LRRFIP1 expression triggers platelet agglutination by enhancing αIIbβ3 expression

Yin, Xingtian; Liu, Peng; Liu, Yao‐Yao; Liu, Ming‐Yong; Fan, Weili; Liu, Baiyi; Zhao, Jianhua

doi:10.3892/etm.2019.7571

Cited by 3 publications

(5 citation statements)

References 32 publications

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“…Their dysregulation or inhibition can wreak havoc, influencing a plethora of crucial pathways and mechanisms. These include DNA damage triggered by hypertranscription or via ATM-P53 axis, arrest in G1 and S-phase of the cell cycle, HR and NHEJ defects due to the suppression of BRCA1-RAD51 and HDAC1 activation, instigating T-cell acute lymphoblastic leukemia by modifying the NOTCH1, PTEN-PI3K-AKT, and MYC pathways, curtailing platelet function by impacting cyclic nucleotide pathways, undermining hemostasis by inhibiting platelet clumping through the reduction in αIIbβ3 expression, obstructing DNA replication due to changes in the RBBP6/ZBTB38/MCM10 axis, and imbalancing the proliferation-to-apoptosis ratio of lymphocytes, among others [9,[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29].…”

Section: Discussionmentioning

confidence: 99%

“…Besides genomic stability, genes crucial for the homeostasis and function of platelets, hematopoietic cells, and leukocytes were also identified. Notable among these are ARHGAP 17 [22], LEF1 [23], LRRFIP1 [24,25], METAP1 [26], PNRC1 [27], PTMA [28], and THBS1 [29]. These cells, each with a distinctive role, collectively maintain the body's hemostatic homeostasis.…”

Section: Genes Engaged In Fusion Events Predominantly Govern Genomic ...mentioning

confidence: 99%

“…The N-terminal segment (1-32 aa) of the fusion gene is derived from the LRRFIP1 gene, encoding the namesake protein, LRRFIP1. This protein plays a crucial role in the inflammatory stress response and mediates platelet activity [24,25,52]. Conversely, the PTMA gene, which encodes Prothymosin-A and comprises a significant portion of the fusion gene (33-128 aa), is also implicated in the inflammatory stress response.…”

Section: Chimeric Protein Proteotoxicity As a Potential Driver Of Bmf...mentioning

confidence: 99%

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Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita

Güllülü,

Mayer,

Toplek

2024

IJMS

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Dyskeratosis Congenita (DC) is a multisystem disorder intrinsically associated with telomere dysfunction, leading to bone marrow failure (BMF). Although the pathology of DC is largely driven by mutations in telomere-associated genes, the implications of gene fusions, which emerge due to telomere-induced genomic instability, remain unexplored. We meticulously analyzed gene fusions in RNA-Seq data from DC patients to provide deeper insights into DC’s progression. The most significant DC-specific gene fusions were subsequently put through in silico assessments to ascertain biophysical and structural attributes, including charge patterning, inherent disorder, and propensity for self-association. Selected candidates were then analyzed using deep learning-powered structural predictions and molecular dynamics simulations to gauge their potential for forming higher-order oligomers. Our exploration revealed that genes participating in fusion events play crucial roles in upholding genomic stability, facilitating hematopoiesis, and suppressing tumors. Notably, our analysis spotlighted a particularly disordered polyampholyte fusion protein that exhibits robust higher-order oligomerization dynamics. To conclude, this research underscores the potential significance of several high-confidence gene fusions in the progression of BMF in DC, particularly through the dysregulation of genomic stability, hematopoiesis, and tumor suppression. Additionally, we propose that these fusion proteins might hold a detrimental role, specifically in inducing proteotoxicity-driven hematopoietic disruptions.

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Section: Discussionmentioning

confidence: 99%

Section: Genes Engaged In Fusion Events Predominantly Govern Genomic ...mentioning

confidence: 99%

Section: Chimeric Protein Proteotoxicity As a Potential Driver Of Bmf...mentioning

confidence: 99%

See 1 more Smart Citation

Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita

Güllülü,

Mayer,

Toplek

2024

IJMS

View full text Add to dashboard Cite

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“…LRRFIP1 serves a key role in regulating the platelet cytoskeleton and then affects the activation process and function of platelets. A previous study showed that LRRFIP1 triggers platelet aggregation by enhancing the expression of α IIb β 3 ( 51 ). Silencing the LRRFIP1 gene can lead to a significant reduction in thrombosis ( 52 ).…”

