The Inhibition of WIP1 Phosphatase Accelerates the Depletion of Primordial Follicles

In the present study, follicles were classified according to the morphology of their granulosa cells. Type B follicles contained only flattened granulosa cells; type B/C follicles had a mixture of flattened and cuboidal granulosa cells in a single layer, and type C follicles had a single layer of cuboidal granulosa cells. The primary objectives of the study were to determine whether 5-bromo-2-deoxyuridine incorporation into type B/C follicles was a marker for initiation of growth and how long type B/C follicles could remain at the same stage before transformation to type C follicles. Female Holtzman rats received bromo-deoxyuridine for 7 days. After the infusion (day minipumps were removed = day 0), rats were ovariectomized on days 0 (n = 9), 30 (n = 8), 90 (n = 8) and 150 (n = 9). The numbers of type B, B/C and C follicles within one ovary were determined using modified fractionator counting. Analysis over all times demonstrated that there were more (P < 0.0001) type B/C (941 +/- 61 per ovary) than type C (140 +/- 18 per ovary) or type B (159 +/- 19 per ovary) follicles. The numbers of type B and type C follicles did not differ from each other at any time. Only one of 34 rats evaluated had bromo-deoxyuridine-labelled type B follicles. On day 150, 57% of the bromo-deoxyuridine-labelled type B/C follicles remained from day 0. It is concluded that (1) DNA synthesis in granulosa cells of type B/C follicles is not a reliable indicator of impending growth; and (2) type B and type B/C follicles are both components of the pool of primordial follicles.

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Faculty Opinions recommendation of Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1017697.207703 ◽

2004 ◽

Author(s):

Francesc Posas

Keyword(s):

P38 Mapk ◽

Mammary Tumorigenesis ◽

Wip1 Phosphatase ◽

P16 Ink4a

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Faculty Opinions recommendation of WIP1 phosphatase suppresses the DNA damage response during G2/prophase arrest in mouse oocytes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733195347.793548972 ◽

2018 ◽

Author(s):

Keith Jones ◽

Jessica Sanders

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Mouse Oocytes ◽

Wip1 Phosphatase ◽

Damage Response

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MicroRNA profiling and identification of let-7a as a target to prevent chemotherapy-induced primordial follicles apoptosis in mouse ovaries

Scientific Reports ◽

10.1038/s41598-019-45642-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 8

Author(s):

C. Alexandri ◽

B. Stamatopoulos ◽

F. Rothé ◽

Y. Bareche ◽

M. Devos ◽

...

Keyword(s):

Primordial Follicles ◽

Microrna Profiling

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Cadmium exposure in newborn rats ovary induces developmental disorders of primordial follicles and the differential expression of SCF/c-kit gene

Toxicology Letters ◽

10.1016/j.toxlet.2017.08.004 ◽

2017 ◽

Vol 280 ◽

pp. 20-28 ◽

Cited By ~ 11

Author(s):

Wenchang Zhang ◽

Tingting Wu ◽

Chenyun Zhang ◽

Lingfeng Luo ◽

Meimei Xie ◽

...

Keyword(s):

Differential Expression ◽

Developmental Disorders ◽

Cadmium Exposure ◽

Newborn Rats ◽

Primordial Follicles ◽

Kit Gene

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Kisspeptin level in the aging ovary is regulated by the sympathetic nervous system

Journal of Endocrinology ◽

10.1530/joe-16-0181 ◽

2017 ◽

Vol 232 (1) ◽

pp. 97-105 ◽

Cited By ~ 12

Author(s):

Daniela Fernandois ◽

Gonzalo Cruz ◽

Eun Kyung Na ◽

Hernán E Lara ◽

Alfonso H Paredes

Keyword(s):

Adrenergic Receptor ◽

Follicular Development ◽

Sympathetic Nerves ◽

Female Rats ◽

Reproductive Aging ◽

Beta Adrenergic Receptor ◽

Beta Adrenergic ◽

Primordial Follicles ◽

Follicular Cyst

Previous work has demonstrated that the increase in the activity of sympathetic nerves, which occurs during the subfertility period in female rats, causes an increase in follicular cyst development and impairs follicular development. In addition, the increase in ovarian sympathetic activity of aged rats correlates with an increased expression of kisspeptin (KISS1) in the ovary. This increase in KISS1 could participate in the decrease in follicular development that occurs during the subfertility period. We aimed to determine whether the blockade of ovarian sympathetic tone prevents the increase in KISS1 expression during reproductive aging and improves follicular development. We performed 2 experiments in rats: (1) an in vivo blockade of beta-adrenergic receptor with propranolol (5.0 mg/kg) and (2) an ovarian surgical denervation to modulate the sympathetic system at these ages. We measured Kisspeptin and follicle-stimulating hormone receptor (FSHR) mRNA and protein levels by qRT-PCR and western blot and counted primordial, primary and secondary follicles at 8, 10 and 12 months of age. The results showed that ovarian KISS1 decreased but FSHR increased after both propranolol administration and the surgical denervation in rats of 8, 10 and 12 months of age. An increase in FSHR was related to an increase in the number of smaller secondary follicles and a decreased number of primordial follicles at 8, 10 and 12 months of age. These results suggest that intraovarian KISS1 is regulated by sympathetic nerves via a beta-adrenergic receptor and participates locally in ovarian follicular development in reproductive aging.

