Serine 26 in Early Growth Response‐1 Is Critical for Endothelial Proliferation, Migration, and Network Formation

Santiago, Fernando S.; Li, Yue; Khachigian, Levon M.

doi:10.1161/jaha.120.020521

Cited by 9 publications

(3 citation statements)

References 59 publications

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“…The reduction of EGR1 in Pdgfra GFP/GFP XY KI gonads suggest that EGR1 might be involved in vascular development of XY gonads. EGR1-knockout human vascular endothelial cells exhibit slower rates of proliferation and migration 45 , and here our analyses revealed that Egr1-knockdown mouse gonadal and mesonephric cells showed significantly compromised cell migration. Taken together, disruptions in vascular development in Pdgfra GFP/GFP XY KI gonads might be due to a deficiency in Egr1-mediated cell migration.…”

Section: Discussionsupporting

confidence: 60%

Testis morphogenesis and fetal Leydig cell development are mediated through ERK signaling activated by platelet derived growth factor receptor alpha

Li¹,

Matsuyama²,

Whiteside³

et al. 2023

Preprint

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Platelet derived growth factor receptor alpha (Pdgfra) plays a crucial role in the morphogenesis and differentiation of the fetal testis, but the molecular signaling involved in these processes remains unclear. Here, we use XY Pdgfra-null knock-in (KI) gonads to investigate the molecular mechanisms underlying Pdgfra-mediated testis cord formation and development of fetal Leydig cells (FLCs). The extracellular signal-regulated kinase (ERK) pathway, a well-known mitogen-activated protein kinase signaling pathway, was significantly inhibited in XY Pdgfra KI gonads, suggesting that ERK signaling is activated downstream of PDGFRA. Using ex vivo whole-organ culture, small interfering RNA (siRNA) cell culture methods, transwell assays and a genetic mouse model to disrupt ERK signaling in gonadal cells, we found that the ERK pathway promoted testis cord formation via early growth response 1 (Egr1)-mediated cell migration and regulated the expression of steroidogenic enzymes in FLCs via activating the transcription factor cAMP responsive element binding protein 1 (CREB; official name CREB1). These findings highlight the significance of PDGFRA and its downstream signaling in fetal testis morphogenesis and cellular differentiation, thus providing insights into the etiology of and potential therapeutic targets for disorders related to gonadal development.

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Section: Discussionsupporting

confidence: 60%

Testis morphogenesis and fetal Leydig cell development are mediated through ERK signaling activated by platelet derived growth factor receptor alpha

Li¹,

Matsuyama²,

Whiteside³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Santiago et al found that ERK1 (Mitogen-Activated Protein Kinase 3) could phosphorylate the serine residue at the 26th position (Ser26) in EGR1 in human vascular endothelial cells, which has a protective effect against apoptosis. If Ser26 is mutated, endothelial cells will undergo apoptosis ( 24 ). In one study, Fasolo et al determined the effect of the long non-coding RNA myocardial invasion-associated transcript (MIAT) on advanced atherosclerotic lesions.…”

Section: Egr-1 Is Involved In Cardiac Cell Deathmentioning

confidence: 99%

Early growth response-1: Key mediators of cell death and novel targets for cardiovascular disease therapy

Xie

Chen

et al. 2023

Front. Cardiovasc. Med.

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SignificanceCardiovascular diseases are seen to be a primary cause of death, and their prevalence has significantly increased across the globe in the past few years. Several studies have shown that cell death is closely linked to the pathogenesis of cardiovascular diseases. Furthermore, many molecular and cellular mechanisms are involved in the pathogenesis of the cardiac cell death mechanism. One of the factors that played a vital role in the pathogenesis of cardiac cell death mechanisms included the early growth response-1 (Egr-1) factor.Recent AdvancesStudies have shown that abnormal Egr-1 expression is linked to different animal and human disorders like heart failure and myocardial infarction. The biosynthesis of Egr-1 regulates its activity. Egr-1 can be triggered by many factors such as serum, cytokines, hormones, growth factors, endotoxins, mechanical injury, hypoxia, and shear stress. It also displays a pro-apoptotic effect on cardiac cells, under varying stress conditions. EGR1 mediates a broad range of biological responses to oxidative stress and cell death by combining the acute changes occurring in the cellular environment with sustained changes in gene expression.Future DirectionsThe primary regulatory role played by the Egr-1-targeting DNAzymes, microRNAs, and oligonucleotide decoy strategies in cardiovascular diseases were identified to provide a reference to identify novel therapeutic targets for cardiovascular diseases.

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“…Early growth response-1 (EGR-1) is an important upstream transcription factor that regulates cell proliferation and differentiation and plays an essential role in tumor angiogenesis ( 28 , 29 ). EGR-1 is a common intermediate of VEGF and fibroblast growth factor (FGF) in regulating cell function ( 30 ).…”

Section: Normalization Of Tumor Vasculaturementioning

confidence: 99%

Targeting vascular normalization: a promising strategy to improve immune–vascular crosstalk in cancer immunotherapy

Qian,

Liu,

Liu

et al. 2023

Front. Immunol.

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Blood vessels are a key target for cancer therapy. Compared with the healthy vasculature, tumor blood vessels are extremely immature, highly permeable, and deficient in pericytes. The aberrantly vascularized tumor microenvironment is characterized by hypoxia, low pH, high interstitial pressure, and immunosuppression. The efficacy of chemotherapy, radiotherapy, and immunotherapy is affected by abnormal blood vessels. Some anti-angiogenic drugs show vascular normalization effects in addition to targeting angiogenesis. Reversing the abnormal state of blood vessels creates a normal microenvironment, essential for various cancer treatments, specifically immunotherapy. In addition, immune cells and molecules are involved in the regulation of angiogenesis. Therefore, combining vascular normalization with immunotherapy may increase the efficacy of immunotherapy and reduce the risk of adverse reactions. In this review, we discussed the structure, function, and formation of abnormal vessels. In addition, we elaborated on the role of the immunosuppressive microenvironment in the formation of abnormal vessels. Finally, we described the clinical challenges associated with the combination of immunotherapy with vascular normalization, and highlighted future research directions in this therapeutic area.

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Serine 26 in Early Growth Response‐1 Is Critical for Endothelial Proliferation, Migration, and Network Formation

Cited by 9 publications

References 59 publications

Testis morphogenesis and fetal Leydig cell development are mediated through ERK signaling activated by platelet derived growth factor receptor alpha

Testis morphogenesis and fetal Leydig cell development are mediated through ERK signaling activated by platelet derived growth factor receptor alpha

Early growth response-1: Key mediators of cell death and novel targets for cardiovascular disease therapy

Targeting vascular normalization: a promising strategy to improve immune–vascular crosstalk in cancer immunotherapy

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