DC-SCRIPT is a novel regulator of the tumor suppressor gene CDKN2B and induces cell cycle arrest in ERα-positive breast cancer cells

Ansems, Marleen; Søndergaard, Jonas Nørskov; Sieuwerts, Anieta M.; Looman, Maaike W. G.; Smid, Marcel; Graaf, Annemarie M.A. de; Weerd, Vanja de; Zuidscherwoude, Malou; Foekens, John A.; Martens, John W.M.; Adema, Gosse J.

doi:10.1007/s10549-015-3281-y

Cited by 10 publications

(10 citation statements)

References 43 publications

(70 reference statements)

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“…The transcription regulator DC-SCRIPT is not only an important NR coregulator important in DC and cancer biology (30)(31)(32)(33)(34)50), it also affects TLR-mediated cytokine production by DCs (26). Our current findings now show that the pleiotropic protein DC-SCRIPT modulates NF-kBp65 activity in DCs.…”

Section: Discussionmentioning

confidence: 50%

DC-SCRIPT Regulates IL-10 Production in Human Dendritic Cells by Modulating NF-κBp65 Activation

Søndergaard

Poghosyan

Hontelez

et al. 2015

The Journal of Immunology

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The balance between tolerance and immunity is important for the outcome of an infection or cancer, and dendritic cells (DCs) are key regulators of this balance. DC-specific transcript (DC-SCRIPT) is a protein expressed by DCs and has been demonstrated to suppress both TLR-mediated expression of IL-10 and glucocorticoid receptor–mediated transcription of glucocorticoid-induced leucine zipper (GILZ). Because GILZ is known to promote IL-10 production, we investigated whether these two processes are linked. Dual-knockdown and inhibition experiments demonstrated that neither GILZ nor glucocorticoid receptor play a role in TLR-induced IL-10 production after DC-SCRIPT knockdown. The NF-κB pathway is another route involved in IL-10 production after DC activation. Strikingly, inhibition of NF-κB led to a decreased TLR-mediated IL-10 production in DC-SCRIPT knockdown DCs. Moreover, DC-SCRIPT knockdown DCs showed enhanced phosphorylation, acetylation, and IL10 enhancer binding of the NF-κB subunit p65. These data demonstrate that besides nuclear receptor regulation, DC-SCRIPT also modulates activation of NF-κBp65 after TLR activation in human DCs.

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Section: Discussionmentioning

confidence: 50%

DC-SCRIPT Regulates IL-10 Production in Human Dendritic Cells by Modulating NF-κBp65 Activation

Søndergaard

Poghosyan

Hontelez

et al. 2015

The Journal of Immunology

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“…Unlike CDKN2A, CDKN2B expression is induced by transforming growth factor-β (TGF-β) via a complex of mothers against decapentaplegic homolog 2/3/4 (Smad2/3/4) and specificity protein 1 (Sp1) [7,8], with high TGF-β expression promoting p15 (encoded by CDKN2B) protein stability, which subsequently promotes CDK4/cyclin D1 binding [8,9]. Thus, CDKN2B expression not only promotes G1/S phase arrest, but also influences the G2/M phase [10,11] and is associated with cyclin D1, c-myc, and c-Ha-ras inhibition [10].…”

Section: Introductionmentioning

confidence: 99%

Ara-c induces cell cycle G1/S arrest by inducing upregulation of the INK4 family gene or directly inhibiting the formation of the cell cycle-dependent complex CDK4/cyclin D1

