Regulation of expression and signalling modulator function of mammalian tribbles is cell-type specific

Sung, Hye Youn; Francis, Sheila E.; Crossman, David C.; Kiss-Tóth, Endre

doi:10.1016/j.imlet.2005.11.010

Cited by 66 publications

(55 citation statements)

References 55 publications

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“…Genes in the Tribbles family encode a kinase-like domain but lack catalytic core motifs and kinase activities (Sung et al 2006). A carboxy-terminal hexapeptide motif is shared among the three tribbles proteins and it is the binding site for E3 ubiquitin ligase constitutive photomorphogenic protein 1 (COP1) that participates in the proteasomemediated degradation of some targets of tribbles (Qi et al 2006, Yokoyama & Nakamura 2011.…”

Section: Introductionmentioning

confidence: 99%

“…A carboxy-terminal hexapeptide motif is shared among the three tribbles proteins and it is the binding site for E3 ubiquitin ligase constitutive photomorphogenic protein 1 (COP1) that participates in the proteasomemediated degradation of some targets of tribbles (Qi et al 2006, Yokoyama & Nakamura 2011. TRIB1-3 also provides a motif for MEK1 binding at near C-termini, which can enhance or inhibit MEK/MAPK signaling dependently on cell type and target molecule (Sung et al 2006). The MEK1 binding domain is also involved in molecular interaction with CCAAT/enhancer binding proteins (CEBPA and CEBPB; Keeshan et al 2006, Yokoyama et al 2010.…”

Section: Introductionmentioning

confidence: 99%

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TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions

Ishizuka¹,

Nakayama²,

Ogawa³

et al. 2014

Journal of Molecular Endocrinology

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Mammalian tribbles homolog 1 (TRIB1) regulates hepatic lipogenesis and is genetically associated with plasma triglyceride (TG) levels and cholesterol, but the molecular mechanisms remain obscure. We explored these mechanisms in mouse livers transfected with a TRIB1 overexpression, a shRNA template or a control (LacZ) adenovirus vector. The overexpression of TRIB1 reduced, whereas induction of the shRNA template increased, plasma glucose, TG, and cholesterol and simultaneously hepatic TG and glycogen levels. The involvement of TRIB1 in hepatic lipid accumulation was supported by the findings of a human SNP association study. A TRIB1 SNP, rs6982502, was identified in an enhancer sequence, modulated enhancer activity in reporter gene assays, and was significantly (PZ9.39!10 K7 ) associated with ultrasonographically diagnosed nonalcoholic fatty liver disease in a population of 5570 individuals. Transcriptome analyses of mouse livers revealed significant modulation of the gene sets involved in glycogenolysis and lipogenesis. Enforced TRIB1 expression abolished CCAAT/enhancer binding protein A (CEBPA), CEBPB, and MLXIPL proteins, whereas knockdown increased the protein level. Levels of TRIB1 expression simultaneously affected MKK4 (MAP2K4), MEK1 (MAP2K1), and ERK1/2 (MAPK1/3) protein levels and the phosphorylation of JNK, but not of ERK1/2. Pull-down and mammalian two-hybrid analyses revealed novel molecular interaction between TRIB1 and a hepatic lipogenic master regulator, MLXIPL. Co-expression of TRIB1 and CEBPA or MLXIPL reduced their protein levels and proteasome inhibitors attenuated the reduction. These data suggested that the modulation of TRIB1 expression affects hepatic lipogenesis and glycogenesis through multiple molecular interactions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions

Ishizuka¹,

Nakayama²,

Ogawa³

et al. 2014

Journal of Molecular Endocrinology

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“…TG and TRIB1 encodes a human homolog of the Drosophila tribbles protein ( 7 ). Proteins in the tribbles family include a pseudokinase domain, an E3 ubiquitin ligase (COP1)-binding domain, and a MEK1-binding domain, each of which are involved in the interaction with respective partners ( 3,(8)(9)(10). Depending on the partner, tribbles proteins degrade or support the target proteins.…”

