Gestational Week

Type 1 diabetes mellitus (T1DM) is associated with reduced fetal growth in early pregnancy, but a contributing role of the placenta has remained elusive. Thus, we investigated whether T1DM alters placental development in the first trimester. Using a protein array, the level of 60 cell-cycle-related proteins was determined in human first trimester placental tissue (gestational week 5–11) from control (n = 11) and T1DM pregnancies (n = 12). Primary trophoblasts (gestational week 7–12, n = 32) were incubated in the absence (control) or presence of hyperglycemia (25 mM D-glucose) and hyperosmolarity (5.5 mM D-glucose + 19.5 mM D-mannitol). We quantified the number of viable and dead trophoblasts (CASY Counter) and assessed cell cycle distribution (FACS) and trophoblast invasion using a transwell assay. T1DM was associated with a significant (p < 0.05) downregulation of Ki67 (−26%), chk1 (−25%), and p73 (−26%). The number of viable trophoblasts was reduced under hyperglycemia (−23%) and hyperosmolarity (−18%), whereas trophoblast invasion was increased only under hyperglycemia (+6%). Trophoblast cell death and cell cycle distribution remained unaffected. Collectively, our data demonstrate that hyperglycemia decreases trophoblast proliferation as a potential contributing factor to the reduced placental growth in T1DM in vivo.

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