Molecular mechanisms of syndecan-4 upregulation by TNF-  in the endothelium-like EAhy926 cells

Okuyama, Eriko; Suzuki, Atsuo; Murata, Moe; Ando, Yumiko; Kato, Io; Takagi, Yuki; Takagi, Akira; Murate, Takashi; Saito, Hidehiko; Kojima, Tetsuhito

doi:10.1093/jb/mvt024

Cited by 31 publications

(17 citation statements)

References 30 publications

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“…We previously reported that in the NP inflammatory cytokines, TNF‐α and IL‐1β regulate expression of SDC4 through NF‐κB signaling (18). Our studies showed that p65/RelA interacts with a conserved κB element located at –97/–88 bp in SDC4 promoter in NP cells, resulting in increased gene expression, an observation also confirmed in endothelium‐like cells very recently (19). Notably, our work showed that SDC4, through its HS chains, promotes Agc1 degradation by enhancing post‐translational processing of a disintegrin‐like and metalloprotease with thrombospondin type I motifs 5 (ADAMTS‐5) protein, likely playing a key role in pathogenesis of disc disease (18).…”

supporting

confidence: 83%

HIF‐1‐PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells

et al. 2014

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Intervertebral disc degeneration is the leading cause of chronic back pain. Recent studies show that raised level of SDC4, a cell-surface heparan sulfate (HS) proteoglycan, plays a role in pathogenesis of disc degeneration. However, in nucleus pulposus (NP) cells of the healthy intervertebral disc, the mechanisms that control expression of SDC4 and its physiological function are unknown. Hypoxia induced SDC4 mRNA and protein expression by ~2.4- and 4.4-fold (P<0.05), respectively, in NP cells. While the activity of the SDC4 promoter containing hypoxia response element (HRE) was induced 2-fold (P<0.05), the HRE mutation decreased the activity by 40% in hypoxia. Transfections with plasmids coding prolyl-4-hydroxylase domain protein 2 (PHD2) and ShPHD2 show that hypoxic expression of SDC4 mRNA and protein is regulated by PHD2 through controlling hypoxia-inducible factor 1α (HIF-1α) levels. Although overexpression of HIF-1α significantly increased SDC4 protein levels, stable suppression of HIF-1α and HIF-1β decreased SDC4 expression by 50% in human NP cells. Finally, suppression of SDC4 expression, as well as HS function, resulted in an ~2-fold increase in sex-determining region Y (SRY)-box 9 (Sox9) mRNA, and protein (P<0.05) and simultaneous increase in Sox9 transcriptional activity and target gene expression. Taken together, our findings suggest that in healthy discs, SDC4, through its HS side chains, contributes to maintenance of the hypoxic tissue niche by controlling baseline expression of Sox9.

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confidence: 83%

HIF‐1‐PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells

et al. 2014

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“…Although little is known about the regulation of syndecan-4 synthesis, studies confirmed its increased expression in vascular smooth muscle cells [27] and osteoblasts [28] and decreased expression in satellite cells [29] following exposure to FGF-2. Furthermore, in vascular endothelial cells, tumor necrosis factor-α [30,31], lipopolysaccharide, and interleukin-1β [25] induce syndecan-4 expression; however, the signaling pathways that mediate syndecan-4 expression remained unclear. Recently, it was reported that the HIF-1-PHD2 axis upregulates syndecan-4 expression in cultured nucleus pulposus cells [32], indicating that regulation of syndecan-4 expression can be mediated by the HIF-1α/β pathway.…”

Section: Discussionmentioning

confidence: 99%

Induction of Syndecan-4 by Organic–Inorganic Hybrid Molecules with a 1,10-Phenanthroline Structure in Cultured Vascular Endothelial Cells

Hara

Kojima

Matsuzaki

et al. 2017

IJMS

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Organic–inorganic hybrid molecules constitute analytical tools used in biological systems. Vascular endothelial cells synthesize and secrete proteoglycans, which are macromolecules consisting of a core protein and glycosaminoglycan side chains. Although the expression of endothelial proteoglycans is regulated by several cytokines/growth factors, there may be alternative pathways for proteoglycan synthesis aside from downstream pathways activated by these cytokines/growth factors. Here, we investigated organic–inorganic hybrid molecules to determine a variant capable of analyzing the expression of syndecan-4, a transmembrane heparan-sulfate proteoglycan, and identified 1,10-phenanthroline (o-Phen) with or without zinc (Zn-Phen) or rhodium (Rh-Phen). Bovine aortic endothelial cells in culture were treated with these compounds, and the expression of syndecan-4 mRNA and core proteins was determined by real-time reverse transcription polymerase chain reaction and Western blot analysis, respectively. Our findings indicated that o-Phen and Zn-Phen specifically and strongly induced syndecan-4 expression in cultured vascular endothelial cells through activation of the hypoxia-inducible factor-1α/β pathway via inhibition of prolyl hydroxylase-domain-containing protein 2. These results demonstrated an alternative pathway involved in mediating induction of endothelial syndecan-4 expression and revealed organic–inorganic hybrid molecules as effective tools for analyzing biological systems.

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“…Soon after the identification of syndecan-1, there were some studies of its promoter [207, 208], indicating sites for Sp1 family (specifically Sp3 in more recent studies [209]), NF-kB, MyoD (Ebox) and Antennapedia [207] as well as Wilms’ tumor suppressor gene (WT1; [210]). However, syndecan-1 is not well known as an early response gene, unlike syndecan-4, where its expression has been well documented to be NF-kB and hypoxia sensitive [211, 212]. …”

Section: Syndecans and Their Roles In Breast Cancermentioning

confidence: 99%

Insights into the key roles of proteoglycans in breast cancer biology and translational medicine

Theocharis

Skandalis

Neill

et al. 2015

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

114

127

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Proteoglycans control numerous normal and pathological processes, among which are morphogenesis, tissue repair, inflammation, vascularization and cancer metastasis. During tumor development and growth, proteoglycan expression is markedly modified in the tumor microenvironment. Altered expression of proteoglycans on tumor and stromal cell membranes affects cancer cell signaling, growth and survival, cell adhesion, migration and angiogenesis. Despite the high complexity and heterogeneity of breast cancer, the rapid evolution in our knowledge that proteoglycans are among the key players in the breast tumor microenvironment suggests their potential as pharmacological targets in this type of cancer. It has been recently suggested that pharmacological treatment may target proteoglycan metabolism, their utilization as targets for immunotherapy or their direct use as therapeutic agents. The diversity inherent in the proteoglycans that will be presented herein provides the potential for multiple layers of regulation of breast tumor behavior. This review summarizes recent developments concerning the biology of selected proteoglycans in breast cancer, and presents potential targeted therapeutic approaches based on their novel key roles in breast cancer.

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Molecular mechanisms of syndecan-4 upregulation by TNF- in the endothelium-like EAhy926 cells

Cited by 31 publications

References 30 publications

HIF‐1‐PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells

HIF‐1‐PHD2 axis controls expression of syndecan 4 in nucleus pulposus cells

Induction of Syndecan-4 by Organic–Inorganic Hybrid Molecules with a 1,10-Phenanthroline Structure in Cultured Vascular Endothelial Cells

Insights into the key roles of proteoglycans in breast cancer biology and translational medicine

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