Section: Animal Experimentsmentioning

confidence: 99%

Sin3A-associated protein, 18 kDa, a novel binding partner of TRIB1, regulates MTTP expression [S]

Makishima

Boonvisut

Ishizuka

et al. 2015

Journal of Lipid Research

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Mammalian tribbles homolog 1 ( TRIB1 ) is a human locus that has been shown to exhibit convincing impact on cardiovascular diseases and plasma lipid concentrations across several ethnic groups. These genetic associations have been demonstrated both in genome-wide SNP association studies ( 1 ) and in subsequent replication studies ( 2 ). In addition, we recently showed the deep association of a TRIB1 regulatory SNP with nonalcoholic fatty liver disease (NAFLD) in individuals of Japanese ancestry ( P = 9.39E-7 ) ( 3 ). Association of TRIB1 SNP with NAFLD was replicated in a Japanese population ( 4 ) and association with plasma alanine aminotransferase (ALT) was reported in a study of individuals of European ancestry ( 5 ), supporting the involvement of TRIB1 in the development of NAFLD. The risk allele of NAFLD decreased transactivation activity ( 3 ). Knockdown of the expression of the mouse homolog ( Trib1 ) in mouse liver increased murine plasma and hepatic lipid levels, whereas Trib1 overexpression decreased these parameters ( 3 ). The enhanced lipogenesis in mouse liver was estimated to result from the reduced protein decay of carbohydrate response element binding protein [ChREBP (MLXIPL)], which is a master regulator for energy storage, coordinating the switch from carbohydrate to lipid via upregulation of glycolysis and lipogenic genes. While the ChREBP knockout mouse is resistant to dietary induced steatosis ( 6 ), ChREBP is not associated with NAFLD in human genetic studies, despite the deep genetic association with plasma TG levels ( 1 ). This observation suggested that an undefi ned pathway might be involved in the pathogenesis of NAFLD associated with TRIB1 .Abstract Mammalian tribbles homolog 1 ( TRIB1 ) is a human locus that has been shown to signifi cantly impact plasma lipid levels across several ethnic groups. In addition, the gene has been associated with the occurrence of nonalcoholic fatty liver disease. In the present study, a yeast-twohybrid system was used to screen for novel molecular targets of TRIB1 binding. Loci corresponding to clones that were positive for TRIB1 binding subsequently were assessed for roles in lipid metabolism in mice using adenoviral constructs to induce knockdown or overexpression. Sin3A-associated protein, 18 kDa (SAP18) was identifi ed as a novel binding partner of TRIB1. Knockdown of the Sap18 in mouse liver decreased plasma lipid levels and increased hepatic lipid levels; SAP18 overexpression showed the opposite effects. Transcriptome analysis of the mouse liver revealed that Sap18 knockdown decreased and SAP18 overexpression increased microsomal TG transfer protein ( MTTP ) expression levels. Chromatin immunoprecipitation analysis showed that halo-tagged SAP18, halo-tagged TRIB1, and anti-mSin3A antibody enriched precipitates for regulatory sequences of the MTTP gene. Enforced expression of SAP18 enhanced and SAP18 knockdown conversely attenuated the enrichment of MTTP regulatory sequences seen with antimSin3A antibody. These studies indicated that SAP18 expressi...

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“…TRIBs appear to function in a cell-type-and stimulus-specific manner. In response to inflammatory stimuli, it was demonstrated that TRIB1 was rapidly and transiently upregulated in aortic smooth muscle cells and monocytes, whilst a profound but delayed activation was observed in synoviocytes (22). In addition, TRIB2 expression was reported to be upregulated at 6 h post inflammatory stimuli (interleukin-1) in monocytes, whereas TRIB2 expression was significantly decreased in response to identical stimuli in synovial fibroblasts (22).…”

