From mammals to viruses: the Schlafen genes in developmental, proliferative and immune processes

Casa-Esperón, Elena de la

doi:10.1515/bmc.2011.018

Cited by 22 publications

(19 citation statements)

References 60 publications

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“…Reexamination of our published microarray data comparing primary lung endothelial cells from WT and cd47 −/− mice [GSE43133, (20)] identified a 3.6-fold decrease in mRNA expression of Slfn9 , a presumed murine ortholog of the SLFN11 gene (42), in cd47 −/− cells, suggesting that CD47 regulation of mRNA expression for SLFN11 orthologs is conserved across species (Figure 4A). However, RNAseq analysis of unstimulated mouse NK cells (GSE113980) revealed increased Slfn4 and Slfn14 in cd47 −/− NK cells but no significant difference in Slfn9 mRNA expression comparing sorted Lin − NK1.1 + NKp46 + cells isolated from naïve cd47 −/− and cd47 +/+ mouse spleens (43) (Figure 4A), suggesting that CD47 regulation of murine Slfn9 expression is cell type-specific.…”

Section: Resultsmentioning

confidence: 99%

Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors

et al. 2019

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Knockdown or gene disruption of the ubiquitously expressed cell surface receptor CD47 protects non-malignant cells from genotoxic stress caused by ionizing radiation or cytotoxic chemotherapy but sensitizes tumors in an immune competent host to genotoxic stress. The selective radioprotection of non-malignant cells is mediated in part by enhanced autophagy and protection of anabolic metabolism pathways, but differential H2AX activation kinetics suggested that the DNA damage response is also CD47-dependent. A high throughput screen of drug sensitivities indicated that CD47 expression selectively sensitizes Jurkat T cells to inhibitors of topoisomerases, which are known targets of Schlafen-11 (SLFN11). CD47 mRNA expression positively correlated with schlafen-11 mRNA expression in a subset of human cancers but not the corresponding non-malignant tissues. CD47 mRNA expression was also negatively correlated with SLFN11 promoter methylation in some cancers. CD47 knockdown, gene disruption, or treatment with a CD47 function-blocking antibody decreased SLFN11 expression in Jurkat cells. The CD47 signaling ligand thrombospondin-1 also suppressed schlafen-11 expression in wild type but not CD47-deficient T cells. Re-expressing SLFN11 restored radiosensitivity to a CD47-deficient Jurkat cells. Disruption of CD47 in PC3 prostate cancer cells similarly decreased schlafen-11 expression and was associated with a CD47-dependent decrease in acetylation and increased methylation of histone H3 in the SLFN11 promoter region. The ability of histone deacetylase or topoisomerase inhibitors to induce SLFN11 expression in PC3 cells was lost when CD47 was targeted in these cells. Disrupting CD47 in PC3 cells increased resistance to etoposide but, in contrast to Jurkat cells, not to ionizing radiation. These data identify CD47 as a context-dependent regulator of SLFN11 expression and suggest an approach to improve radiotherapy and chemotherapy responses by combining with CD47-targeted therapeutics.

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Section: Resultsmentioning

confidence: 99%

Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors

et al. 2019

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“…However, humans express only long (SLFN5, SLFN11, SLFN12, SLFN13, SLFN14) Schlafens and one intermediate Schlafen, which is SLFN12. Schlafens play diverse roles in cell differentiation, immune cell proliferation and maturation, and cancer [ 22 , 23 ]. The role of Schlafens in lung cancer is poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Schlafen 12 Is Prognostically Favorable and Reduces C-Myc and Proliferation in Lung Adenocarcinoma but Not in Lung Squamous Cell Carcinoma

Al-Marsoummi

Pacella

Dockter

et al. 2020

Cancers

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Schlafen 12 (SLFN12) is an intermediate human Schlafen that induces differentiation in enterocytes, prostate, and breast cancer. We hypothesized that SLFN12 influences lung cancer biology. We investigated survival differences in high versus low SLFN12-expressing tumors in two databases. We then adenovirally overexpressed SLFN12 (AdSLFN12) in HCC827, H23, and H1975 cells to model lung adenocarcinoma (LUAD), and in H2170 and HTB-182 cells representing lung squamous cell carcinoma (LUSC). We analyzed proliferation using a colorimetric assay, mRNA expression by RT-qPCR, and protein by Western blot. To further explore the functional relevance of SLFN12, we correlated SLFN12 with seventeen functional oncogenic gene signatures in human tumors. Low tumoral SLFN12 expression predicted worse survival in LUAD patients, but not in LUSC. AdSLFN12 modulated expression of SCGB1A1, SFTPC, HOPX, CK-5, CDH1, and P63 in a complex fashion in these cells. AdSLFN12 reduced proliferation in all LUAD cell lines, but not in LUSC cells. SLFN12 expression inversely correlated with expression of a myc-associated gene signature in LUAD, but not LUSC tumors. SLFN12 overexpression reduced c-myc protein in LUAD cell lines but not in LUSC, by inhibiting c-myc translation. Our results suggest SLFN12 improves prognosis in LUAD in part via a c-myc-dependent slowing of proliferation.

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“…In mice, ten SLFNs have been identified, whereas there are six human SLFN isoforms (SLFN5, SLFN11, SLFN12, SLFN12L, SLFN13, and SLFN14). All of these human SLFNs, except SLFN12 and 12L, possess a putative ATPases-Associated with various cellular activities (AAA) domain and a putative RNA helicase motif, which is similar to the DNA/RNA helicase domains of nucleic acid sensors such as retinoic acid inducible gene-I (RIG-I) and melanoma differentiation associate gene 5 (MDA5) (de la Casa-Esperon, 2011). Recent reports suggested that SLFNs are involved in important cellular functions, such as immune cell development (Berger et al, 2010; Ahmadi and Veinotte, 2011) and regulation of tumorigenesis (Companioni Napoles et al, 2017; Mavrommatis et al, 2013a,b).…”

Section: Introductionmentioning

confidence: 99%

Schlafen 14 (SLFN14) is a novel antiviral factor involved in the control of viral replication

et al. 2017

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Schlafen (SLFN) proteins have been suggested to play important functions in cell proliferation and immune cell development. In this study, we determined the antiviral activities of putative RNA-helicase domain-containing SLFN14. Murine SLFN14 expression was specifically induced by TLR3-mediated pathways and type I interferon (IFN) in RAW264.7 mouse macrophages. To examine the role of SLFN during viral infection, cells were infected with either wild-type PR8 or delNS1/PR8 virus. SLFN14 expression was specifically induced following influenza virus infection. Overexpression of SLFN14 in A549 cells reduced viral replication, whereas knockdown of SLFN14 in RAW264.7 cells enhanced viral titers. Furthermore, SLFN14 promoted the delay in viral NP translocation from cytoplasm to nucleus and enhanced RIG-I-mediated IFN-β signaling. In addition, SLFN14 over-expression promoted antiviral activity against varicella zoster virus (VZV), a DNA virus. In conclusion, our data suggest that SLFN14 is a novel antiviral factor for both DNA and RNA viruses.

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From mammals to viruses: the Schlafen genes in developmental, proliferative and immune processes

Cited by 22 publications

References 60 publications

Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors

Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors

Schlafen 12 Is Prognostically Favorable and Reduces C-Myc and Proliferation in Lung Adenocarcinoma but Not in Lung Squamous Cell Carcinoma

Schlafen 14 (SLFN14) is a novel antiviral factor involved in the control of viral replication

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