Deregulation of c‐Src tyrosine kinase and its downstream targets in pre‐eclamptic placenta

İrtegün, Sevgi; Yildiz, Dilara Akçora; Pektanc, Gulsum; Karabulut, Cagla

doi:10.1111/jog.13350

Cited by 9 publications

(5 citation statements)

References 31 publications

(79 reference statements)

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“…RNA editing site was also localized within 3’UTR of CD99L2 , that is mostly expressed on leukocytes, endothelial cells and plays a role in extravasation of neutrophils under inflammatory conditions [77]. Selection and maturation of T-cells are regulated by both LCK proto-oncogene, Src family tyrosine kinase ( LCK ) and tyrosine kinases ( ZAP70 ), as key signaling molecules essential for lymphokine production [78,79], moreover, LCK affects trophoblast invasion and decidualization [80,81]. Our analysis revealed underexpression of ZAP70 (log2FC = −2.14) and LCK (log2FC = −2.13), what could have an impact on growth-retarded fetus.…”

Section: Discussionmentioning

confidence: 99%

Placenta Transcriptome Profiling in Intrauterine Growth Restriction (IUGR)

Majewska

Lipka

Paukszto

et al. 2019

IJMS

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Intrauterine growth restriction (IUGR) is a serious pathological complication associated with compromised fetal development during pregnancy. The aim of the study was to broaden knowledge about the transcriptomic complexity of the human placenta by identifying genes potentially involved in IUGR pathophysiology. RNA-Seq data were used to profile protein-coding genes, detect alternative splicing events (AS), single nucleotide variant (SNV) calling, and RNA editing sites prediction in IUGR-affected placental transcriptome. The applied methodology enabled detection of 37,501 transcriptionally active regions and the selection of 28 differentially-expressed genes (DEGs), among them 10 were upregulated and 18 downregulated in IUGR-affected placentas. Functional enrichment annotation indicated that most of the DEGs were implicated in the processes of inflammation and immune disorders related to IUGR and preeclampsia. Additionally, we revealed that some genes (S100A13, GPR126, CTRP1, and TFPI) involved in the alternation of splicing events were mainly implicated in angiogenic-related processes. Significant SNVs were overlapped with 6533 transcripts and assigned to 2386 coding sequence (CDS), 1528 introns, 345 5’ untranslated region (UTR), 1260 3’UTR, 918 non-coding RNA (ncRNA), and 10 intergenic regions. Within CDS regions, 543 missense substitutions with functional effects were recognized. Two known mutations (rs4575, synonymous; rs3817, on the downstream region) were detected within the range of AS and DEG candidates: PA28β and PINLYP, respectively. Novel genes that are dysregulated in IUGR were detected in the current research. Investigating genes underlying the IUGR is crucial for identification of mechanisms regulating placental development during a complicated pregnancy.

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Section: Discussionmentioning

confidence: 99%

Placenta Transcriptome Profiling in Intrauterine Growth Restriction (IUGR)

Majewska

Lipka

Paukszto

et al. 2019

IJMS

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“…Interestingly, several reports have shown that c-myc expression was dysregulated in preeclamptic placentas versus normal third-trimester placentas [41,42]. NF-kB protein expression and NF-kB phosphorylation in placentas were decreased significantly in patients with preeclampsia compared with controls [43,44]. These findings suggest that the downregulation of myc and NF-kB might cause the increase in the expression of miR-29a in the placentas of patients with preeclampsia.…”

Section: Discussionmentioning

confidence: 89%

Upregulation of miR-29a suppressed the migration and invasion of trophoblasts by directly targeting LOXL2 in preeclampsia