Section: F E D C B Amentioning

confidence: 99%

“…In response to inflammatory stimuli, it was demonstrated that TRIB1 was rapidly and transiently upregulated in aortic smooth muscle cells and monocytes, whilst a profound but delayed activation was observed in synoviocytes (22). In addition, TRIB2 expression was reported to be upregulated at 6 h post inflammatory stimuli (interleukin-1) in monocytes, whereas TRIB2 expression was significantly decreased in response to identical stimuli in synovial fibroblasts (22). Furthermore, TRIB3 expression was differentially regulated in the various cell types examined; low TRIB3 mRNA levels were detected at 3 and 6 h following inflammatory stimuli in synovial fibroblasts and vascular smooth muscle cells; by contrast, in THP-1 cells, TRIB3 expression was significantly upregulated, with the highest levels observed at 10 h following stimuli.…”

Section: F E D C B Amentioning

confidence: 99%

Tribbles homolog 3 is induced by high glucose and associated with apoptosis in human endothelial cells

Guo

Gong

et al. 2015

Molecular Medicine Reports

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Abstract. Tribbles homolog 3 (TRIB3) is an intracellular kinase-like molecule that modifies cellular survival and metabolism. The present study aimed to investigate the function of TRIB3 regulation in the process of high glucose-induced apoptosis in endothelial cells, with the aim of identifying a novel intervention target for the prevention and treatment of diabetes mellitus. Human umbilical vein endothelial cells (HUVECs) grown in medium with various concentrations of glucose (5.5, 10, 20, 30 and 40 mmol/l) were assessed for mRNA expression of TRIB1, TRIB2 and TRIB3 using reverse transcription quantitative polymerase chain reaction. In addition, protein expression of TRIB3 was examined using western blot analysis. Immunofluorescence staining was performed in order to determine the distribution and localization of TRIB3 in HUVECs. Furthermore, cells grown in normal (5.5 mmol/l) or high glucose (HG; 30 mmol/l) medium were subjected to TRIB3 inhibition through small interfering (si)RNA knockdown. These cells were then examined in order to determine whether TRIB3 upregulation was associated with endothelial cell apoptosis. HUVECs treated with 30 and 40 mmol/l glucose for 48 h and 72 h showed significantly lower survival rates compared with those treated with normal glucose levels. In addition, slight but not significant increases in TRIB1 and TRIB2 mRNA expression were observed in HUVECs incubated with various concentrations of glucose for different durations. By contrast, TRIB3 mRNA expression was increased 7.2-fold following incubation with HG. Western blot analysis revealed a 5.44-fold increase in TRIB3 protein levels in cells grown in HG medium for 24 h compared with those grown in normal medium. Immunostaining assays revealed a markedly higher and well-defined nucleolar fluorescence intensity for TRIB3 expression at 24 h in HG medium compared with that of the control group. Furthermore, the apoptotic rate of HG-treated TRIB3 siRNA-transfected HUVECs was significantly increased compared with that of those transfected with control siRNA In conclusion, the results of the present study suggested that TRIB3 was associated with high glucose-induced HUVECs apoptosis, which was attenuated following transfection with TRIB3 siRNA. IntroductionMacroangiopathy is a major cause of mortality and morbidity in diabetes mellitus. In addition, atherosclerotic and/or arteriosclerotic changes in the cardiovascular system may result in the development and progression of cardiovascular diseases associated with diabetes (1). Endothelial dysfunction is recognized as one of the early and prominent stages in the formation and development of atherosclerotic lesions (2), in which endothelial proliferation and apoptosis have been observed (3). Impairment of endothelial function has been reported to occur in the early stage of diabetes, prior to clinically detectable angiopathy and hypertension (4). Hyperglycemia has been demonstrated to disrupt the cell cycle, increase DNA damage, delay cell replication and induce apoptosis in endothelia...

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Regulation of expression and signalling modulator function of mammalian tribbles is cell-type specific

Cited by 66 publications

References 55 publications

TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions

TRIB1 downregulates hepatic lipogenesis and glycogenesis via multiple molecular interactions

Sin3A-associated protein, 18 kDa, a novel binding partner of TRIB1, regulates MTTP expression [S]

Tribbles homolog 3 is induced by high glucose and associated with apoptosis in human endothelial cells

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