In Vivo and In Vitro Regulation of Akt Activation in Human Endometrial Cells Is Estrogen Dependent

Kayisli, Ozlem; Kayisli, Umit A.; Lülecı, Güven; Arıcı, Aydın

doi:10.1095/biolreprod.104.027235

Cited by 84 publications

(26 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this regard, we recently showed that a direct NgPLD-Akt interaction occurs during infection of pex cells, which results in increased Akt activity and which is critical for successful gonococcal infection and invasion of these cells (7). Although not shown for the cervix, Akt activity can be hormonally modulated in some cell types (14,15,40,48,57). Thus, I also wanted to determine whether Pg could rescue the impaired invasive capability of pld mutant gonococci, potentially, by contributing to Akt activation.…”

Section: Resultsmentioning

confidence: 99%

Neisseria gonorrhoeae Survival during Primary Human Cervical Epithelial Cell Infection Requires Nitric Oxide and Is Augmented by Progesterone

Edwards

2010

Infect Immun

View full text Add to dashboard Cite

Neisseria gonorrhoeae is an obligate human pathogen that causes gonorrhea. We have shown previously that complement receptor 3 and Akt kinase play important roles in mediating cervical infection. At present, there are limited data to indicate how hormonally induced changes to the mucosal epithelia of the female genital tract mediate the course of gonococcal disease. Hence, I have expanded upon previous work to investigate the interaction of gonococci with primary human cervical epithelial (pex) cells under the variable estrogen and progesterone concentrations likely to be encountered in vivo throughout the female menstrual cycle. My data indicated that the ability of gonococci to survive and to replicate within pex cells was increased under progesterone-predominant conditions. Using bacterial survival, immunological, and kinase assays, I show that progesterone functioned in an additive manner with gonococcal phospholipase D to augment Akt kinase activity. This, in turn, resulted in a parallel increase in nitric oxide synthase expression. Nitric oxide production by pex cells was dependent upon Akt activity and was increased under progesterone-predominant conditions. Whereas both inducible and endothelial nitric oxide synthase contributed to nitric oxide production, only inducible nitric oxide synthase activity promoted gonococcal survival within pex cells. Collectively, these data provide the first clues as to how steroid hormones potentially modulate the course of gonococcal disease in women. In addition, these data demonstrate that host-derived nitric oxide likely is not protective against gonococci, in vivo; rather, nitric oxide may be required to sustain cervical bacterial disease.Neisseria gonorrhoeae is an exclusive human pathogen that causes the sexually transmitted disease, gonorrhea. The gonococcus is highly human adapted and thus has developed variable mechanisms of pathogenesis that are, in part, dependent upon the site of infection (reviewed in reference 6). We have shown previously that complement receptor type 3 (CR3) serves as the key receptor by which gonococci initiate cervical infection in vivo, as well as ex vivo in primary human cervical epithelial (pex) cells (8). Gonococci exposed to pex cells release a group of proteins, including a phospholipase D (NgPLD), that facilitate cervical adherence and invasion (9).Invasion of certain epithelial cells by gonococci triggers (host) Akt activity (7, 31). Akt is a serine-threonine kinase implicated in diverse cellular functions, and several bacterial and viral pathogens have developed mechanisms by which to subvert Akt signaling to promote disease (7,22,26,28,53,56). In contrast to vulvular epidermal carcinoma (A-431) cells, in which gonococcus-induced Akt activity requires phosphatidylinositol 3-kinase (PI3K) (31), Akt activation in pex cells occurs independently of PI3K and results from the direct interaction of NgPLD with cervical Akt (7).Despite the many advances made in our understanding of gonococcal pathogenesis, the factors governing the diver...

show abstract

Section: Resultsmentioning

confidence: 99%

Neisseria gonorrhoeae Survival during Primary Human Cervical Epithelial Cell Infection Requires Nitric Oxide and Is Augmented by Progesterone

Edwards

2010

Infect Immun

View full text Add to dashboard Cite

show abstract

“…Morey et al (26) described the presence of membrane receptors in primary cultures of human vascular smooth muscle cells, which appear to be ERs, and also have shown that, when transfected into Chinese hamster ovary cells, the ER is membrane bound and can activate several signaling pathways, such as the ERK and c-Jun N-terminal kinase pathways (27). Previously, Guzeloglu-Kayisli et al (28) have shown that E 2 rapidly induces the phosphorylation of Akt/protein kinase B (PKB), which is a downstream regulator of phosphotidylinositol-3 kinase in ESCs. Recently, Acconcia et al (29) demonstrated the stimulation of Akt/PKB, ERK, and p38 MAPK by E 2 in ER␣-and/or ER␤-containing cell lines.…”

Section: Discussionmentioning

confidence: 99%

Estrogen-Mediated Regulation of p38 Mitogen-Activated Protein Kinase in Human Endometrium