Section: Discussionmentioning

confidence: 99%

Proteomics changes after negative pressure wound therapy in diabetic foot ulcers

et al. 2021

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Label-free quantitative mass spectrometry was used to analyze the differences in the granulation tissue protein expression profiles of patients with diabetic foot ulcers (DFUs) before and after negative-pressure wound therapy (NPWT) to understand how NPWT promotes the healing of diabetic foot wounds. A total of three patients with DFUs hospitalized for Wagner grade 3 were enrolled. The patients received NPWT for one week. The granulation tissue samples of the patients prior to and following NPWT for one week were collected. The protein expression profiles were analyzed with label-free quantitative mass spectrometry and the differentially expressed proteins (DEPs) in the DFU patients prior to and following NPWT for one week were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to annotate the DEPs and DEP-associated signaling pathways. Western blotting and ELISA were performed to validate the results. By comparing the differences in the protein profiles of granulation tissue samples prior to and following NPWT for one week, 36 proteins with significant differences were identified (P<0.05); 33 of these proteins were upregulated and three proteins were downregulated. NPWT altered proteins mainly associated with antioxidation and detoxification, the cytoskeleton, regulation of the inflammatory response, complement and coagulation cascades and lipid metabolism. The functional validation of the DEPs demonstrated that the levels of cathepsin S in peripheral blood and granulation tissue were significantly lower than those prior to NPWT (P<0.05), while the levels of protein S isoform 1, inter α-trypsin inhibitor heavy chain H4 and peroxiredoxin-2 in peripheral blood and granulation tissue were significantly higher than those prior to NPWT (P<0.05). The present study identified multiple novel proteins altered by NPWT and laid a foundation for further studies investigating the mechanism of action of NPWT.

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“…NF-κB has shown to be involved in the regulation of endothelial function through multiple pathways [13,14]. The leucine-rich repeat flightless-interacting protein 1 (LRRFIP1) gene has previously been found to be involved in a variety of pathological processes, such as thrombosis, inflammation, wound healing, and obesity [15,16]. In addition, LRRFIP1 (also known as TRIP) has been shown to inhibit TNF receptor-associated factor 2 (TRAF2)-mediated NF-κB activation through interaction with the TRAF family [17,18].…”

Section: Introductionmentioning

confidence: 99%

Nuclear Factor Kappa-B/Homeobox A9-Mediated Modulation of Leucine-Rich Repeat Flightless-Interacting Protein 1 Is Involved in Advanced Glycation End Product-Induced Endothelial Dysfunction

Zhu

et al. 2021

J Vasc Res

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Background: Pathogenesis of cardiovascular diseases begins with endothelial dysfunction. Our previous study has shown that advanced glycation end products (AGE) could inhibit the expression of homeobox A9 (Hoxa9), thereby inducing endothelial dysfunction. Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1) has been found to participate in a variety of pathological processes, but reports of its role in endothelial dysfunction are rare. Objectives: This study aims to investigate whether LRRFIP1 is involved in AGE-induced endothelial dysfunction through Hoxa9-mediated transcriptional activation. Methods: Chromatin immunoprecipitation was used to detect the transcriptional regulation of Hoxa9 on LRRFIP1 promoters. Human umbilical vein endothelial cells were treated with AGE or pyrrolidinedithiocarbamate (nuclear factor kappa-B [NF-κB] inhibitor). Moreover, changes in apoptosis, proliferation, migration, release of nitric oxide, and angiogenesis were detected. Results: Hoxa9 promotes LRRFIP1 expression by binding to the LRRFIP1 promoter. Meanwhile, overexpression of LRRFIP1 inhibited phosphorylation of P65 and elevated expression of Hoxa9. Overexpression of LRRFIP1 or/and Hoxa9 reversed the effects of AGE on HUVEC. AGE-induced inhibition on the expression of LRRFIP1 and Hoxa9 could be reversed by the NF-κB inhibitor. Conclusion: LRRFIP1 is involved in AGE-induced endothelial dysfunction via being regulated by the NF-κB/Hoxa9 axis.

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LRRFIP1 expression triggers platelet agglutination by enhancing αIIbβ3 expression

Cited by 3 publications

References 32 publications

Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita

Linking Gene Fusions to Bone Marrow Failure and Malignant Transformation in Dyskeratosis Congenita

Proteomics changes after negative pressure wound therapy in diabetic foot ulcers

Nuclear Factor Kappa-B/Homeobox A9-Mediated Modulation of Leucine-Rich Repeat Flightless-Interacting Protein 1 Is Involved in Advanced Glycation End Product-Induced Endothelial Dysfunction

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