GFPT2作为己糖胺代谢重要的转录因子,在动物的多种疾病发生发展中起着重要作用。利用生物信息学方法对GFPT2蛋白的组分、功能、正选择位点及其分子进化进行了详细的分析。结果表明:13条不同物种氨基酸序列组分分析显示亮氨酸占比最高为9...GFPT2作为己糖胺代谢重要的转录因子,在动物的多种疾病发生发展中起着重要作用。利用生物信息学方法对GFPT2蛋白的组分、功能、正选择位点及其分子进化进行了详细的分析。结果表明:13条不同物种氨基酸序列组分分析显示亮氨酸占比最高为9.86%,含量最低的氨基酸为色氨酸(0.15%),平均长度为664.8。系统进化树和结构域显示人和猴子的亲缘性最近,其次是大鼠、小鼠,所有氨基酸均包含两个SIS保守结构域。混合效应-演化模型(mixed effects model of evolution,MEME)和固定效应(fixed effects likelihood,REL)方法共发现8个正选择位点。基因本体论(gene ontology,GO)功能富集分析发现GFPT2主要参与GFPT酶活性、蛋白结合、碳水化合物衍生物结合方面发挥作用等生物学过程。京都基因与基因组百科全书(Kyoto encyclopedia of gene and genomes,KEGG)分析显示差异基因主要参与氨基糖和核苷酸糖代谢,丙氨酸、天冬氨酸和谷氨酸代谢,胰岛素抵抗3条信号通路。并且筛选到与GFPT2相互作用的10个基因:GFPT1、GLUL、GNPDA1、GNPNAT1、GPI、HK1、MPI、PPAT、AMDHD2、CAD。研究结果可以为GFPT2分子功能的深层次研究提供一定的借鉴作用,对进一步探究由己糖胺代谢导致的代谢异常及心血管疾病治疗具有重要的现实意义。展开更多
Objective Glutamine fructose-6-phosphate transaminase 2(GFPT2)is involved in a wide range of biological functions in human cancer.However,few studies have comprehensively analyzed the correlation between GFPT2 and dif...Objective Glutamine fructose-6-phosphate transaminase 2(GFPT2)is involved in a wide range of biological functions in human cancer.However,few studies have comprehensively analyzed the correlation between GFPT2 and different cancer prognoses and tumor microenvironments(TMEs).Methods We evaluated the expression level and prognostic value of GFPT2 using updated public databases and multiple comprehensive bioinformatics analysis methods and explored the relationship between GFPT2 expression and immune infiltration,immune neoantigens,tumor mutational burden(TMB),and microsatellite instability in pan-cancer.Results GFPT2 was highly expressed in five cancers.GFPT2 expression correlates with the prognosis of several cancers from The Cancer Genome Atlas(TCGA)and is significantly associated with stromal and immune scores in pan-cancer.High GFPT2 expression in BLCA,BRCA,and CHOL was positively correlated with the infiltration of immune cells,such as B-cells,CD4+T,CD8+T cells,dendritic cells,neutrophils,and macrophages.Conclusion High GFPT2 expression may modify the outcomes of patients with BLCA,BRCA,or CHOL cancers by increasing immune cell infiltration.These findings may provide insights for further investigation into GFPT2 as a potential target in pan-cancer.展开更多
The BMP signaling pathway plays a crucial role in regulating early embryonic development and tissue homeostasis.SMAD6 encodes a negative regulator of BMP,and rare variants of SMAD6 are recurrently found in individuals...The BMP signaling pathway plays a crucial role in regulating early embryonic development and tissue homeostasis.SMAD6 encodes a negative regulator of BMP,and rare variants of SMAD6 are recurrently found in individuals with birth defects.However,we observed that a subset of rare pathogenic variants of SMAD6 consistently exhibited positive regulatory effects instead of the initial negative effects on the BMP signaling pathway.We sought to determine whether these SMAD6 variants have common pathogenic mechanisms.Here,we showed that pathogenic SMAD6 variants accompanying this functional reversal exhibit similar increases in deamidation.Mechanistically,increased deamidation of SMAD6 variants promotes the accumulation of the BMP receptor BMPR1A and the formation of new complexes,both of which lead to BMP signaling pathway activation.Specifically,two residues,N262 and N404,in SMAD6 were identified as the crucial sites of deamidation,which was catalyzed primarily by glutamine-fructose-6-phosphate transaminase 2(GFPT2).Additionally,treatment of cells harboring SMAD6 variants with a deamidase inhibitor restored the inhibitory effect of SMAD6 on the BMP signaling pathway.Conversely,when wild-type SMAD6 was manually simulated to mimic the deamidated state,the reversed function of activating BMP signaling was reproduced.Taken together,these findings show that deamidation of SMAD6 plays a crucial role in the functional reversal of BMP signaling activity,which can be induced by a subset of various SMAD6 variants.Our study reveals a common pathogenic mechanism shared by these variants and provides a potential strategy for preventing birth defects through deamidation regulation,which might prevent the off-target effects of gene editing.展开更多