Xu¹,

Tang²,

Fan³

et al. 2021

Journal of Hypertension

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Objective: Preeclampsia is a pregnancy-specific disorder that is a major cause of maternal and foetal morbidity and mortality, with a prevalence of 6-8% of pregnancies. Although the downregulation of lysyl oxidase (LOX) and LOX-like protein 2 (LOXL2), which leads to reduced trophoblast cell migration and invasion through activation of the TGF-b1/Smad3/collagen pathway, is relevant to preeclampsia, the mechanisms regulating differences in the gene expression of LOX and LOXL2 in placentas are not yet understood. This study aimed to investigate the mechanisms regulating differences in the gene expression of LOX and LOXL2 in placentas. Methods:The expression of miRNAs, LOX and LOXL2 in preeclamptic placentas and control placentas was analysed by qPCR. Localisation of miR29a and LOXL2 in preeclamptic placentas was performed by RNA-Fluorescence in-situ hybridization assay. The direct regulation of LOXL2 by miR-29a was assessed by dualluciferase reporter assays in human extravillous trophoblast cells (HTR8/SVneo). Cell migration and invasion were evaluated by Transwell assays in HTR8/SVneo cells.Results: miR-29a expression was upregulated in preeclamptic placentas and negatively correlated with LOXL2 mRNA expression levels. RNA-Fluorescence in-situ hybridization assay revealed a clear overlap between miR-29a and LOXL2 in the placentas of preeclampic women. LOXL2 was a direct target gene of miR-29a, as confirmed by a dual-luciferase reporter assay in HTR8/SVneo trophoblast cells. miR-29a suppressed HTR8/SVneo trophoblast cell migration and invasion. LOXL2 overexpression reversed the inhibitory effects of miR-29a on HTR8/SVneo trophoblast cell migration and invasion. Conclusion:Our results suggest that the upregulation of miR-29a suppresses the migration and invasion of HTR8/ SVneo trophoblast cells by directly targeting LOXL2 in preeclampsia.

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“…c-Src is a tyrosine kinase protein that regulates many intracellular processes such as cell growth, differentiation, and proliferation phosphorylating intracellular proteins. c-Src is expressed in most the human cells, and a dysfunction [1][2][3] in its activation is related to the onset of neoplastic progression [4][5][6][7][8][9]. Such a protein is formed by a myristoylated SH4 domain that anchors the kinase on the membrane surface, the Unique domain, the structural SH3 and SH2 domains and the kinase domain (KD), which contains the active site [10][11][12] (see Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…The dephosphorylation of Tyr 527 triggers a conformational rearrangement leading to the open/active form, where the interaction between the C-terminal tail and the SH2 domain vanished. The successive autophosphorylation of Tyr 416 further stabilizes the active form [2,17]. Therefore, the conformational equilibrium between the active and inactive states is tightly regulated by different molecular interactions that are dependent on different input signals (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Modelling the Activation Pathways in Full-Length Src Kinase

2021

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Src kinases play fundamental roles in several crucial cell processes. Their activity is tightly regulated by conformational transitions between the active and the inactive forms, which are carried out by complex protein structural rearrangements. Here, we present an in-depth study of such structural transitions coupling extensive all-atoms molecular dynamic simulations coupled to an algorithm able to drive the system between defined conformational states. Our results, in line with the available experimental data, confirm the complexity of such a process indicating the main molecular determinants involved. Moreover, the role of an Src inhibitor—able to bind to the protein inactive state—is discussed and compared with available experimental data.

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Deregulation of c‐Src tyrosine kinase and its downstream targets in pre‐eclamptic placenta

Abstract: The c-Src/MAPK/NF-ĸB signaling pathway may contribute to the pathogenesis of pre-eclampsia.

Cited by 9 publications

References 31 publications

Placenta Transcriptome Profiling in Intrauterine Growth Restriction (IUGR)

Placenta Transcriptome Profiling in Intrauterine Growth Restriction (IUGR)

Upregulation of miR-29a suppressed the migration and invasion of trophoblasts by directly targeting LOXL2 in preeclampsia

Modelling the Activation Pathways in Full-Length Src Kinase

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