1.SRSF2 mutation in patients with chronic myelomonocytic leukemia.
Xiang-chou YANG ; Su-jiang ZHANG ; Chun QIAO ; Rui GUO ; Hong-xia QIU ; Jian-Yong LI
Chinese Journal of Hematology 2013;34(12):1024-1027
OBJECTIVETo investigate SRSF2 mutations in patients with chronic myelomonocytic leukemia (CMML) and the clinical characteristics of patients with SRSF2 mutants.
METHODSIn this study, the frequency of SRSF2 mutation in a cohort of 20 patients with CMML was detected by polymerase chain reaction (PCR) followed by direct sequencing to couple with their clinical features.
RESULTSOf 20 patients, 4 patients were found harboring SRSF2 mutations, including 2 P95L, 1 P95H and 1 P95R point mutations. There were no significantly statistical differences in terms of their clinical characteristics between mutant and wild type group.
CONCLUSIONSRSF2 mutation was not frequently occurred in CMML patients and might associated with poor prognosis. It might be a practically diagnostic maker and therapeutic target in CMML.
Adult ; Aged ; DNA Mutational Analysis ; Female ; Genotype ; Humans ; Leukemia, Myelomonocytic, Chronic ; genetics ; Male ; Middle Aged ; Mutation ; Nuclear Proteins ; genetics ; Prognosis ; Ribonucleoproteins ; genetics ; Serine-Arginine Splicing Factors
2.lncR-GAS5 upregulates the splicing factor SRSF10 to impair endothelial autophagy, leading to atherogenesis.
Yuhua FAN ; Yue ZHANG ; Hongrui ZHAO ; Wenfeng LIU ; Wanqing XU ; Lintong JIANG ; Ranchen XU ; Yue ZHENG ; Xueqing TANG ; Xiaohan LI ; Limin ZHAO ; Xin LIU ; Yang HONG ; Yuan LIN ; Hui CHEN ; Yong ZHANG
Frontiers of Medicine 2023;17(2):317-329
Long noncoding RNAs (lncRNAs) play a critical role in the regulation of atherosclerosis. Here, we investigated the role of the lncRNA growth arrest-specific 5 (lncR-GAS5) in atherogenesis. We found that the enforced expression of lncR-GAS5 contributed to the development of atherosclerosis, which presented as increased plaque size and reduced collagen content. Moreover, impaired autophagy was observed, as shown by a decreased LC3II/LC3I protein ratio and an elevated P62 level in lncR-GAS5-overexpressing human aortic endothelial cells. By contrast, lncR-GAS5 knockdown promoted autophagy. Moreover, serine/arginine-rich splicing factor 10 (SRSF10) knockdown increased the LC3II/LC3I ratio and decreased the P62 level, thus enhancing the formation of autophagic vacuoles, autolysosomes, and autophagosomes. Mechanistically, lncR-GAS5 regulated the downstream splicing factor SRSF10 to impair autophagy in the endothelium, which was reversed by the knockdown of SRSF10. Further results revealed that overexpression of the lncR-GAS5-targeted gene miR-193-5p promoted autophagy and autophagic vacuole accumulation by repressing its direct target gene, SRSF10. Notably, miR-193-5p overexpression decreased plaque size and increased collagen content. Altogether, these findings demonstrate that lncR-GAS5 partially contributes to atherogenesis and plaque instability by impairing endothelial autophagy. In conclusion, lncR-GAS5 overexpression arrested endothelial autophagy through the miR-193-5p/SRSF10 signaling pathway. Thus, miR-193-5p/SRSF10 may serve as a novel treatment target for atherosclerosis.
Humans
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Atherosclerosis/genetics*
;
Autophagy/genetics*
;
Cell Cycle Proteins/metabolism*
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Endothelial Cells/metabolism*
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Endothelium/metabolism*
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MicroRNAs/metabolism*
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Repressor Proteins/metabolism*
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RNA Splicing Factors
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Serine-Arginine Splicing Factors/genetics*
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RNA, Long Noncoding/metabolism*
3.Research progress on genes associated with transformation of myelodysplastic syndromes to acute myeloid leukemia.