文摘目的研究谷氨酰胺果糖-6-磷酸转氨酶2(glutamine fructose-6-phosphate transaminase 2,GFPT2)对前列腺癌细胞迁移的影响及其潜在的分子机制。方法采用qRT-PCR检测RWPE-1细胞及五种人前列腺癌细胞系中GFPT2基因mRNA的表达水平;分析人类蛋白质图谱(The Human Protein Atlas,HPA)中前列腺正常组织和癌组织的GFPT2免疫组化数据;利用siRNA构建GFPT2基因干扰的细胞模型;利用Transwell实验和细胞划痕实验评估细胞迁移能力;通过Western blot检测细胞上皮-间充质转化(epithelial-mesenchymal transition,EMT)相关生物标志物的变化。结果与RWPE-1细胞相比,高转移潜能的前列腺癌细胞系PC3和DU145中GFPT2 mRNA的表达水平显著升高。HPA数据库GFPT2免疫组化数据表明,前列腺癌组织中GFPT2的蛋白水平明显高于正常前列腺组织。干扰GFPT2明显降低了前列腺癌细胞的O-GlcNAc糖基化水平。体外实验表明,干扰GFPT2显著抑制了前列腺癌细胞的迁移能力,并导致EMT相关蛋白E-cadherin的水平上调,N-cadherin和Vimentin的水平下调。结论GFPT2在前列腺癌中表达升高并促进肿瘤细胞迁移,有望成为抑制前列腺癌转移的新靶点。
文摘GFPT2作为己糖胺代谢重要的转录因子,在动物的多种疾病发生发展中起着重要作用。利用生物信息学方法对GFPT2蛋白的组分、功能、正选择位点及其分子进化进行了详细的分析。结果表明:13条不同物种氨基酸序列组分分析显示亮氨酸占比最高为9.86%,含量最低的氨基酸为色氨酸(0.15%),平均长度为664.8。系统进化树和结构域显示人和猴子的亲缘性最近,其次是大鼠、小鼠,所有氨基酸均包含两个SIS保守结构域。混合效应-演化模型(mixed effects model of evolution,MEME)和固定效应(fixed effects likelihood,REL)方法共发现8个正选择位点。基因本体论(gene ontology,GO)功能富集分析发现GFPT2主要参与GFPT酶活性、蛋白结合、碳水化合物衍生物结合方面发挥作用等生物学过程。京都基因与基因组百科全书(Kyoto encyclopedia of gene and genomes,KEGG)分析显示差异基因主要参与氨基糖和核苷酸糖代谢,丙氨酸、天冬氨酸和谷氨酸代谢,胰岛素抵抗3条信号通路。并且筛选到与GFPT2相互作用的10个基因:GFPT1、GLUL、GNPDA1、GNPNAT1、GPI、HK1、MPI、PPAT、AMDHD2、CAD。研究结果可以为GFPT2分子功能的深层次研究提供一定的借鉴作用,对进一步探究由己糖胺代谢导致的代谢异常及心血管疾病治疗具有重要的现实意义。
基金Supported by a grant from the National Natural Science Foundation of China(No.81700256).
文摘Objective Glutamine fructose-6-phosphate transaminase 2(GFPT2)is involved in a wide range of biological functions in human cancer.However,few studies have comprehensively analyzed the correlation between GFPT2 and different cancer prognoses and tumor microenvironments(TMEs).Methods We evaluated the expression level and prognostic value of GFPT2 using updated public databases and multiple comprehensive bioinformatics analysis methods and explored the relationship between GFPT2 expression and immune infiltration,immune neoantigens,tumor mutational burden(TMB),and microsatellite instability in pan-cancer.Results GFPT2 was highly expressed in five cancers.GFPT2 expression correlates with the prognosis of several cancers from The Cancer Genome Atlas(TCGA)and is significantly associated with stromal and immune scores in pan-cancer.High GFPT2 expression in BLCA,BRCA,and CHOL was positively correlated with the infiltration of immune cells,such as B-cells,CD4+T,CD8+T cells,dendritic cells,neutrophils,and macrophages.Conclusion High GFPT2 expression may modify the outcomes of patients with BLCA,BRCA,or CHOL cancers by increasing immune cell infiltration.These findings may provide insights for further investigation into GFPT2 as a potential target in pan-cancer.
基金supported by the National Key Research and Development Program of China(2021YFC2701101)the National Natural Science Foundation of China(82150008,81930036)+1 种基金Commission for Science and Technology of Shanghai Municipality(20JC1418500)Open Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202202)。
文摘The BMP signaling pathway plays a crucial role in regulating early embryonic development and tissue homeostasis.SMAD6 encodes a negative regulator of BMP,and rare variants of SMAD6 are recurrently found in individuals with birth defects.However,we observed that a subset of rare pathogenic variants of SMAD6 consistently exhibited positive regulatory effects instead of the initial negative effects on the BMP signaling pathway.We sought to determine whether these SMAD6 variants have common pathogenic mechanisms.Here,we showed that pathogenic SMAD6 variants accompanying this functional reversal exhibit similar increases in deamidation.Mechanistically,increased deamidation of SMAD6 variants promotes the accumulation of the BMP receptor BMPR1A and the formation of new complexes,both of which lead to BMP signaling pathway activation.Specifically,two residues,N262 and N404,in SMAD6 were identified as the crucial sites of deamidation,which was catalyzed primarily by glutamine-fructose-6-phosphate transaminase 2(GFPT2).Additionally,treatment of cells harboring SMAD6 variants with a deamidase inhibitor restored the inhibitory effect of SMAD6 on the BMP signaling pathway.Conversely,when wild-type SMAD6 was manually simulated to mimic the deamidated state,the reversed function of activating BMP signaling was reproduced.Taken together,these findings show that deamidation of SMAD6 plays a crucial role in the functional reversal of BMP signaling activity,which can be induced by a subset of various SMAD6 variants.Our study reveals a common pathogenic mechanism shared by these variants and provides a potential strategy for preventing birth defects through deamidation regulation,which might prevent the off-target effects of gene editing.
