The mechanisms of DIRAS family members in role of tumor suppressor

Li, Xueli; Liu, Shuiping; Xiao, Fang; He, Chao

doi:10.1002/jcp.27376

Cited by 14 publications

(15 citation statements)

References 87 publications

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“…No genes were significantly downregulated in both leukocytes and liver from IMBAL cows, although there was one pair of closely related genes: expression of DIRAS2 was lower in blood and DIRAS3 was in the top 10 list of most downregulated genes in liver. The DIRAS family members encode GTPases, which compete with RAS for binding to deactivate multiple downstream effect targets of the RAS signaling pathway and they can also interfere with other key signaling pathways including JAK/STAT, PI-3K/AKT, mTOR, and NF-κB signal transduction (Li et al, 2019). This suggests that RAS signaling may be important in regulating responses to an energy deficit, an aspect that is worth further investigation.…”

Section: Deg Common To Both Leukocytes and Livermentioning

confidence: 99%

Relationships between metabolic profiles and gene expression in liver and leukocytes of dairy cows in early lactation

Wathes

Cheng

Salavati

et al. 2021

Journal of Dairy Science

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Homeorhetic mechanisms assist dairy cows in the transition from pregnancy to lactation. Less successful cows develop severe negative energy balance (NEB), placing them at risk of metabolic and infectious diseases and reduced fertility. We have previously placed multiparous Holstein Friesian cows from 4 herds into metabolic clusters, using as biomarkers measurements of plasma nonesterified fatty acids, β-hydroxybutyrate, glucose and IGF-1 collected at 14 and 35 d in milk (DIM). This study characterized the global transcriptomic profiles of liver and circulating leukocytes from the same animals to determine underlying mechanisms associated with their metabolic and immune function.Liver biopsy and whole-blood samples were collected around 14 DIM for RNA sequencing. All cows with available RNA sequencing data were placed into balanced (BAL, n = 44), intermediate (n = 44), or imbalanced (IMBAL, n = 19) metabolic cluster groups. Differential gene expression was compared between the 3 groups using ANOVA, but only the comparison between BAL and IMBAL cows is reported. Pathway analysis was undertaken using DAVID Bioinformatic Resources (https: / / david .ncifcrf .gov/ ). Milk yields did not differ between BAL and IMBAL cows but dry matter intake was less in IMBAL cows and they were in greater energy deficit at 14 DIM (−4.48 v −11.70 MJ/d for BAL and IMBAL cows). Significantly differentially expressed pathways in hepatic tissue included AMPK signaling, glucagon signaling, adipocytokine signaling, and insulin resistance. Genes involved in lipid metabolism and cholesterol transport were more highly expressed in IMBAL cows but IGF1 and IG-FALS were downregulated. Leukocytes from BAL cows had greater expression of histones and genes involved in nucleosomes and cell division. Leukocyte expression of heat shock proteins increased in IMBAL cows, suggesting an unfolded protein response, and several key genes involved in immune responses to pathogens were upregulated (e.g., DEFB13, HP, OAS1Z, PTX3, and TLR4). Differentially expressed genes upregulated in IMBAL cows in both tissues included CD36, CPT1, KFL11, and PDK4, all central regulators of energy metabolism. The IMBAL cows therefore had greater difficulty maintaining glucose homeostasis and had dysregulated hepatic lipid metabolism. Their energy deficit was associated with a reduced capacity for cell division and greater evidence of stress responses in the leukocyte population, likely contributing to an increased risk of infectious disease.

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Section: Deg Common To Both Leukocytes and Livermentioning

confidence: 99%

Relationships between metabolic profiles and gene expression in liver and leukocytes of dairy cows in early lactation

Wathes

Cheng

Salavati

et al. 2021

Journal of Dairy Science

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“…In contrast to these mutant Rab proteins, which promote cancer by forming trimeric complexes with SmgGDS and an oncogenic small GTPase ( Nissim et al, 2019 ; Liao et al, 2020 ), the GTPase DiRas1 (also known as Rig) seems to inhibit cancer by blocking the binding of small GTPases to SmgGDS. DiRas1 is a Ras family member that acts as a tumor suppressor in many types of cancer (reviewed in Li et al, 2019 ). DiRas1 binds to SmgGDS ( Bergom et al, 2016 ; Gonyo et al, 2017 ; Garcia-Torres and Fierke, 2019 ) ( Figure 1B ) and inhibits the binding of other small GTPases, including RhoA, K-Ras4B, and Rap1A ( Bergom et al, 2016 ).…”