Chen ZHU ; Yan MA ; Xiao-Ping XU
Journal of Experimental Hematology 2014;22(3):873-878
Myelodysplastic syndrome (MDS) is highly heterogeneous clonal hematological malignancy, having a high rate of progression to acute myeloid leukemia (AML). With the rapid development of molecular biological techniques, plenty of gene mutations were found to have close relationships with the transformation from MDS to AML. SRSF2 is a RNA splicing-related gene, which mutation may prompt a poor prognosis, and have a higher rate of progressing to AML. DNMT3A plays an important role in DNA methylation, its mutation often indicate a worse overall survival and a more rapid progression to AML. ASXL1 regulates the synthesis of histone, which frameshift mutations are molecular marks of an adverse outcome. IDH contains IDH1 and IDH2, which are related with the Krebs cycle. Patients with IDH1 mutation have a shorter overall survival and a higher risk of AML transformation than that of patients with wild-type IDH1, while IDH2 was a poor prognostic factor for overall survival in patients with lower-risk MDS. Another gene related with DNA methylation is TET2, which is the most frequently mutated gene in MDS known so far and it may act as tumor-suppressor gene, but the opinions on its impact on patients' outcomes are still controversial. Some studies show that its mutations relate to a shorter time to progression to AML. Because of the differentiations in patients' races, regions and clinical characteristics, the results of different studies are varied. In this review, the recent advances on these related genes are summarized.
DNA (Cytosine-5-)-Methyltransferases
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genetics
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DNA-Binding Proteins
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genetics
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Genotype
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Humans
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Isocitrate Dehydrogenase
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genetics
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Leukemia, Myeloid, Acute
;
genetics
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pathology
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Myelodysplastic Syndromes
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genetics
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pathology
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Nuclear Proteins
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genetics
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Oncogenes
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Proto-Oncogene Proteins
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genetics
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Repressor Proteins
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genetics
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Ribonucleoproteins
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genetics
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Serine-Arginine Splicing Factors
4.Antisense transcription regulates the expression of sense gene via alternative polyadenylation.
Ting SHEN ; Huan LI ; Yifan SONG ; Jun YAO ; Miao HAN ; Ming YU ; Gang WEI ; Ting NI
Protein & Cell 2018;9(6):540-552
Natural antisense transcripts (NAT) and alternative polyadenylation (APA) of messenger RNA (mRNA) are important contributors of transcriptome complexity, each playing a critical role in multiple biological processes. However, whether they have crosstalk and function collaboratively is unclear. We discovered that APA enriched in human sense-antisense (S-AS) gene pairs, and finally focused on RNASEH2C-KAT5 S-AS pair for further study. In cis but not in trans over-expression of the antisense KAT5 gene promoted the usage of distal polyA (pA) site in sense gene RNASEH2C, which generated longer 3' untranslated region (3'UTR) and produced less protein, accompanying with slowed cell growth. Mechanistically, elevated Pol II occupancy coupled with SRSF3 could explain the higher usage of distal pA site. Finally, NAT-mediated downregulation of sense gene's protein level in RNASEH2C-KAT5 pair was specific for human rather than mouse, which lacks the distal pA site of RNASEH2C. We provided the first evidence to support that certain gene affected phenotype may not by the protein of its own, but by affecting the expression of its overlapped gene through APA, implying an unexpected view for understanding the link between genotype and phenotype.
Cell Proliferation
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genetics
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Evolution, Molecular
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Gene Expression Regulation
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genetics
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HEK293 Cells
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Humans
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Polyadenylation
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genetics
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RNA, Antisense
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genetics
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RNA, Messenger
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genetics
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Ribonuclease H
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genetics
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Serine-Arginine Splicing Factors
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metabolism
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Transcription, Genetic
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Up-Regulation
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genetics
5.Construction and analysis of transcriptome-based hepatolenticular degeneration regulatory network.
