Egr-1 upregulates OPN through direct binding to its promoter and OPN upregulates Egr-1 via the ERK pathway

Liu, Qifeng; Yu, Hao; Gui-nan, Liu

doi:10.1007/s11010-009-0176-4

Cited by 11 publications

(11 citation statements)

References 36 publications

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“…Our transient transfection experiments suggested that Egr1 and Egr2 mediate the activation of Osteopontin promoter by MEK-MAPK signaling in chondrocytes. Consistent with our observations, Egr1 has been shown to bind to the Osteopontin promoter in vascular smooth muscle cells (31) . Genetic studies in mice have also implicated Egr1 and Egr2 in the regulation of terminal chondrocyte differentiation (19,32) .…”

Section: Discussionsupporting

confidence: 91%

“…Consistent with our observations, Egr1 has been shown to bind to the Osteopontin promoter in vascular smooth muscle cells. (31) Genetic studies in mice have also implicated Egr1 and Egr2 in the regulation of terminal chondrocyte differentiation. (19,32) Taken together, our observations suggest that MEK-MAPK signaling regulates chondrocyte terminal differentiation at least in part through Egr1 and Egr2.…”

Section: Discussionmentioning

confidence: 99%

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ERK1 and ERK2 Regulate Chondrocyte Terminal Differentiation During Endochondral Bone Formation

Chen

Yue

Zhou

et al. 2014

Journal of Bone and Mineral Research

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Chondrocytes in the epiphyseal cartilage undergo terminal differentiation prior to their removal through apoptosis. To examine the role of ERK1 and ERK2 in chondrocyte terminal differentiation, we generated Osx-Cre; ERK1−/−; ERK2flox/flox mice (cKOosx), in which ERK1 and ERK2 were deleted in hypertrophic chondrocytes. These cKOosx mice were grossly normal in size at birth, but by 3 weeks of age exhibited shorter long bones. Histological analysis in these mice revealed that the zone of hypertrophic chondrocytes in the growth plate was markedly expanded. In situ hybridization and quantitative real-time PCR analyses demonstrated that Mmp13 and Osteopontin expression was significantly decreased, indicating impaired chondrocyte terminal differentiation. Moreover, Egr1 and Egr2, transcription factors whose expression is restricted to the last layers of hypertrophic chondrocytes in wild type mice, were also strongly downregulated in these cKOosx mice. In transient transfection experiments in the RCS rat chondrosarcoma cell line, the expression of Egr1, Egr2, or a constitutively active mutant of MEK1 increased the activity of an Osteopontin promoter, while the MEK1-induced activation of the Osteopontin promoter was inhibited by the co-expression of Nab2, an Egr1 and Egr2 co-repressor. These results suggest that MEK1-ERK signaling activates the Osteopontin promoter in part through Egr1 and Egr2. Finally, our histological analysis of cKOosx mice demonstrated enchondroma-like lesions in the bone marrow that are reminiscent of human metachondromatosis, a skeletal disorder caused by mutations in PTPN11. Our observations suggest that the development of enchondromas in metachondromatosis may be caused by reduced ERK MAPK signaling.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

ERK1 and ERK2 Regulate Chondrocyte Terminal Differentiation During Endochondral Bone Formation

Chen

Yue

Zhou

et al. 2014

Journal of Bone and Mineral Research

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“…b-Catenin has been considered a strong target for chemotherapeutical interventions, owing to its disruption in multiple cancers and its action as a proto-oncogenic TR in cultured cells. 18,28 Since FH535 was originally identified as a transcriptional inhibitor for b-catenin from a blind screen, the identification of nonspecific effects on b-catenin expression and EGR-1 was unsurprising, but insightful. 17 The work here with FH535 demonstrates that depletion of b-catenin from the cytoplasmic face through prolonged FH535 treatment was associated with disruption of tight junctions and acquisition of a mesenchymal cell shape.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple outcomes of FH535 and/or CSC treatment identified in these studies, including fibronectin and osteopontin, are transcriptional targets of EGR-1. 14,18 The EGR-1 accumulated in the nuclei following 24 hours of CSC, FH535 or combination CSC, FH535 treatment of BEAS-2B cells ( Figure 4A and B). The CSC induced a dose-dependent nuclear accumulation of EGR-1, which was accompanied by a similar dose-dependent increase in the EGR-1 target gene PTEN ( Figure 4C).…”

