Changes related to phosphatidylinositol 3-kinase/Akt signaling in leiomyomas: possible involvement of glycogen synthase kinase 3α and cyclin D2 in the pathophysiology

Karra, Laila; Shushan, Asher; Ben‐Meir, Assaf; Rojansky, Nathan; Klein, Benjamin Y.; Shveiky, David; Levitzki, Rubina; Ben-Bassat, Hanna

doi:10.1016/j.fertnstert.2009.03.100

Cited by 48 publications

(42 citation statements)

References 27 publications

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“…The pathophysiology of myomas appears to involve Akt signaling, since myomas show higher levels of Akt than myometrium as well as aberrant Akt activation (identified by its phosphorylation, p-Akt) [7], which is essential for their growth and survival [64, 69]. Progesterone mediates rapid changes in myoma cells through a non-genomic PR signaling pathway [44] that phosphorylates Akt at Ser473 [13].…”

Section: Discussionmentioning

confidence: 99%

Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation

Courtoy

Donnez

Marbaix

et al. 2017

Gynecol Obstet Invest

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Objective: To investigate whether ulipristal acetate (UPA) treatment modifies the expression of progesterone receptor (PR), its nuclear cofactors steroid receptor coactivator-1 (SRC1) and nuclear corepressor-1 (NCoR1), prosurvival factor B-cell lymphoma 2 (Bcl-2), and Akt in uterine myomas. Patients: Prospective study of 59 women with symptomatic myomas undergoing myomectomy. Forty-two patients were treated preoperatively with UPA; the remaining 17 were not and they served as controls. Method: Tissue microarrays were obtained from surgical specimens and immunohistochemistry was performed. Blinded quantification of expression of PR (PR-A vs. PR-B), coactivator SRC1 and corepressor NCoR1, and prosurvival factor Bcl-2, and Akt and evaluation of Akt phosphorylation levels. Results: Compared with the control group, UPA does not alter PR protein levels or expression patterns in myomas, and the PR-A/PR-B ratio was similar, as well as cytoplasmic or nuclear expression of cofactors SRC1 and NCoR1. Bcl-2 was heterogeneously expressed throughout the samples and no significant modification in expression was evidenced. No significant difference was found in Akt expression and phosphorylation between treated and untreated myomas. Conclusion: This study did not find any significant change in the expression of the studied factors in myomas after UPA exposure. In conclusion, various theories on myomas cells proposed on the basis of in vitro studies are not supported in vivo.

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Section: Discussionmentioning

confidence: 99%

Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation

Courtoy

Donnez

Marbaix

et al. 2017

Gynecol Obstet Invest

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“…Karra and colleagues (92) found increased expression of glycogen synthase kinase 3 (GSK3) and cyclin D 2 in leiomyoma compared with myometrium, with interaction between phosphorylated GSK3 and Akt. In addition, Jeong and colleagues (93) demonstrated that leiomyomas express lower levels of phospho-Akt and phosphatidylinositol-3,4,5-triphosphate (PIP 3 ) but higher PTEN levels.…”

Section: Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Borahay

Al-Hendy

Kılıç

et al. 2015

Mol Med

128

147

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Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics.

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“…Alternative mechanisms including epigenetic variations, microRNA-mediated posttranscriptional gene regulation, and altered cell signaling have recently gained traction as putative disease initiating events (7)(8)(9)(10)(11)(12). Several recent studies have demonstrated a central role for a dysregulated phosphoinositide 3-kinase-protein kinase B/AKT (PI3K/AKT) pathway leading to the activation of mammalian target of rapamycin (mTOR) in the pathogenesis of leiomyomas (13)(14)(15). There is a need to identify signaling molecules upstream of mTOR that differentially activate this pathway in fibroids compared with normal myometrium.…”

mentioning

confidence: 99%

Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway

Varghese¹,

Koohestani²,

McWilliams³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Uterine fibroids (leiomyomas) are the most common tumors of the female reproductive tract, occurring in up to 77% of reproductiveaged women, yet molecular pathogenesis remains poorly understood. A role for atypically activated mammalian target of rapamycin (mTOR) pathway in the pathogenesis of uterine fibroids has been suggested in several studies. We identified that G protein-coupled receptor 10 [GPR10, a putative signaling protein upstream of the phosphoinositide 3-kinase-protein kinase B/AKT-mammalian target of rapamycin (PI3K/AKT-mTOR) pathway] is aberrantly expressed in uterine fibroids. The activation of GPR10 by its cognate ligand, prolactin releasing peptide, promotes PI3K-AKT-mTOR pathways and cell proliferation specifically in cultured primary leiomyoma cells. Additionally, we report that RE1 suppressing transcription factor/neuron-restrictive silencing factor (REST/NRSF), a known tumor suppressor, transcriptionally represses GPR10 in the normal myometrium, and that the loss of REST in fibroids permits GPR10 expression. Importantly, mice overexpressing human GPR10 in the myometrium develop myometrial hyperplasia with excessive extracellular matrix deposition, a hallmark of uterine fibroids. We demonstrate previously unrecognized roles for GPR10 and its upstream regulator REST in the pathogenesis of uterine fibroids. Importantly, we report a unique genetically modified mouse model for a gene that is misexpressed in uterine fibroids.

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Changes related to phosphatidylinositol 3-kinase/Akt signaling in leiomyomas: possible involvement of glycogen synthase kinase 3α and cyclin D2 in the pathophysiology

Cited by 48 publications

References 27 publications

Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation

Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway

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