Ablation of bcl-2 gene expression decreases the numbers of oocytes and primordial follicles established in the post-natal female mouse gonad.

Ratts, Valerie S.; Flaws, Jodi A.; Kolp, Rebecca; Sorenson, Christine M.; Tilly, J L

doi:10.1210/endo.136.8.7628407

Cited by 249 publications

(104 citation statements)

References 12 publications

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“…In physiological granulosa cells, genes of Bcl-2 family are known to play key role in the regulation of the intrinsic apoptosis pathway (Pru & Tilly 2001). In animal studies, Bcl-2 knockout mice demonstrate decreased number of follicles (Ratts et al 1995), whereas granulosa cell apoptosis is compromised in transgenic mice overexpressing Bcl-2 (Hsu et al 1996). Intriguingly, the transcription factor GATA4 is known to regulate the expression of Bcl-2 in human GCTs (Kyronlahti et al 2008).…”

Section: Discussionmentioning

confidence: 99%

“…In ovaries, the physiological importance of Bcl-2 family in regulating the intrinsic pathway has been extensively studied (Pru & Tilly 2001). Granulosa cell apoptosis is compromised in transgenic mice overexpressing the anti-apoptotic factor Bcl-2 (Hsu et al 1996), whereas the number of follicles is reduced in Bcl-2 null mice (Ratts et al 1995). Recently, we have demonstrated high level expression of Bcl-2 in a majority of human GCTs, suggesting a role for Bcl-2 in the regulation of apoptosis in these tumors (Kyronlahti et al 2008).…”

Section: Introductionmentioning

confidence: 99%

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GATA4 protects granulosa cell tumors from TRAIL-induced apoptosis

Kyrönlahti¹,

Kauppinen²,

Lind³

et al. 2010

Endocrine-Related Cancer

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Disturbances in granulosa cell apoptosis have been implicated in the pathogenesis of human granulosa cell tumors (GCTs). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cytokine that induces apoptosis in a variety of malignancies without toxic effects on benign cells. The aim of this study was to investigate the expression and functionality of the TRAIL receptors DR4 and DR5 in human GCTs. Additionally, we examined the role of GATA4, a transcription factor expressed in normal and malignant granulosa cells, in TRAIL-induced GCT apoptosis. For this purpose, a tissue microarray of 80 primary and 12 recurrent GCTs was subjected to immunohistochemistry for DR4 and DR5, and freshly isolated primary GCT cultures were utilized to evaluate the functional effects of TRAIL on GCT cells. To clarify the role of GATA4 in the regulation of TRAIL-induced apoptosis, a human GCT-derived cell line (KGN) was transduced with lentiviral vectors expressing small hairpin RNAs targeting GATA4 or transfected with adenovirus expressing either wild-type or dominant negative mutant GATA4. We found that receptors DR4 and DR5 are expressed in a vast majority of GCTs as well as in primary GCT cultures, and that TRAIL induces apoptosis in the primary GCT cultures. Moreover, we showed that overexpressing GATA4 protects GCTs from TRAIL-induced apoptosis in vitro, whereas disrupting GATA4 function induces apoptosis and potentiates the apoptotic effect of TRAIL administration. Our results demonstrate that the TRAIL pathway is functional in GCT cells, and suggest that transcription factor GATA4 may function as a survival factor in this ovarian malignancy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GATA4 protects granulosa cell tumors from TRAIL-induced apoptosis

Kyrönlahti¹,

Kauppinen²,

Lind³

et al. 2010

Endocrine-Related Cancer

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“…Bcl-2 is found mainly in developing follicles while Bax is seen mainly in atretic follicles (Van Nassauw et al 1999). Moreover, several previous studies described the important role of Bcl-2 in ovarian apoptosis (Hussein 2005), including decreased numbers of follicles in Bcl-2-deficient mice (Ratts et al 1995). Excessive expression of Bcl-2 leads to decreased follicular apoptosis and atresia (Hsu et al 1996, Morita & Tilly 1999.…”

