Forkhead box-O transcription factor: critical conductors of cancer's fate

Weidinger, Carl; Krause, Kerstin; Klagge, Antje; Karger, S.; Führer, Dagmar

doi:10.1677/erc-08-0153

Cited by 43 publications

(41 citation statements)

References 99 publications

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“…FoxO transcription factors regulate diverse cell functions (Accili and Arden, 2004) through regulation of genes involved in cell proliferation and apoptosis (Weidinger et al, 2008). Specifically, FoxO3a has been reported to activate genes that induce cell cycle arrest, such as p27 (Dijkers et al, 2000), p21 (Seoane et al, 2004), p15 and p19 (Katayama et al, 2008), and to suppress the expression of cyclin D2 (Fernandez de Mattos et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells

Peng

2011

Oncogene

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Nodal, a member of the transforming growth factor-b superfamily, has been recently shown to suppress cell proliferation and to stimulate the expression of cyclin G2 (CCNG2) in human epithelial ovarian cancer cells. However, the precise mechanisms underlying these events are not fully understood. In this study, we investigated the transcriptional regulation of CCNG2 by the Nodal signaling pathway. In ovarian cancer cells, overexpression of Nodal or its receptors, activin receptorlike kinase 7 (ALK7) or ALK4, resulted in an increase in the CCNG2 promoter activity. Several putative Forkhead box class O (FoxO)3a-binding sites are present in the human CCNG2 promoter and overexpression of FoxO3a enhanced the CCNG2 promoter activity. The functional FoxO3a-binding element (FBE) was mapped to a proximal region located between À398 and À380 bp (FBE1) through deletion and mutation analyses, as well as chromatin immunoprecipitation (IP) assay. Interestingly, mutation of the FBE1 not only abolished the effect of FoxO3a, but also blocked Nodal-induced CCNG2 transcription. Nodal stimulated FoxO3a mRNA and protein expression through the canonical Smad pathway and suppressed FoxO3a inactivation by inhibiting AKT activity. Silencing of FoxO3a using small interfering RNA significantly reduced the effect of Nodal on the CCNG2 promoter activity. On the other hand, overexpression of Smad2 and Smad3 enhanced the FoxO3a-induced CCNG2 promoter activity whereas knockdown of Smad4 blocked the activity of FoxO3a. Furthermore, IP assays revealed that FoxO3a formed complexes with Smad proteins and that Nodal enhanced the binding of FoxO3a to the CCNG2 promoter. Finally, silencing of FoxO3a reversed the inhibitory effect of Nodal on cell proliferation. Taken together, these findings demonstrated that Nodal signaling promotes CCNG2 transcription by upregulating FoxO3a expression, inhibiting FoxO3a phosphorylation and enhancing its synergistic interaction with Smads. These results also suggest that FoxO3a is an important mediator of Nodal signaling in ovarian cancer cells.

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Section: Introductionmentioning

confidence: 99%

Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells

Peng

2011

Oncogene

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“…28 FOXO3a expression in ovarian cancer is largely unknown. Fei et al 29 studied a total of 63 ovarian cancer cases and found that low FOXO3a expression was significantly associated with worse clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma

et al. 2012

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BRCA1/BRCA2 mutations are common and the hallmarks of high-grade serous ovarian carcinoma. We found that MIR182, a negative BRCA1 regulator, is significantly overexpressed in high-grade serous ovarian carcinoma. To examine whether overexpression of MIR182 and its target genes, including BRCA1, HMGA2 (high-mobility group A2), FOXO3 and MTSS1, are associated with high-grade serous ovarian carcinoma tumor types and clinical outcome, we studied MIR182 by in situ hybridization and its target gene expression by immunohistochemistry in 117 cases of advanced ovarian cancer. We found that high-grade serous ovarian carcinoma had significantly higher MIR182 (P ¼ 0.0003) and HMGA2 (P ¼ 0.04) expression, and significantly lower BRCA1 (Po0.0001) and FOXO3 (Po0.001) expression than normal controls. MIR182 is significantly correlated with MTSS1 expression (r ¼ 0.31; Po0.001), whereas other target genes did not show a significant correlation with MIR182, indicating a complicated regulatory mechanisms of these genes in high-grade serous ovarian carcinoma. Among the examined MIR182 target genes, only HMGA2 was significantly associated with serous type carcinomas (Po0.01), ascites (Po0.01) and high death rate (P ¼ 0.02). FOXO3 expression was associated with lower-stage disease (P ¼ 0.04) and solid growth pattern (P ¼ 0.03). MIR182 expression is significantly higher in high-grade serous ovarian carcinoma than in fallopian tubes. Modern Pathology (2012) 25, 1644-1653; doi:10.1038/modpathol.2012.118; published online 13 July 2012Keywords: miR-182; ovarian cancer; BRCA1; HMGA2; MTSS1 High-grade serous ovarian carcinoma is an aggressive and deadly form of ovarian cancer, yet its pathogenesis is poorly understood. Despite significant efforts of clinical researchers, the survival rate of women with high-grade serous ovarian carcinoma has not changed in the past 50 years. 1 These tumors are often high-grade and aggressive at presentation, with a poor prognosis. Recent recognition of the existence of high-grade serous ovarian carcinoma precursor lesions, serous tubal intraepithelial carcinoma, 2,3 in the distal (fimbriated) ends of the fallopian tubes has renewed hope that we will be able to identify early tumorigenic events leading to high-grade serous ovarian carcinoma and reveal new opportunities for early detection and treatment that may decrease the mortality rate among women with this cancer.BRCA1 and BRCA2 mutations are a hallmark of high-grade serous ovarian carcinoma tumorigenesis. 4 Women with germline BRCA1/2 mutations have a 30-70% chance of developing high-grade serous ovarian carcinoma by age 70. 5 Germline BRCA mutations, 6 somatic mutations and epigenetic inactivation of BRCA1/2 (via methylation) can be found in nearly 30% of high-grade serous ovarian carcinoma cases. 7 BRCA1 has a broader role upstream of BRCA2, participating in various cellular

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“…In addition, FOXOs induce expression the sterol carrier proteins SCPx/SCP2, which stimulate peroxisomal metabolism of branchedchain FAs, protect FAs against peroxidation, and function to mitigate the toxicity of oxidized lipids such as cholesterol hydroperoxide (Weinhouse 1976;Dansen et al 2004;Samuel et al 2006;Zhang et al 2006;Weidinger et al 2008;Kriska et al 2010).…”

Section: Metabolic Alterations Supporting Balanced Redox Status Reactmentioning

confidence: 99%

Cancer Cell Metabolism

Cairns

Harris²,

McCracken³

et al. 2011

Cold Spring Harbor Symposia on Quantitative Biology

145

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Forkhead box-O transcription factor: critical conductors of cancer's fate

Cited by 43 publications

References 99 publications

Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells

Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells

Expression analysis of MIR182 and its associated target genes in advanced ovarian carcinoma

Cancer Cell Metabolism

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