Xiaoxi YANG ; Song HE ; Xiaojin LI ; Donghu ZHOU ; Xiaochen BO ; Jian HUANG
Chinese Journal of Biotechnology 2022;38(10):3844-3858
A transcriptional regulatory network for wild-type and ATP7B-knockout HepG2 cells exposed to copper was constructed by bioinformatics methods to explore the potential mechanism of key transcription factors in the pathogenesis of hepatolenticular degeneration. The differentially expressed genes (DEGs) for wild-type and ATP7B-knockout HepG2 cell lines without copper and exposed to copper were collected from the gene expression omnibus (GEO) database. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis were performed for DEGs induced by copper. The key functional modules and genes were identified based on the protein-protein interaction (PPI) network. Moreover, the enrichment analysis of genes in functional modules was performed. Finally, a transcriptional regulatory network was constructed to screen the core transcription factors. A total of 1 034 genes, including 509 down-regulated genes and 525 up-regulated genes, were selected as DEGs. The up-regulated and down-regulated functional modules based on PPI network included 3 785 and 3 931 genes, respectively. Genes in key functional modules were enriched in cell-substrate junction, chromosomal region, spliceosomal complex and ribosome. They were involved in mRNA processing, histone modification, RNA splicing, regulation of DNA metabolic process, protein phosphorylation and other biological processes. Moreover, they were correlated to transcriptional coregulator activity, DNA-binding transcription factor binding, ubiquitin-like protein ligase binding and other molecular functions. KEGG analysis showed that genes in key functional modules were significantly enriched in hepatitis B, MAPK signaling pathway, cellular senescence and apoptosis, neurotrophin signaling pathway and pathways of neurodegeneration-multiple diseases. The transcriptional regulatory network contained 11 differentially expressed transcription factors and 96 DEGs. Among them, U2AF1, NFRKB, FUS, MAX, SRSF1, CEBPA and RXRA were the core transcription factors, which may facilitate the study of the biological function of relevant molecules in transcriptional regulation of hepatolenticular degeneration.
Humans
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Transcriptome
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Gene Expression Profiling/methods*
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Hepatolenticular Degeneration/genetics*
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Copper
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Gene Regulatory Networks
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Computational Biology/methods*
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Transcription Factors/genetics*
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DNA
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DNA-Binding Proteins/genetics*
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Serine-Arginine Splicing Factors/genetics*
6.Expression of neural salient serine-/arginine-rich protein 1 (NSSR1) in colorectal cancer.
Wei ZHANG ; Quan SHEN ; Jia-xi SHEN
Journal of Zhejiang University. Medical sciences 2011;40(5):540-544
OBJECTIVETo investigate the expression of neural salient serine/arginine-rich protein 1 (NSSR1) in colorectal cancer.
METHODSRT-PCR, Western blot and immunohistochemical staining were used to detect the expression of NSSR1 mRNA and protein in different mouse tissues and human colorectal cancer, respectively.
RESULTSNSSR1 mRNA was expressed in mouse cerebrum, cerebellum, heart, liver, intestine, kidney and lung tissue, but NSSR1 protein was only expressed in neural tissues. In normal human intestinal mucosa, NSSR1 was expressed in the colorectal epithelial cells. In colorectal cancer, NSSR1 was highly expressed in the nucleus of tumor cells.
CONCLUSIONThe extensive expression of NSSR1 in colorectal cancer cells may hint it's roles in the biological function of colorectal cancer.
Animals ; Cell Cycle Proteins ; genetics ; metabolism ; Colon ; metabolism ; Colorectal Neoplasms ; metabolism ; Humans ; Mice ; Neoplasm Proteins ; genetics ; metabolism ; RNA, Messenger ; genetics ; RNA-Binding Proteins ; genetics ; metabolism ; Rectum ; metabolism ; Repressor Proteins ; genetics ; metabolism ; Serine-Arginine Splicing Factors
7.Clinical manifestation of the SRSF2 gene mutation in Chinese patients with chronic myelomonocytic leukemia.
