MicroRNA-21 regulates T-cell apoptosis by directly targeting the tumor suppressor gene Tipe2

Ruan, Qingguo; Wang, P; Wang, T; Qi, Ji; Wei, Monica; Wang, S; Fan, Tingting; Johnson, Derek; Wan, Xiaochun; Shi, Wenna; Sun, Honghong; Chen, Y H

doi:10.1038/cddis.2014.47

Cited by 78 publications

(65 citation statements)

References 58 publications

(67 reference statements)

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“…66 Furthermore, TIPE2 has recently been implicated as the molecular bridge for the microRNA (miRNA)-21-mediated suppression of T-cell apoptosis; miRNA-21 was found to be a direct target of NF-κB and to decrease TIPE2 expression, which results in apoptosis resistance. 67 TIPE2 has also been found to bind to and inhibit Rac, inhibiting downstream activation of AKT and Ral; deficiency in TIPE2 protein increased the activation of Ral and AKT, with associated resistance to cell death and increased cell migration as well as the dysregulation of exocyst complex formation. In vascular smooth muscle cells, TIPE2 was found to inhibit Rac1-mediated STAT3 activation, nuclear translocation and Erk1/2 activation.…”

Section: Tipe2 Is a Negative Regulator Of Immunity And Inflammationmentioning

confidence: 99%

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

Goldsmith

Chen

2017

Cell Mol Immunol

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The TIPE (tumor necrosis factor-α-induced protein 8-like) family are newly described regulators of immunity and tumorigenesis consisting of four highly homologous mammalian proteins: TNFAIP8 (tumor necrosis factor-α-induced protein 8), TIPE1 (TNFAIP8-like 1, or TNFAIP8L1), TIPE2 (TNFAIP8L2) and TIPE3 (TNFAIP8L3). They are the only known transfer proteins of the lipid secondary messengers PIP2 (phosphatidylinositol 4,5-bisphosphate) and PIP3 (phosphatidylinositol 3,4,5-trisphosphate). Cell-surface receptors, such as G-protein-coupled receptors and receptor tyrosine kinases, regulate inflammation and cancer via several signaling pathways, including the nuclear factor (NF)-κB and phosphoinositide-3 kinase (PI3K) pathways, the latter of which is upstream of both Akt and STAT3 activation. An expression analysis in humans demonstrated that the TIPE family is dysregulated in cancer and inflammation, and studies both in mice and in vitro have demonstrated that this family of proteins plays a critical role in tumorigenesis and inflammatory responses. In this review, we summarize the current literature for all four family members, with a special focus on the phenotypic manifestations present in the various knockout murine strains, as well as the related cell signaling that has been elucidated to date.

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Section: Tipe2 Is a Negative Regulator Of Immunity And Inflammationmentioning

confidence: 99%

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

Goldsmith

Chen

2017

Cell Mol Immunol

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“…Other significantly enriched processes, including regulation of apoptosis and cell death, the M1-specific enhancement of nitric oxide biosynthesis, and the regulation of NF-kB functions (supplemental Table 7) have previously been associated with altered miR-21 expression. [66][67][68] These results suggest that the CSF-1R pTyr-721/miR-21/miR-21 substrate network negatively regulates macrophage M1 polarization. For personal use only.…”