Section: Effect Of Resistin On Cell Apoptosismentioning

confidence: 99%

Resistin is a survival factor for porcine ovarian follicular cells

Rak¹,

Drwal²,

Wróbel³

et al. 2015

Reproduction

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Previously, we demonstrated the expression of resistin in the porcine ovary, the regulation of its expression and its direct effect on ovarian steroidogenesis. The objective of this study was to examine the effect of resistin on cell proliferation and apoptosis in a co-culture model of porcine granulosa and theca cells. First, we analysed the effect of resistin at 1 and 10 ng/ml alone or in combination with FSHand IGF1 on ovarian cell proliferation with an alamarBlue assay and protein expression of cyclins A and B using western blot. Next, the mRNA and protein expression of selected pro-apoptotic and pro-survival regulators of cell apoptosis, caspase-9, -8 and -3 activity and DNA fragmentation using real time PCR, western blot, fluorescent assay and an ELISA kit, respectively, were analysed after resistin treatment. Furthermore, we determined the effect of resistin on the protein expression of ERK1/2, Stat and Akt kinase. Using specific inhibitors of these kinases, we also checked caspase-3 activity and protein expression. We found that resistin, at both doses, has no effect on cell proliferation. The results showed that resistin decreased pro-apoptotic genes, which was confirmed on protein expression of selected factors. We demonstrate an inhibitory effect of resistin on caspase activity and DNA fragmentation. Finally, resistin stimulated phosphorylation of the ERK1/2, Stat and Akt and kinases inhibitors reversed resistin action on caspase-3 activity and protein expression to control. All of these results showed that resistin has an inhibitory effect on porcine ovarian cell apoptosis by activation of the MAPK/ERK, JAK/Stat and Akt/PI3 kinase signalling pathways. Reproduction (2015) 150 343-355

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“…Several studies suggest that germ cell death is mediated by the intrinsic (also known as the 'mitochondrial', 'BCL2-regulated' or 'stress-induced') apoptosis pathway (Ratts et al 1995, Felici et al 1999, Rucker et al 2000, Greenfeld et al 2007a, Ene et al 2013, Myers et al 2014. The intrinsic apoptosis pathway is regulated by the relative levels and activities of pro-and anti-apoptotic members of the BCL2 protein family (Youle & Strasser 2008, Czabotar et al 2014.…”

Section: Introductionmentioning

confidence: 99%

BCL2-modifying factor promotes germ cell loss during murine oogenesis

Vaithiyanathan¹,

Liew²,

Zerafa³

et al. 2016

Reproduction

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Apoptosis plays a prominent role during ovarian development by eliminating large numbers of germ cells from the female germ line. However, the precise mechanisms and regulatory proteins involved in germ cell death are yet to be determined. In this study, we characterised the role of the pro-apoptotic BH3-only protein, BCL2-modifying factor (BMF), in germ cell apoptosis in embryonic and neonatal mouse ovaries. BMF protein was immunohistochemically localised to germ cells at embryonic days 15.5 (E15.5) and E17.5 and postnatal day 1 (PN1), coincident with entry into the meiotic prophase, but was undetectable at E13.5, and only present at low levels at PN3 and PN5. Consistent with this expression pattern, loss of BMF in female mice was associated with a decrease in apoptosis at E15.5 and E17.5. Furthermore, increased numbers of germ cells were found in ovaries from Bmf −/− mice compared with WT animals at E15.5 and PN1. However, germ cell numbers were comparable between Bmf −/− and WT ovaries at PN3, PN5 and PN10. Collectively, these data indicate that BMF mediates foetal oocyte loss and its action limits the maximal number of germ cells attained in the developing ovary, but does not influence the number of primordial follicles initially established in ovarian reserve.

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Ablation of bcl-2 gene expression decreases the numbers of oocytes and primordial follicles established in the post-natal female mouse gonad.

Cited by 249 publications

References 12 publications

GATA4 protects granulosa cell tumors from TRAIL-induced apoptosis

GATA4 protects granulosa cell tumors from TRAIL-induced apoptosis

Resistin is a survival factor for porcine ovarian follicular cells

BCL2-modifying factor promotes germ cell loss during murine oogenesis

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