Seval

Çakmak

Kayisli

et al. 2006

The Journal of Clinical Endocrinology & Metabolism

Self Cite

View full text Add to dashboard Cite

Context: Estrogen predominantly exerts its biological effects through the genomic pathway by binding to its intracellular receptors, interacting with the estrogen response element located in the promoter region of the target gene, and thus regulating gene transcription. There has been an increasing body of evidence regarding nongenomic actions of estrogen. Estrogen activates multiple signaling cascades, including the MAPK pathway. p38 MAPK plays key roles in mediating apoptosis, proliferation, and inflammation, which all take place in the endometrium during cyclical changes under the influence of estrogen.Objective: We hypothesized that estrogen might activate the p38 MAPK pathway in endometrial cells and exert some of its actions through this pathway in the endometrium.Interventions: p38 MAPK phosphorylation was analyzed using in vivo and in vitro techniques.Results: Total and phosphorylated p38 MAPK immunostainings were more intense in epithelial cells compared with stromal cells, and the phosphorylated/total p38 MAPK ratio was significantly higher in the functional endometrial layer compared with the basal layer (P Ͻ 0.05). Estradiol significantly increased p38 MAPK phosphorylation in endometrial stromal cells in culture within 2 min (P Ͻ 0.05), and this phosphorylation was blocked by a specific p38 MAPK inhibitor. Moreover, tamoxifen and raloxifene also increased phosphorylation of p38 MAPK. The estrogen receptor antagonist ICI 182,780 reversed the estrogen-induced p38 MAPK phosphorylation in endometrial stromal and epithelial cells, suggesting involvement of the estrogen receptor. Conclusion:Our results indicate the involvement of estrogen in regulating p38 MAPK activity in endometrial cells, suggesting a nongenomic action of estrogen through this MAPK in the endometrium.

show abstract

“…The E2 activation of the PIK3 protein thereafter induces the phosphorylation of AKT in endometrial cells (25) and the inactivation of the proapoptotic protein BAD, a member of the Bcl2 family that regulates the apoptotic response. E2 also inhibits SH3GLB1, an endophilin known to interact with the proapoptotic protein BAX and to promote cell death in mouse hematopoietic cells following interleukin-3 withdrawal (13), these genes being well known to contribute to apoptosis protection (52).…”

Section: Discussionmentioning

confidence: 99%

Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus

Ivanga

Labrie

Calvo

et al. 2007

Physiological Genomics

View full text Add to dashboard Cite

Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus. Physiol Genomics 29: 13-23, 2007; doi:10.1152 doi:10. /physiolgenomics.00291.2005 is well known to be associated with uterine cancer, endometriosis, and leiomyomas. Although insulin-like growth factor I (IGF-I) has been identified as a mediator of the uterotrophic effect of E2 in several studies, this mechanism is still not well understood. In the present study, identification of the genes modulated by a physiological dose of E2, in the uterus, has been done in ovariectomized mice using Affymetrix microarrays. The E2-induced genomic profile shows that multiple genes belonging to the IGF-I pathway are affected after exposure to E2. Two phases of regulation could be identified. First, from 0 to 6 h, the expression of genes involved in the cell cycle, growth factors, protein tyrosine phosphatases, and MAPK phosphatases is quickly upregulated by E2, while IGF-I receptor and several genes of the MAPK and phosphatidylinositol 3-kinase pathways are downregulated. Later, i.e., from 6 to 24 h, transporters and peptidases/ proteases are stimulated, whereas defense-related genes are differentially regulated by E2. Finally, cytoarchitectural genes are modulated later. The present data show that a physiological dose of E2 induces, within 24 h, a series of transcriptional events that promote the uterotrophic effect. Among these, the E2-mediated activation of the IGF-I pathway seems to play a pivotal role in the uterotrophic effect. Furthermore, the protein tyrosine phosphatases and MAPK phosphatases are likely to modulate the estrogenic uterotrophic action by targeting, at different steps, the IGF-I pathway.17␤-estradiol; 17␤-estradiol modulation; ovariectomized mice; oligonucleotide microarray; protein tyrosine phosphatase IN MAMMALS, THE UTERUS of a mature female undergoes multiple changes during the estrous cycle that reflect modifications of the uterine endometrium in continuous preparation for embryo implantation. Since the majority of cycles are not associated with conception, they often lead to endometrial degeneration and menstrual bleeding. The endometrium thus exhibits a cyclic pattern of growth, regression, disruption, bleeding, and regeneration throughout reproductive life. These changes are mainly under the control of estrogens, progesterone, and androgens. Disregulation of the uterine vasculature has been found to accompany different sex steroid disturbances (28).17␤-Estradiol (E2) is well known to play the key role in mammalian endometrial physiology, since the proliferation of endometrial cells and the extension of spiral vessels that occur during the proliferative phase of the menstrual cycle are controlled by E2 (20, 46). Estrogen is also frequently associated with endometrial cancer, which comprises two subtypes: endometrioid carcinomas (type I) related to estrogen exposure and nonendometrioid carcinomas (type II), which are independent of E2 action (16). Type I cancers ar...

show abstract

In Vivo and In Vitro Regulation of Akt Activation in Human Endometrial Cells Is Estrogen Dependent

Cited by 84 publications

References 27 publications

Neisseria gonorrhoeae Survival during Primary Human Cervical Epithelial Cell Infection Requires Nitric Oxide and Is Augmented by Progesterone

Neisseria gonorrhoeae Survival during Primary Human Cervical Epithelial Cell Infection Requires Nitric Oxide and Is Augmented by Progesterone

Estrogen-Mediated Regulation of p38 Mitogen-Activated Protein Kinase in Human Endometrium

Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus

Contact Info

Product

Resources

About