Aroclor1254 disrupts the blood–testis barrier by promoting endocytosis and degradation of junction proteins via p38 MAPK pathway

Jia, Xiaoyu; Xu, Ying; Wu, Weixing; Fan, Yunxia; Wang, Guoli; Zhang, Tianbiao; Su, Wenhui

doi:10.1038/cddis.2017.224

Cited by 52 publications

(34 citation statements)

References 58 publications

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“…Antonetti et al found that changes in occludin phosphorylation state were associated with increased endothelial permeability in response to VEGF . They also demonstrated that phosphorylation at Ser‐490 and ubiquitination were related to occludin decrease in response to VEGF in endothelial cells . In our study, the phosphorylation of occludin at Ser‐490 was verified after VEGF treatment with a phosphosite‐specific antibody.…”

Section: Discussionsupporting

confidence: 75%

“…34,35 They also demonstrated that phosphorylation at Ser-490 and ubiquitination were related to occludin decrease in response to VEGF in endothelial cells. [36][37][38][39] In our study, the phosphorylation of occludin at Ser-490 was verified after VEGF treatment with a phosphosite-specific antibody. FLAG-tagged S490DOcc occludin mutants were transfected into HUVECs by plasmid to investigate whether the Ser-490 phosphorylation site is involved in occludin ubiquitination.…”

Section: F I G U R Ementioning

confidence: 52%

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Primary tumor‐secreted VEGF induces vascular hyperpermeability in premetastatic lung via the occludin phosphorylation/ubiquitination pathway

Jiang

et al. 2019

Molecular Carcinogenesis

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Primary tumor can induce the formation of premetastatic niche. The hyperpermeability of the vessels in the premetastatic niche is the first step in the development of metastasis. However, the cellular and molecular mechanisms of vascular hyperpermeability remain to be elucidated. In this study, 4T1 breast cells were injected into the breasts of mice to establish a tumor model. Our results showed that primary tumors induced hyperpermeability of the vessels in the premetastatic lung. Subsequent studies showed that the level of vascular endothelial growth factor (VEGF) was elevated in the tumor‐bearing mice serum and the levels of tight junction (TJ) proteins occludin and ZO‐1 were decreased in the premetastatic lung. In vitro studies demonstrated that VEGF increased the permeability of dextran and decreased the levels of occludin and ZO‐1 in human umbilical vein endothelial cells. Moreover, the hyperpermeability of vessels and the degradation of occludin was blocked by bevacizumab. Overexpression of occludin alleviated the VEGF‐induced hyperpermeability. Further investigations revealed that VEGF‐induced occludin phosphorylation at Ser‐490 and ubiquitination. Finally, we showed that VEGF accelerated the process of occludin degradation through the ubiquitin‐proteasome system. In conclusion, primary tumor‐secrete VEGF induce the occludin phosphorylation/ubiquitination and downregulation, resulting in the disruption of TJs and hyperpermeability of vessels in premetastatic lung. The occludin phosphorylation/ubiquitination pathway may be the mechanism of VEGF‐induced vascular hyperpermeability in the lung premetastatic niche.

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Section: Discussionsupporting

confidence: 75%

Section: F I G U R Ementioning

confidence: 52%

Primary tumor‐secreted VEGF induces vascular hyperpermeability in premetastatic lung via the occludin phosphorylation/ubiquitination pathway

Jiang

et al. 2019

Molecular Carcinogenesis

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“…The integrity of the BTB was evaluated by using EZ-Link Sulfo-NHS-LC-Biotin (Pierce Biotechnology, Rockford, IL, USA) as an indicator as described previously [34-36]. In brief, after TGF-β3 treatment, three or four rats from each group were anesthetized by ketamine HCl (100 mg/kg) via i.p.…”

Section: Methodsmentioning

confidence: 99%

“…To acquire well-purified mature SCs with less germ cells, 20-day-old rats were used for SCs isolation according to a classical method as described [36, 37]. After isolation, the SCs were plated at different densities on Matrigel (BD BioSciences, Franklin Lakes, NJ, USA)-coated culture dishes according to the following detections: 0.5×10 6 /cm 2 on 6-well plates for immunoblot and immunoprecipitation, 1.2×10 6 /cm 2 on Millicell-HA inserts (Millipore, Boston, MA, USA) for SC epithelial permeability barrier assessment, and 0.05×10 6 /cm 2 on cover glass for immunofluorescence analysis.…”

Section: Methodsmentioning

confidence: 99%

MiR-142-3p Inhibits TGF-β3-Induced Blood-Testis Barrier Impairment by Targeting Lethal Giant Larvae Homolog 2

