Protein ISGylation and free ISG15 levels are increased by interferon gamma in breast cancer cells

Tecalco-Cruz, Ángeles C.; Cruz-Ramos, Eduardo

doi:10.1016/j.bbrc.2018.04.030

Cited by 16 publications

(6 citation statements)

References 46 publications

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“…ISG15 mRNA translation should be repressed by hypoxia since it is dependent on the phosphorylation of S6K [39], a process that is repressed by hypoxia through mTOR [6]. However, ISG15 can adopt cell‐type‐specific patterns of activity [40,41] so the regulation is likely multi‐layered. Interestingly, overexpression of GFP‐HIF‐2α led to the accumulation of free ISG15 protein (Fig.…”

Section: Discussionmentioning

confidence: 99%

ISGylation directly modifies hypoxia‐inducible factor‐2α and enhances its polysome association

et al. 2022

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The hypoxia‐inducible factors (HIF)‐1α and HIF‐2α are central regulators of transcriptional programmes in settings such as development and tumour expansion. HIF‐2α moonlights as a cap‐dependent translation factor. We provide new insights into how the interferon‐stimulated gene 15 (ISG15), a ubiquitin‐like modifier, and the HIFs regulate one another in hypoxia and interferon‐induced cells. We show that upon ISGylation induction and HIF‐α stabilization, both HIFs promote protein ISGylates through transcriptional and/or post‐transcriptional pathways. We show the first evidence of HIF‐2α modification by ISG15. ISGylation induces system‐level alterations to the HIF transcriptional programme and increases the cytoplasmic/nuclear fraction and translation activity of HIF‐2α. This work identifies ISG15 as a regulator of hypoxic mRNA translation, which has implications for immune processes and disease progression.

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Section: Discussionmentioning

confidence: 99%

ISGylation directly modifies hypoxia‐inducible factor‐2α and enhances its polysome association

et al. 2022

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“…Similarly, RALA upregulation is a marker of poor prognosis in BC patients [ 28 ]. Notably, our analysis suggested that proteasome-related pathways may be affected by IFNγ signaling, implying that: 1) some proteasome inhibitors could be tested as pharmacological tools for different cancer types, including BC [ 29 , 30 ]; 2) proteasome subunit (as PSMD8 ) deregulation can result in cancer progression, and resistance to proteasome inhibitors [ 31 , 32 ]; 3) IFNγ increases ISGylation, a protein modification associated with protein stability by competing with the ubiquitination pathway in BC [ [33] , [34] , [35] ]; and 4) the IFNγ repression of proteolysis-associated genes may be helpful in the development of novel strategies to treat this pathology.…”

Section: Discussionmentioning

confidence: 99%

Identification of genes modulated by interferon gamma in breast cancer cells

Tecalco-Cruz

Macı́as-Silva

Ramírez-Jarquín

et al. 2021

Biochemistry and Biophysics Reports

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Interferon gamma (IFNγ) plays a context-dependent dual tumor-suppressor and pro-tumorigenic roles in cancer. IFNγ induces morphological changes in breast cancer (BC) cells with or without estrogen receptor alpha (ERα) expression. However, IFNγ-regulated genes in BC cells remain unexplored. Here, we performed a cDNA microarray analysis of MCF-7 (ERα+) and MDA-MB-231 (HER2-/PR-/ERα-) cells with and without IFNγ treatment. We identified specific IFNγ−modulated genes in each cell type, and a small group of genes regulated by IFNγ common in both cell types. IFNγ treatment for an extended time mainly repressed gene expression shared by both cell types. Nonetheless, some of these IFNγ-repressed genes were seemingly deregulated in human mammary tumor samples, along with decreased IFNGR1 (an IFNγ receptor) expression. Thus, IFNγ signaling-elicited anti-tumor activities may be mediated by the downregulation of main IFNγ target genes in BC; however, it may be deregulated by the tumor microenvironment in a tumor stage-dependent manner.