Chao SUN ; Sujiang ZHANG ; Chun QIAO ; Xiangchou YANG ; Jianyong LI
Chinese Medical Journal 2014;127(24):4215-4219
BACKGROUNDSpliceosome mutations have been recently identified and associated with hematological malignancies. SRSF2, one of components of the splicing machinery, has a high mutation frequency during chronic myelomonocytic leukemia, according to previous reports. However, the relevance of this finding in Chinese populations remains unknown.
METHODSWe recruited 50 Chinese patients with chronic myelomonocytic leukemia to analyze the state of SRSF2 and to assess the corresponding clinical features by polymerase chain reaction followed by direct sequencing.
RESULTSTen of 50 patients (20%) harbored SRSF2 mutations, including five P95R, two 95H, and three P95L point mutations. The patient group was older than the wild type group (P < 0.01). No significant statistical differences were observed with regard to the other clinical characteristics (sex, peripheral blood count, serum lactate dehydrogenase, karyotype, World Health Organization classification, etc.) between these two groups. Two of the patients showed an early evolution to acute myeloid leukemia.
CONCLUSIONSSRSF2 mutations are frequent in chronic myelomonocytic leukemia patients, but show a relatively lower incidence in Chinese patients. Moreover, the mutation can be related to old age and an unfavorable prognosis. Our results provide valuable insights for the development of a diagnostic marker, or for the identification of a therapeutic target for chronic myelomonocytic leukemia.
Adult ; Aged ; Aged, 80 and over ; DNA Mutational Analysis ; Female ; Genetic Predisposition to Disease ; genetics ; Humans ; Leukemia, Myelomonocytic, Chronic ; genetics ; Male ; Middle Aged ; Mutation ; Nuclear Proteins ; genetics ; Ribonucleoproteins ; genetics ; Serine-Arginine Splicing Factors
8.Construction of predictive ceRNA network and identification of the patterns of immune cells infiltrated in Graves ' ophthalmopathy.
Jiamin CAO ; Haiyan CHEN ; Bingyu XIE ; Yizhi CHEN ; Wei XIONG ; Mingyuan LI
Journal of Central South University(Medical Sciences) 2023;48(8):1185-1196
OBJECTIVES:
Graves' ophthalmopathy (GO) is a multifactorial disease, and the mechanism of non coding RNA interactions and inflammatory cell infiltration patterns are not fully understood. This study aims to construct a competing endogenous RNA (ceRNA) network for this disease and clarify the infiltration patterns of inflammatory cells in orbital tissue to further explore the pathogenesis of GO.
METHODS:
The differentially expressed genes were identified using the GEO2R analysis tool. The Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology analysis were used to analyze differential genes. RNA interaction relationships were extracted from the RNA interactome database. Protein-protein interactions were identified using the STRING database and were visualized using Cytoscape. StarBase, miRcode, and DIANA-LncBase Experimental v.2 were used to construct ceRNA networks together with their interacted non-coding RNA. The CIBERSORT algorithm was used to detect the patterns of infiltrating immune cells in GO using R software.
RESULTS:
A total of 114 differentially expressed genes for GO and 121 pathways were detected using both the KEGG and gene ontology enrichment analysis. Four hub genes (SRSF6, DDX5, HNRNPC,and HNRNPM) were extracted from protein-protein interaction using cytoHubba in Cytoscape, 104 nodes and 142 edges were extracted, and a ceRNA network was identified (MALAT1-MIR21-DDX5). The results of immune cell analysis showed that in GO, the proportions of CD8+ T cells and CD4+ memory resting T cells were upregulated and downregulated, respectively. The proportion of CD4 memory resting T cells was positively correlated with the expression of MALAT1, MIR21, and DDX5.
CONCLUSIONS
This study has constructed a ceRNA regulatory network (MALAT1-MIR21-DDX5) in GO orbital tissue, clarifying the downregulation of the proportion of CD4+ stationary memory T cells and their positive regulatory relationship with ceRNA components, further revealing the pathogenesis of GO.