Section: Egr-1 Outcomes Are Altered By Csc and Fh535mentioning

confidence: 99%

FH535 Potentiation of Cigarette Smoke Condensate Cytotoxicity is Associated With Changes in β-Catenin and EGR-1 Signaling

Polk¹

2012

Int J Toxicol

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Cigarette smoke condensate (CSC) has been reported to elicit morphological and transcriptional changes that suggest epithelial-to-mesenchymal transition (EMT) in cultured bronchial epithelial cells. The transdifferentiation potential of acute and prolonged CSC exposure alone or in combination with the β-catenin inhibitor, FH535, was investigated in the bronchial epithelial cell line, BEAS-2B, through assessment of cell morphology, transcript expression, protein expression, and protein localization. Changes in morphology, β-catenin translocation, E-cadherin expression, metalloproteinase expression, and fibronectin could be demonstrated independent of molecular or physiological evidence of EMT. FH535 was shown to increase CSC-induced cytotoxicity and depress β-catenin expression. However, FH535 effects were not limited to the β-catenin pathway as it also blocked the expression of early growth responsive protein 1 (EGR-1) target genes, fibronectin and phosphatase and tensin homologue, without affecting EGR-1 nuclear accumulation.

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“…OPN is a multifunctional cytokine that contributes to cell proliferation, survival, drug resistance, invasion, and stem cell behavior [24]. It has been documented that Egr1 upregulates OPN through direct binding to its promoter, and OPN upregulates Egr1 via the ERK pathway [25]. OPN has been linked to sustaining hematopoietic stem cell polarity and attenuating the aging of old hematopoietic stem cells [26].…”

Section: Introductionmentioning

confidence: 99%

Oct4 upregulates osteopontin via Egr1 and is associated with poor outcome in human lung cancer

Yin

Lin

et al. 2019

BMC Cancer

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Background Roles of cancer stem cells and early growth response gene 1 (Egr1) in carcinogenesis have been extensively studied in lung cancer. However, the role of Egr1 in the metastasis of lung cancer remains undetermined, especially in regard to stem cell-related pathways. Methods Egr1, osteopontin (OPN) and Oct4 expression in human lung cancer was determined by performing immunohistochemistry. Immunoblotting, ELISA, luciferase reporter assay, chromatin immunoprecipitation assay and RT-PCR were performed to validate the regulation of Oct4-Egr1-OPN axis. Moreover, the effect of Oct4-Egr1-OPN axis on lung cancer progression was evaluated by cell migration assay and mice study. Results We detected Oct4, Egr1, and OPN expression in clinical specimens from 79 lung cancer patients, including 72 adenocarcinomas and 7 squamous cell carcinomas. High expression of Oct4, Egr1, and OPN accounted for 53, 51, and 57% of the patients, respectively. All of the three biomarkers were positively correlated in clinical human lung cancer. Patients with high expression of OPN were significantly associated with shorter disease-free survivals than those with low expression of OPN ( p < 0.05). In lung cancer cells, Oct4 transactivated the Egr1 promoter and upregulated Egr1 expression. In a human lung cancer xenograft model, Oct4-overexpressing tumors expressed elevated levels of Egr1. Furthermore, overexpression of Oct4 in lung cancer cells increased the metastatic potential. Conclusions Egr1 exerts a promoting effect on cancer metastasis in Oct4-overexpressing lung cancer. Thus, therapeutic strategies targeting the Oct4/Egr1/OPN axis may be further explored for the treatment of lung cancer, especially when lung cancer is refractory to conventional treatment due to cancer stem cells. Electronic supplementary material The online version of this article (10.1186/s12885-019-6014-5) contains supplementary material, which is available to authorized users.

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Egr-1 upregulates OPN through direct binding to its promoter and OPN upregulates Egr-1 via the ERK pathway

Cited by 11 publications

References 36 publications

ERK1 and ERK2 Regulate Chondrocyte Terminal Differentiation During Endochondral Bone Formation

ERK1 and ERK2 Regulate Chondrocyte Terminal Differentiation During Endochondral Bone Formation

FH535 Potentiation of Cigarette Smoke Condensate Cytotoxicity is Associated With Changes in β-Catenin and EGR-1 Signaling

Oct4 upregulates osteopontin via Egr1 and is associated with poor outcome in human lung cancer

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