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Single-Oocyte Gene Expression Suggests That Curcumin Can Protect the Ovarian Reserve by Regulating the PTEN-AKT-FOXO3a Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22126570 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6570

Author(s):

Yue Lv ◽

Rui-Can Cao ◽

Hong-Bin Liu ◽

Xian-Wei Su ◽

Gang Lu ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Reserve ◽

Primordial Follicle ◽

Term Treatment ◽

New Drugs ◽

Gene Profiling ◽

Primordial Follicles ◽

Long Term Treatment ◽

Follicle Activation

A better understanding of the mechanism of primordial follicle activation will help us better understand the causes of premature ovarian insufficiency (POI), and will help us identify new drugs that can be applied to the clinical treatment of infertility. In this study, single oocytes were isolated from primordial and primary follicles, and were used for gene profiling with TaqMan array cards. Bioinformatics analysis was performed on the gene expression data, and Ingenuity Pathway Analysis was used to analyze and predict drugs that affect follicle activation. An ovarian in vitro culture system was used to verify the function of the drug candidates, and we found that curcumin maintains the ovarian reserve. Long-term treatment with 100 mg/kg curcumin improved the ovarian reserve indicators of AMH, FSH, and estradiol in aging mice. Mechanistic studies show that curcumin can affect the translocation of FOXO3, thereby inhibiting the PTEN-AKT-FOXO3a pathway and protecting primordial follicles from overactivation. These results suggest that curcumin is a potential drug for the treatment of POI patients and for fertility preservation.

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WIP1 Inhibition by GSK2830371 Potentiates HDM201 through Enhanced p53 Phosphorylation and Activation in Liver Adenocarcinoma Cells

Cancers ◽

10.3390/cancers13153876 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3876

Author(s):

Chiao-En Wu ◽

Chen-Yang Huang ◽

Chiao-Ping Chen ◽

Yi-Ru Pan ◽

John Wen-Cheng Chang ◽

...

Keyword(s):

Rna Sequencing ◽

Primary Liver Cancer ◽

P53 Protein ◽

Intrahepatic Bile Duct ◽

Cell Cycle Distribution ◽

P53 Signaling ◽

Adenocarcinoma Cells ◽

Wip1 Phosphatase ◽

P53 Activation ◽

Novel Strategy

Background: Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct. It is the second most common primary liver cancer and has a poor prognosis. Activation of p53 by targeting its negative regulators, MDM2 and WIP1, is a potential therapy for wild-type p53 cancers, but few reports for iCCA or liver adenocarcinoma exist. Methods: Both RBE and SK-Hep-1 liver adenocarcinoma cell lines were treated with the HDM201 (Siremadlin) MDM2-p53 binding antagonist alone or in combination with the GSK2830371 WIP1 phosphatase inhibitor. Cell proliferation, clonogenicity, protein and mRNA expression, cell cycle distribution, and RNA sequencing were performed to investigate the effect and mechanism of this combination. Results: GSK2830371 alone demonstrated minimal activity on proliferation and colony formation, but potentiated growth inhibition (two-fold decrease in GI50) and cytotoxicity (four-fold decrease in IC50) by HDM201 on RBE and SK-Hep-1 cells. HDM201 increased p53 protein expression, leading to transactivation of downstream targets (p21 and MDM2). Combination with GSK2830371 increased p53 phosphorylation, resulting in an increase in both p53 accumulation and p53-dependent trans-activation. G2/M arrest was observed by flow cytometry after this treatment combination. RNA sequencing identified 21 significantly up-regulated genes and five downregulated genes following p53 reactivation by HDM201 in combination with GSK2830371 at 6 h and 24 h time points compared with untreated controls. These genes were predominantly known transcriptional targets regulated by the p53 signaling pathway, indicating enhanced p53 activation as the predominant effect of this combination. Conclusion: The current study demonstrated that GSK2830371 enhanced the p53-dependent antiproliferative and cytotoxic effect of HDM201 on RBE and SK-Hep-1 cells, providing a novel strategy for potentiating the efficacy of targeting the p53 pathway in iCCA.

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