Humans
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CD8-Positive T-Lymphocytes
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RNA, Long Noncoding/genetics*
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Algorithms
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CD4-Positive T-Lymphocytes
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Down-Regulation
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Graves Ophthalmopathy/genetics*
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Gene Regulatory Networks
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MicroRNAs/genetics*
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Serine-Arginine Splicing Factors
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Phosphoproteins
9.The class A macrophage scavenger receptor type I (SR-AI) recognizes complement iC3b and mediates NF-κB activation.
Jason W K GOH ; Yen Seah TAN ; Alister W DODDS ; Kenneth B M REID ; Jinhua LU
Protein & Cell 2010;1(2):174-187
The macrophage scavenger receptor SR-AI binds to host tissue debris to perform clearance and it binds to bacteria for phagocytosis. In addition, SR-AI modulates macrophage activation through cell signaling. However, investigation of SR-AI signaling on macrophages is complicated due to its promiscuous ligand specificity that overlaps with other macrophage receptors. Therefore, we expressed SR-AI on HEK 293T cells to investigate its ligand binding and signaling. On 293Tcells, SR-AI could respond to E. coli DH5α, leading to NF-κB activation and IL-8 production. However, this requires E. coli DH5α to be sensitized by fresh serum that is treated with heat-inactivation or complement C3 depletion. Anti-C3 antibody inhibits the binding of SR-AI to serum-sensitized DH5α and blocks DH5α stimulation of SR-AI signaling. Further analysis showed that SR-AI can directly bind to purified iC3b but not C3 or C3b. By mutagenesis, The SRCR domain of SR-AI was found to be essential in SR-AI binding to serum-sensitized DH5α. These results revealed a novel property of SR-AI as a complement receptor for iC3b-opsonized bacteria that can elicit cell signaling.
Amino Acid Sequence
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Carrier Proteins
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genetics
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metabolism
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Complement C3b
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metabolism
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Escherichia coli
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immunology
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HEK293 Cells
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Humans
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Macrophage Activation
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Molecular Sequence Data
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Mutagenesis
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NF-kappa B
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genetics
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metabolism
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Phagocytosis
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Serine-Arginine Splicing Factors
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Signal Transduction
10.Isolation and expression profiling of transformer 2 gene in Aedes aegypti.
Peiwen LIU ; Yuting CHEN ; Jinbao GU ; Xiaoguang CHEN
Journal of Southern Medical University 2013;33(11):1583-1589
OBJECTIVETo isolate, identify and analyze the sex-determining gene Transformer 2 (Aaetra2) of the major vector mosquito Aedes aegypti.
METHODStBLASTn program, RT-PCR and RACE methods were used to obtain the full-length cDNA of Aaetra2. Multiple alignments of nucleotide and amino acid sequences were conducted, and the different domains in tra2 protein were indentified. RT-PCR of the total RNA extracted from different tissue from the mosquitoes in different developmental stages was performed using specific primers.
RESULTSTwo genes, namely Aaetra2-α and Aaetra2-β, were identified in different supercontig locations. The multi-transcripts were expressed by means of alternative promoters or terminators. The different domains in tra2 protein were defined as RS-rich N-terminal region, RNA recognition motif-RRM, linker region, and RS-rich C-terminal region. Both Aaetra2-α and Aaetra2-β showed sustained expression throughout the developmental stages of Ae.aegypti, and in all the tissues without a sex specificity.
CONCLUSIONAaetra2 gene has multiple isoforms and is mapped to multiple locations in the genome. Aaetra2 has conservative functional domains of the sex-determining gene tra2. For Ae.agypti, Aaetra2 shows the potential as a new target for release of insects carrying a dominant lethal (RIDL) technology based on transgenic mosquitoes.
Aedes ; genetics ; growth & development ; Amino Acid Sequence ; Animals ; Drosophila Proteins ; genetics ; Gene Expression Regulation, Developmental ; Genes, Insect ; Insect Proteins ; genetics ; isolation & purification ; Nerve Tissue Proteins ; genetics ; Phylogeny ; RNA-Binding Proteins ; genetics ; Ribonucleoproteins ; genetics ; Sequence Alignment ; Serine-Arginine Splicing Factors ; Sex Differentiation ; genetics