Section: Signaling Events and Protein Partners Of Smggds Control The Prenylation And Trafficking Of Ras And Rho Family Membersmentioning

confidence: 99%

“…In silico docking indicates that DiRas1 directly competes with other small GTPases for binding to SmgGDS ( Bergom et al, 2016 ), and DiRas1 binds with much stronger affinity than other Ras and Rho family members to SmgGDS-558 ( Bergom et al, 2016 ) and to SmgGDS-607 ( Garcia-Torres and Fierke, 2019 ). In cancer cells, ectopic expression of DiRas1 inhibits basal and RhoA-mediated NF-kB activity ( Bergom et al, 2016 ) and provokes responses that can be attributed to reduced signaling by Ras and Rho family members [reviewed in Li et al (2019) ]. Ectopic expression of DiRas1 also alters nucleocytoplasmic shuttling of SmgGDS-558 and diminishes its interaction with UBF in the nucleus ( Gonyo et al, 2017 ).…”

Section: Signaling Events and Protein Partners Of Smggds Control The Prenylation And Trafficking Of Ras And Rho Family Membersmentioning

confidence: 99%

“… The balanced expression of SmgGDS-607 and SmgGDS-558 in cells is regulated through specific splicing programs and spliceosome factors that have yet to be characterized. Additionally, cells control the activities of these splice variants through the actions of DiRas ( Bergom et al, 2016 ), which is expressed in normal cells [reviewed by Li et al (2019) ], and by the actions of mutant forms of both RabL3 and Rab22, which are expressed in cancer cells ( Nissim et al, 2019 ; Liao et al, 2020 ). There are undoubtedly more regulatory mechanisms that control the expression, stability, and activity of these SmgGDS splice variants in different physiological and pathophysiological conditions.…”

Section: Future Directionsmentioning

confidence: 99%

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SmgGDS: An Emerging Master Regulator of Prenylation and Trafficking by Small GTPases in the Ras and Rho Families

Brandt

Koehn

Williams

2021

Front. Mol. Biosci.

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Newly synthesized small GTPases in the Ras and Rho families are prenylated by cytosolic prenyltransferases and then escorted by chaperones to membranes, the nucleus, and other sites where the GTPases participate in a variety of signaling cascades. Understanding how prenylation and trafficking are regulated will help define new therapeutic strategies for cancer and other disorders involving abnormal signaling by these small GTPases. A growing body of evidence indicates that splice variants of SmgGDS (gene name RAP1GDS1) are major regulators of the prenylation, post-prenylation processing, and trafficking of Ras and Rho family members. SmgGDS-607 binds pre-prenylated small GTPases, while SmgGDS-558 binds prenylated small GTPases. This review discusses the history of SmgGDS research and explains our current understanding of how SmgGDS splice variants regulate the prenylation and trafficking of small GTPases. We discuss recent evidence that mutant forms of RabL3 and Rab22a control the release of small GTPases from SmgGDS, and review the inhibitory actions of DiRas1, which competitively blocks the binding of other small GTPases to SmgGDS. We conclude with a discussion of current strategies for therapeutic targeting of SmgGDS in cancer involving splice-switching oligonucleotides and peptide inhibitors.

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“…The distinct subgroup of the Ras family member 3 ( DIRAS3 ) gene, also known as ARHI and NOEY2 , encodes a small GTPase, which belongs to the Ras superfamily and serves as a tumor suppressor against various cancers including breast and ovarian cancers [ 11 , 12 ]. A maternal imprint and paternal monoallelic expression of the human DIRAS3 gene have been reported to establish a functional allele that acts as a negative regulator of growth and development [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Genomic Imprinting at the Porcine DIRAS3 Locus

Ahn

Hwang

Park

et al. 2021

Animals

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The epigenetic mechanisms underlying genomic imprinting include DNA methylation and monoallelic expression of genes in close proximity. Although genes imprinted in humans and mice have been widely characterized, there is a lack of detailed and comprehensive studies in livestock species including pigs. The purpose of this study was to investigate a detailed methylation status and parent-of-origin-specific gene expression within the genomic region containing an underexamined porcine DIRAS3 locus. Through whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) of porcine parthenogenetic embryos and analyses of public RNA-seq data from adult pigs, DNA methylation and monoallelic expression pattern were investigated. As a result, maternal hypermethylation at the DIRAS3 locus and hypothalamus-specific and monoallelic expression of the DIRAS3 gene were found in pigs. In conclusion, the findings from this study suggest that the presence of maternal hypermethylation, or imprints, might be maintained and related to monoallelic expression of DIRAS3 during pig development.

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The mechanisms of DIRAS family members in role of tumor suppressor

Cited by 14 publications

References 87 publications

Relationships between metabolic profiles and gene expression in liver and leukocytes of dairy cows in early lactation

Relationships between metabolic profiles and gene expression in liver and leukocytes of dairy cows in early lactation

SmgGDS: An Emerging Master Regulator of Prenylation and Trafficking by Small GTPases in the Ras and Rho Families

Genomic Imprinting at the Porcine DIRAS3 Locus

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