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“…An emerging body of evidence reveals that the ISG15 pathway, an antagonist of the ubiquitin pathway, is aberrantly elevated in various human malignancies, implicating its potential role underlying the observed defects in protein degradation in cancer. Concurrently, it has been reported that the ISG15 pathway (ISG15 and its conjugating enzymes) is overexpressed in human breast cancer cells and clinical specimens [70,71,152,153] and inhibits protein degradation in cancer cells [70]. Specifically, elevated ISGylation inhibits the camptothecin-dependent proteasome-mediated degradation of topoisomerase I in breast cancer cells, accounting for camptothecin's efficacy as an anticancer chemotherapeutic [70].…”

Section: Isg15 In Cancermentioning

confidence: 99%

“…Breast [70,71,79,152,153,[157][158][159]165] Breast [173] Ataxia telangiectasia [117,221] CMV [209] Colon [220] Lung [72,134,171] Amyotrophic lateral sclerosis [77,81,196] Ebola virus [128,129] Esophageal [163] Acute promyelocytic leukemia [73] Parkinson's disease [133] Inflammatory diseases [216,[218][219][220][221][222][223][224][225] Hepatic [164] Traumatic brain injury [81] Influenza A and B [67,124,125,208] Nasopharyngeal [168] Hepatitis C [213,214] Pancreatic [166,167] HIV [202][203][204]…”

Section: Cancer Neurodegeneration Infections and Inflammatory Diseasesmentioning

confidence: 99%

ISG15 and ISGylation in Human Diseases

Mirzalieva

Juncker

Schwartzenburg

et al. 2022

Cells

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Type I Interferons (IFNs) induce the expression of >500 genes, which are collectively called ISGs (IFN-stimulated genes). One of the earliest ISGs induced by IFNs is ISG15 (Interferon-Stimulated Gene 15). Free ISG15 protein synthesized from the ISG15 gene is post‑translationally conjugated to cellular proteins and is also secreted by cells into the extracellular milieu. ISG15 comprises two ubiquitin-like domains (UBL1 and UBL2), each of which bears a striking similarity to ubiquitin, accounting for its earlier name ubiquitin cross-reactive protein (UCRP). Like ubiquitin, ISG15 harbors a characteristic β‑grasp fold in both UBL domains. UBL2 domain has a conserved C‑terminal Gly-Gly motif through which cellular proteins are appended via an enzymatic cascade similar to ubiquitylation called ISGylation. ISG15 protein is minimally expressed under physiological conditions. However, its IFN‑dependent expression is aberrantly elevated or compromised in various human diseases, including multiple types of cancer, neurodegenerative disorders (Ataxia Telangiectasia and Amyotrophic Lateral Sclerosis), inflammatory diseases (Mendelian Susceptibility to Mycobacterial Disease (MSMD), bacteriopathy and viropathy), and in the lumbar spinal cords of veterans exposed to Traumatic Brain Injury (TBI). ISG15 and ISGylation have both inhibitory and/or stimulatory roles in the etiology and pathogenesis of human diseases. Thus, ISG15 is considered a “double-edged sword” for human diseases in which its expression is elevated. Because of the roles of ISG15 and ISGylation in cancer cell proliferation, migration, and metastasis, conferring anti-cancer drug sensitivity to tumor cells, and its elevated expression in cancer, neurodegenerative disorders, and veterans exposed to TBI, both ISG15 and ISGylation are now considered diagnostic/prognostic biomarkers and therapeutic targets for these ailments. In the current review, we shall cover the exciting journey of ISG15, spanning three decades from the bench to the bedside.

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Protein ISGylation and free ISG15 levels are increased by interferon gamma in breast cancer cells

Cited by 16 publications

References 46 publications

ISGylation directly modifies hypoxia‐inducible factor‐2α and enhances its polysome association

ISGylation directly modifies hypoxia‐inducible factor‐2α and enhances its polysome association

Identification of genes modulated by interferon gamma in breast cancer cells

ISG15 and ISGylation in Human Diseases

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