Xu¹,

Wu²,

Fan³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Transforming growth factor-β3 (TGF-β3) has been proved to perturb the blood-testis barrier (BTB) by accelerating junction protein endocytosis in Sertoli cells (SCs) to accommodate the traversing of preleptotene spermatocytes across the BTB around stage VIII in rat. Yet the molecular network underlying the impairment of TGF-β3 on BTB integrity is not fully elucidated. Our study herein was designed to investigate the participation of microRNA-142-3p (miR-142-3p), which has been reported to affect TGF-β3 signaling via different pathways, during BTB dynamics and the corresponding mechanisms. Methods: MiRNA mimic or agomiRNA was co-administered with or without TGF-β3 in the cultured SCs or in the rat testis. The SC permeability barrier function was reflected by measuring the transepithelial resistance (TER) and the permeability of the sodium fluorescein (Na-F). The BTB integrity was detected by the permeation of biotin. A luciferase reporter assay was used to testify the potential target of miR-142-3p, lethal giant larvae 2 (Lgl2). Laser capture microdissection (LCM) was applied to acquire cell components of different stages of seminiferious tubules, followed by detection of the expression levels of miR-142-3p, TGF-β3, and Lgl2 by qPCR. The SC barrier function was also detected as above in the presence of TGF-β3 after Lgl2 knockdown. Results: We revealed a reversion of TGF-β3-induced BTB impairment after miR-142-3p treatment both in vitro and in vivo. Meanwhile, the activation of Cdc42 and reduction in occludin aroused by TGF-β3 were also reversed by miR-142-3p. The predicted binding of miR-142-3p with 3’-untranslated region (3’-UTR) of Lgl2, was verified by the luciferase assay. Moreover, an increased Lgl2 level in TGF-β3-treated SCs was found and correlated stage-specific expressions of TGF-β3, miR-142-3p, and Lgl2 were revealed. Knockdown of Lgl2 in SCs was shown to partially antagonize the BTB disruption mediated by TGF-β3. Conclusions: Collectively, our results suggest a resistance of miR-142-3p on the BTB impairment caused by TGF-β3 during the seminiferous epithelial cycle by targeting Lgl2.

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“…During this process, regulation of endocytic trafficking of junctional proteins provides a way of rapidly restructuring cell–cell junctions. Failure in any of these steps during endocytosis by Sertoli cells can lead to structural cell junctional defects in the seminiferous epithelium and subsequently an unstable environment for spermatogenesis (Cheng et al, 2011; Jia et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Functional importance of JMY expression by Sertoli cells in mediating mouse spermatogenesis

Fan

Yan

et al. 2018

Preprint

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3Sertoli cells are crucial for spermatogenesis in the seminiferous epithelium because 2 4 their actin cytoskeleton supports vesicle transport, cell junction, protein anchoring and 2 5 spermiation. Here, we show that junction-mediating and regulatory protein (JMY), an 2 6 actin regulating protein, also affects endocytic vesicle trafficking and Sertoli cell 2 7 junction remodeling since disruption of these functions induced male subfertility in 2 8Sertoli cell-specific Jmy knockout mice. Specifically, these mice have: a) impaired 2 9 BTB integrity and spermatid adhesion in the seminiferous tubules; b) high incidence 3 0 of sperm structural deformity; c) reduced sperm count and poor sperm motility. 3 1 Moreover, the cytoskeletal integrity in Sertoli cell-specific Jmy knockout mice was 3 2 compromised along with endocytic vesicular trafficking. These effects impaired 3 3 junctional protein recycling and reduced Sertoli cell junctions. In addition, JMY 3 4 interaction with α -actinin1 and Sorbs2 was related to JMY activity and in turn actin 3 5 cytoskeletal organization. In summary, JMY affects control of spermatogenesis 3 6 through regulating actin filament organization and endocytic vesicle trafficking in 3 7 Sertoli cells. 3 8 3 9

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Aroclor1254 disrupts the blood–testis barrier by promoting endocytosis and degradation of junction proteins via p38 MAPK pathway

Cited by 52 publications

References 58 publications

Primary tumor‐secreted VEGF induces vascular hyperpermeability in premetastatic lung via the occludin phosphorylation/ubiquitination pathway

Primary tumor‐secreted VEGF induces vascular hyperpermeability in premetastatic lung via the occludin phosphorylation/ubiquitination pathway

MiR-142-3p Inhibits TGF-β3-Induced Blood-Testis Barrier Impairment by Targeting Lethal Giant Larvae Homolog 2

Functional importance of JMY expression by Sertoli cells in mediating mouse spermatogenesis

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