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confidence: 70%

Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21

Caescu

Guo

Tesfa³

et al. 2015

Blood

128

118

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Key Points• Analysis of CSF-1R pTyrregulated messenger RNAs identifies novel signaling nodes and networks that can be targeted to modulate macrophage functions.• miR-21 is a novel CSF-1R pTyr-721-induced molecule that suppresses the macrophage M1 phenotype and enhances the M2 phenotype.Macrophage polarization between the M2 (repair, protumorigenic) and M1 (inflammatory) phenotypes is seen as a continuum of states. The detailed transcriptional events and signals downstream of colony-stimulating factor 1 receptor (CSF-1R) that contributes to amplification of the M2 phenotype and suppression of the M1 phenotype are largely unknown. Macrophage CSF-1R pTyr-721 signaling promotes cell motility and enhancement of tumor cell invasion in vitro. Combining analysis of cellular systems for CSF-1R gain of function and loss of function with bioinformatic analysis of the macrophage CSF-1R pTyr-721-regulated transcriptome, we uncovered microRNA-21 (miR-21) as a downstream molecular switch controlling macrophage activation and identified extracellular signal-regulated kinase 1/2 and nuclear factor-kB as CSF-1R pTyr-721-regulated signaling nodes. We show that CSF-1R pTyr-721 signaling suppresses the inflammatory phenotype, predominantly by induction of miR-21. Profiling of the miR-21-regulated messenger RNAs revealed that 80% of the CSF-1-regulated canonical miR-21 targets are proinflammatory molecules. Additionally, miR-21 positively regulates M2 marker expression. Moreover, miR-21 feeds back to positively regulate its own expression and to limit CSF-1R-mediated activation of extracellular signal-regulated kinase 1/2 and nuclear factor-kB. Consistent with an anti-inflammatory role of miRNA-21, intraperitoneal injection of mice with a miRNA-21 inhibitor increases the recruitment of inflammatory monocytes and enhances the peritoneal monocyte/macrophage response to lipopolysaccharide. These results identify the CSF-1R-regulated miR-21 network that modulates macrophage polarization. (Blood. 2015;125(8):e1-e13) IntroductionMacrophages protect the host against infection and injury and facilitate tissue remodeling.1 However, they frequently accumulate in pathological settings, including cancers, 2 atherosclerosis, 3 metabolic disease, 4 and sepsis, 5 where they respond to microenvironmental cues that can be detrimental to the host. Two distinct extreme states of polarized activation have been described in macrophages:6,7 the classically activated (M1) and the alternatively activated (M2) macrophage phenotypes, each characterized by well-described markers. 5,6,[8][9][10][11] M1 macrophages produce proinflammatory cytokines, elevate the expression of inducible nitric oxide synthase 2 (iNOS) and major histocompatibility complex class II (MHC II), 12 and can play antitumorigenic roles. 5,9 In contrast, the M2 macrophages have increased expression of scavenger receptors, increased activation of the arginase pathway, low expression of interleukin-12 (IL-12), high expression of IL-10 and IL-1RA, and increased anti-inflammatory responses a...

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“…Each of the 6 identified miRNAs are involved in innate or adaptive immune response [16][17][18][19][20] ; we speculate that increased expression of the miRNAs associated with shorter gestations may be evidence of a miRNA-mediated response that contributes to preterm birth. Notably, network analysis of the 212 mRNA targets of the 6 significantly upregulated miRNAs identified tumor necrosis factor (TNF) as a central node of a network that was enriched for DNA replication.…”

Section: Discussionmentioning

confidence: 94%

microRNA expression in the cervix during pregnancy is associated with length of gestation

et al. 2015

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(2015) microRNA expression in the cervix during pregnancy is associated with length of gestation , Epigenetics, 10:3, 221-228, DOI: 10.1080/15592294.2015 Preterm birth is a leading cause of infant mortality and can lead to poor life-long health and adverse neurodevelopmental outcomes. The pathophysiologic mechanisms that precede preterm labor remain elusive, and the role that epigenetic phenomena play is largely unstudied. The objective of this study was to assess the association between microRNA (miRNA) expression levels in cervical cells obtained from swabs collected during pregnancy and the length of gestation. We analyzed cervical samples obtained between 16 and 19 weeks of gestation from 53 women in a prospective cohort from Mexico City, and followed them until delivery. Cervical miRNA was extracted and expression was quantified using the NanoString nCounter Analysis System. Linear regression models were used to examine the association between miRNA expression levels and gestational age at delivery, adjusted for maternal age, education, parity, body mass index, smoke exposure, and inflammation assessed on a Papanicolaou smear. We identified 6 miRNAs that were significantly associated with gestational age at the time of delivery, including miR-21, 30e, 142, 148b, 29b, and 223. Notably, per each doubling in miR-21 expression, gestations were 0.9 (95% CI: 0.2-1.5) days shorter on average (P D 0.009). Per each doubling in miR-30e, 142, 148b, 29b, and 223 expression, gestations were shorter by 1.0 to 1.6 days. The predicted targets of the miRNAs were enriched for molecules involved in DNA replication and inflammatory processes. The levels of specific miRNAs in the human cervix during pregnancy are predictive of gestational age at delivery, and should be validated in future studies as potential biomarkers of preterm birth risk.

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MicroRNA-21 regulates T-cell apoptosis by directly targeting the tumor suppressor gene Tipe2

Cited by 78 publications

References 58 publications

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

Colony stimulating factor-1 receptor signaling networks inhibit mouse macrophage inflammatory responses by induction of microRNA-21

microRNA expression in the cervix during pregnancy is associated with length of gestation

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