Sun

Tong

et al. 2019

Cell Cycle

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Cytosine arabinoside (Ara-c) is a pyrimidine anti-metabolite that is capable of interfering with cellular proliferation by inhibiting DNA synthesis. Each inhibitor of cyclin-dependent kinase 4 (INK4) family member has the ability to bind to cyclin-dependent kinase 4 (CDK4) and inhibit the formation of the cell cycle-dependent CDK4/cyclin D1 complex, subsequently leading to cell cycle arrest in the G1/S phase. In this study, the expression of INK4 family genes in kidney cancer and the impact of these genes on patient prognosis were examined. Additionally, the effects of INK4 family genes and Ara-c on cell proliferation and tumor formation and development were examined. Finally, a potential association between Ara-c-induced cell cycle arrest and INK4-associated gene expression was evaluated. An upregulation of INK4 family genes was found to be positively correlated with the prognosis of patients with kidney cancer. Both the INK4 family genes and Arac were shown to induce cell cycle arrest and inhibit tumor formation and development. Moreover, Ara-c-induced cell cycle arrest was found to be associated with an Ara-c-induced upregulation of INK4 family gene expression, which ultimately inhibited the formation of the CDK4/cyclin D1 complex. These findings suggested that an upregulation of INK4 family genes has a positive effect on kidney cancer prognosis and can inhibit the formation and development of tumors. Moreover, Ara-c was shown to promote the upregulation of INK4 family genes, at the same time, Ara-c could directly regulate the cell cycle-dependent genes CDK4 and cyclin D1 (CCND1), independent of the INK4 family genes.

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“…CDKN1A and CDKN2B are potent cyclin-dependent kinase inhibitors and serve roles in the regulation of cell cycle progression at the G 1 stage (30,31). CDKN1A and CDKN2B have been reported in relation to breast (32), liver (33) and prostate cancer (34). Although an association between CDKN1A and CDKN2B and colon and rectal cancer has been reported, the majority of studies reported activities specific to potent cyclin-dependent kinase inhibitors (32,35,36).…”

Section: Discussionmentioning

confidence: 99%

Identification of key pathways and genes in colorectal cancer to predict the prognosis based on mRNA interaction network

Zhu

Li³

et al. 2019

Oncol Lett

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The aim of the present study was to identify key genes in colorectal cancer (CRC) that could be used to reliably diagnose this disease and to explore the potential underlying mechanisms in silico. The gene expression profiles of primary human cancer datasets GSE21510 and GSE32323 were downloaded from the Gene Expression Omnibus database. The limma R software package was used to identify differentially expressed (DE) genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on DE genes using the Database for Annotation, Visualization and Integrated Discovery. The Search Tool for the Retrieval of Interacting Genes/Proteins database was used to construct a protein-protein interaction (PPI) network of the DE genes. Survival rate was analyzed and visualized using The Cancer Genome Atlas (TCGA). A total of 1,126 genes were significantly DE in the present study. All DE genes were enriched in KEGG pathways including 'cell cycle', 'mineral absorption', 'pancreatic secretion', 'pathways in cancer', 'metabolic pathways', 'aldosterone-regulated sodium reabsorption' and 'Wnt signaling pathway'. A total of 5 hub genes enriched in cell cycle and tumor-associated pathways, including E2F2, SKP2, MYC, CDKN1A and CDKN2B, were significantly DE and validated between tumor and normal tissues. CDKN1A and CDKN2B were identified within the PPI network using the Molecular Complex Detection algorithm. Survival and content distribution analyses of 362 clinical samples from TCGA revealed that CDKN1A effectively predicted the prognosis of patients. The present study identified key genes and potential signaling pathways involved in CRC. These findings may provide new insights for survival assessment during the clinical diagnosis of CRC.

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DC-SCRIPT is a novel regulator of the tumor suppressor gene CDKN2B and induces cell cycle arrest in ERα-positive breast cancer cells

Cited by 10 publications

References 43 publications

DC-SCRIPT Regulates IL-10 Production in Human Dendritic Cells by Modulating NF-κBp65 Activation

DC-SCRIPT Regulates IL-10 Production in Human Dendritic Cells by Modulating NF-κBp65 Activation

Ara-c induces cell cycle G1/S arrest by inducing upregulation of the INK4 family gene or directly inhibiting the formation of the cell cycle-dependent complex CDK4/cyclin D1

Identification of key pathways and genes in colorectal cancer to predict the prognosis based on mRNA interaction network

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