Early growth response-1 is a new substrate of the GSK3β-FBXW7 axis

Li, Yin; Jia-gui, Zhang; Sun, Yi

doi:10.1016/j.neo.2022.100839

Cited by 5 publications

(5 citation statements)

References 57 publications

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“…As mentioned above, numerous anti-cancer factors and pro-cancer factors are directly modified by NEDD8 [3], and certain neddylation substrates such as CRL, EGR1, and HIF-1α can simultaneously regulate both types of factors [5,12,28,29]. Therefore, the neddylation pathway can inhibit or promote cancer cell proliferation and invasion.…”

Section: Neddylation Substratesmentioning

confidence: 98%

“…EGR1 is regulated by CRL1 [28], and its roles in cancer are cell-type-dependent [83]. EGR1 is considered to have a greater tendency to function as an anti-cancer factor.…”

Section: Early Growth Response 1 (Egr1)mentioning

confidence: 99%

“…EGR1 has also been found to be an oncogene which can promote prostate cancer metastasis [89]. As a substrate of CRL1, EGR1 can be stabilized in cancer cells following MLN4924 treatment [28]. Therefore, ERG1 accumulation triggered by MLN4924 can undoubtedly promote the spread of EGR1-promoted cancers mentioned above, which compromises its anti-cancer activity.…”

Section: Early Growth Response 1 (Egr1)mentioning

confidence: 99%

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The Double-Edged Effects of MLN4924: Rethinking Anti-Cancer Drugs Targeting the Neddylation Pathway

Tang,

Pang,

et al. 2024

Biomolecules

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(1) Background: The neddylation pathway assumes a pivotal role in the initiation and progression of cancer. MLN4924, a potent small-molecule inhibitor of the NEDD8-activating enzyme (NAE), effectively intervenes in the early stages of the neddylation pathway. By instigating diverse cellular responses, such as senescence and apoptosis in cancer cells, MLN4924 also exerts regulatory effects on non-malignant cells within the tumor microenvironment (TME) and tumor virus-infected cells, thereby impeding the onset of tumors. Consequently, MLN4924 has been widely acknowledged as a potent anti-cancer drug. (2) Recent findings: Nevertheless, recent findings have illuminated additional facets of the neddylation pathway, revealing its active involvement in various biological processes detrimental to the survival of cancer cells. This newfound understanding underscores the dual role of MLN4924 in tumor therapy, characterized by both anti-cancer and pro-cancer effects. This dichotomy is herein referred to as the “double-edged effects” of MLN4924. This paper delves into the intricate relationship between the neddylation pathway and cancer, offering a mechanistic exploration and analysis of the causes underlying the double-edged effects of MLN4924—specifically, the accumulation of pro-cancer neddylation substrates. (3) Perspectives: Here, the objective is to furnish theoretical support and novel insights that can guide the development of next-generation anti-cancer drugs targeting the neddylation pathway.

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Section: Neddylation Substratesmentioning

confidence: 98%

“…EGR1 is regulated by CRL1 [28], and its roles in cancer are cell-type-dependent [83]. EGR1 is considered to have a greater tendency to function as an anti-cancer factor.…”

Section: Early Growth Response 1 (Egr1)mentioning

confidence: 99%

Section: Early Growth Response 1 (Egr1)mentioning

confidence: 99%

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The Double-Edged Effects of MLN4924: Rethinking Anti-Cancer Drugs Targeting the Neddylation Pathway

Tang,

Pang,

et al. 2024

Biomolecules

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“…SIVA1 is a transcriptional target of the Tp53 gene, and it induces the oxidative stress-induced apoptosis process ( 61 ). Additionally, the Siva-1 gene encodes for an E3 ubiquitin ligase that suppresses the anti-apoptotic activity of BCL2, leads to caspase-dependent apoptosis, localizes in the mitochondria, and regulates cell cycle progression, cell proliferation, and apoptosis ( 62 , 63 ).…”

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 genes 1(EGR1) is a nuclear protein that acts as a transcriptional regulator of a variety of genes, including tumor suppressor genes and oncogenes [ 5 ]. EGR1 plays a regulatory function in cell growth, but the role of EGR1 varies in different tumors [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

EGR1 mediates MDR1 transcriptional activity regulating gemcitabine resistance in pancreatic cancer

Yang,

Chen,

Wei

et al. 2024

BMC Cancer

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Background Gemcitabine is a cornerstone drug for the treatment of all stages of pancreatic cancer and can prolong the survival of patients with pancreatic cancer, but resistance to gemcitabine in pancreatic cancer patients hinders its efficacy. The overexpression of Early growth response 1(EGR1) in pancreatic ductal adenocarcinoma as a mechanism of gemcitabine chemoresistance in pancreatic cancer has not been explored. The major mechanisms of gemcitabine chemoresistance are related to drug uptake, metabolism, and action. One of the common causes of tumor multidrug resistance (MDR) to chemotherapy in cancer cells is that transporter proteins increase intracellular drug efflux and decrease drug concentrations by inducing anti-apoptotic mechanisms. It has been reported that gemcitabine binds to MDR1 with high affinity. The purpose of this research was to investigate the potential mechanisms by which EGR1 associates with MDR1 to regulate gemcitabine resistance in pancreatic cancer cells. Methods The following in vitro and in vivo techniques were used in this research to explore the potential mechanisms by which EGR1 binds to MDR1 to regulate gemcitabine resistance in pancreatic cancer cells. Cell culture; in vitro and in vivo study of EGR1 function by loss of function analysis. Binding of EGR1 to the MDR1 promoter was detected using the ChIP assay. qRT-PCR, Western blot assays to detect protein and mRNA expression; use of Annexin V apoptosis detection assay to test apoptosis; CCK8, Edu assay to test cell proliferation viability. The animal model of pancreatic cancer subcutaneous allograft was constructed and the tumours were stained with hematoxylin eosin and Ki-67 expression was detected using immunohistochemistry. Findings We revealed that EGR1 expression was increased in different pancreatic cancer cell lines compared to normal pancreatic ductal epithelial cells. Moreover, gemcitabine treatment induced upregulation of EGR1 expression in a dose- and time-dependent manner. EGR1 is significantly enriched in the MDR1 promoter sequence.Upon knockdown of EGR1, cell proliferation was impaired in CFPAC-1 and PANC-1 cell lines, apoptosis was enhanced and MDR1 expression was decreased, thereby partially reversing gemcitabine chemoresistance. In animal experiments, knockdown of EGR1 enhanced the inhibitory effect of gemcitabine on tumor growth compared with the sh-NC group. Conclusions Our study suggests that EGR1 may be involved in the regulation of MDR1 to enhance gemcitabine resistance in pancreatic cancer cells. EGR1 could be a novel therapeutic target to overcome gemcitabine resistance in pancreatic cancer.

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Early growth response-1 is a new substrate of the GSK3β-FBXW7 axis

Cited by 5 publications

References 57 publications

The Double-Edged Effects of MLN4924: Rethinking Anti-Cancer Drugs Targeting the Neddylation Pathway

The Double-Edged Effects of MLN4924: Rethinking Anti-Cancer Drugs Targeting the Neddylation Pathway

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

EGR1 mediates MDR1 transcriptional activity regulating gemcitabine resistance in pancreatic cancer

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