Alternative splicing generates an isoform of the human Sef gene with altered subcellular localization and specificity

Preger, Ella; Ziv, Inbal; Shabtay, Ariel; Sher, Ifat; Tsang, Michael; Dawid, Igor B.; Altuvia, Yaël; Ron, Dina

doi:10.1073/pnas.0307952100

Cited by 61 publications

(102 citation statements)

References 37 publications

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“…This growth factor is abundant in small capillaries in the CL, where it can activate FGF-receptor signaling in the endothelial cells. The reported ability of SEF to regulate FGF2 action (Kovalenko et al 2003, Preger et al 2004, Ziv et al 2006, Zisman-Rozen et al 2007) and the present finding that Sef expression is restricted to endothelial cells in the CL point to the existence of counter-regulatory mechanisms that prevent growth factor-induced SEF expression in the GLC. One such plausible mechanism might involve Spry2, which contrary to SEF is expressed in GLC in both human and rodent ovaries (Haimov-Kochman et al 2005).…”

Section: Discussionsupporting

confidence: 51%

“…Within the human reproductive system, SEF transcripts were detected in testes, ovarian surface epithelium (OSE), and mammary and prostate epithelium (Preger et al 2004, Zisman-Rozen et al 2007. SEF expression is downregulated in ovarian, breast and prostate carcinomas in a manner that correlates with tumor aggressiveness and poor prognosis, underscoring its role as a tumor suppressor (Darby et al 2006, Zisman-Rozen et al 2007, Murphy et al 2010.…”

Section: Introductionmentioning

confidence: 99%

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Expression and regulation of the tumor suppressor, SEF, during folliculogenesis in humans and mice

et al. 2014

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Similar expression to FGF (SEF or IL17RD), is a tumor suppressor and an inhibitor of growth factors as well as of pro-inflammatory cytokine signaling. In this study, we examined the regulation of Sef expression by gonadotropins during ovarian folliculogenesis. In sexually immature mice, in situ hybridization (ISH) localized Sef gene expression to early developing oocytes and granulosa cells (GC) but not to theca cells. Sef was also expressed in mouse ovarian endothelial cells, in the fallopian tube epithelium as well as in adipose tissue venules. SEF protein expression, determined by immunohistochemistry (IHC), correlated well with Sef mRNA expression in GC, while differential expression was noticed in oocytes. High Sef mRNA but undetectable SEF protein levels were observed in the oocytes of primary/secondary follicles, while an inverse correlation was found in the oocytes of preantral and small antral follicles. Sef mRNA expression dropped after pregnant mare's serum gonadotropin (PMSG) administration, peaked at 6-8 h after human chorionic gonadotropin (hCG) treatment, and declined by 12 h after this treatment. ISH and IHC localized the changes to oocytes and mural GC following PMSG treatment, whereas Sef expression increased in mural GC and declined in granulosa-lutein cells upon hCG treatment. The ovarian expression of SEF was confirmed using human samples. ISH localized SEF transcripts to human GC of antral follicles but not to corpora lutea. Furthermore, SEF mRNA was detected in human GC recovered from preovulatory follicles. These results are the first to demonstrate Sef expression in a healthy ovary during folliculogenesis. Hormonal regulation of its expression suggests that Sef may be an important factor involved in intra-ovarian control mechanisms.

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Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Expression and regulation of the tumor suppressor, SEF, during folliculogenesis in humans and mice

et al. 2014

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“…Fulllength Sef is predicted to contain a signal peptide and transmembrane domain and is ubiquitously expressed in human tissues. The short isoform is thought to be primarily cytosolic and has a more restricted pattern of expression (Preger et al, 2004). Both human isoforms have been shown to inhibit RTK signalling in cell line models Ziv et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Similar expression to FGF (Sef) inhibits fibroblast growth factor-induced tumourigenic behaviour in prostate cancer cells and is downregulated in aggressive clinical disease

et al. 2009

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The fibroblast growth factor (FGF) axis is an important mitogenic stimulus in prostate carcinogenesis. We have previously reported that transcript level of human similar expression to FGF (hSef), a key regulator of this pathway, is downregulated in clinical prostate cancer. In this study we further analysed the role of hSef in prostate cancer. METHODS: hSef function was studied in in vitro and in vivo prostate cancer models using stable over-expression clones. Protein expression of hSef was studied in a comprehensive tissue microarray. RESULTS: Stable over-expression of hSef resulted in reduced in vitro cancer cell proliferation, migration and invasive potential. In an in vivo xenograft model, the expression of hSef significantly retarded prostate tumour growth as compared with empty vector (P ¼ 0.03) and non-transfected (P ¼ 0.0001) controls. Histological examination further showed a less invasive tumour phenotype and reduced numbers of proliferating cells (P ¼ 0.0002). In signalling studies, hSef inhibited FGF-induced ERK phosphorylation, migration to the nucleus and activation of a reporter gene. Constitutively active Ras, however, was able to reverse these effects, suggesting that hSef exerts an effect either above or at the level of Ras in prostate cancer cells. In a large tissue microarray, we observed a significant loss of hSef protein in high-grade (Po0.0001) and metastatic (Po0.0001) prostate cancer. CONCLUSION: Considered together, the role of hSef in attenuating FGF signalling and evidence of downregulation in advanced tumours argue strongly for a tumour suppressor function in human prostate cancer.

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“…To date, Sef has been reported to be an antagonist of FGF signaling and to regulate Ras/MAPK signaling at different levels in vertebrates [2][3][4][5][6][7][8]. Evidence has been provided that heterozygous expression of Sef inhibits FGF signaling, but that underexpression of Sef leads to too much signaling, causing characteristic malformations in zebrafish embryos [1,2].…”

Section: Introductionmentioning

confidence: 99%

hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation

Ren

Cheng

Rong

et al. 2008

Cellular Signalling

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Sef (similar expression to fgf genes) was identified as an effective antagonist of fibroblast growth factor (FGF) in vertebrates. Previous reports have demonstrated that Sef interacts with FGF receptors (FGFRs) and inhibits FGF signaling, however, its role in regulating epidermal growth factor receptor (EGFR) signaling remains unclear. In this report, we found that hSef localizes to the plasma membrane (PM) and is subjected to rapid internalization and well localizes in early/ recycling endosomes while poorly in late endosomes/lysosomes. We observed that hSef interacts and functionally colocalizes with EGFR in early endosomes in response to EGF stimulation. Importantly, we demonstrated that overexpression of hSef attenuates EGFR degradation and potentiates EGF-mediated mitogen-activated protein kinase (MAPK) signaling by interfering EGFR trafficking. Finally, our data showed that, with overexpression of hSef, elevated levels of Erk phosphorylation and differentiation of rat pheochromocytoma (PC12) cells occur in response to EGF stimulation. Taken together, these data suggest that hSef plays a positive role in the EGFRmediated MAPK signaling pathway. This report, for the first time, reveals opposite roles for Sef in EGF and FGF signalings.

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Alternative splicing generates an isoform of the human Sef gene with altered subcellular localization and specificity

Cited by 61 publications

References 37 publications

Expression and regulation of the tumor suppressor, SEF, during folliculogenesis in humans and mice

Expression and regulation of the tumor suppressor, SEF, during folliculogenesis in humans and mice

Similar expression to FGF (Sef) inhibits fibroblast growth factor-induced tumourigenic behaviour in prostate cancer cells and is downregulated in aggressive clinical disease

hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation

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