Overlapping but distinct roles for NOTCH receptors in human cardiovascular disease

Meester, Josephina; Verstraeten, Aline; Alaerts, Maaike; Schepers, Dorien; Laer, Lut Van; Loeys, Bart

doi:10.1111/cge.13382

Cited by 46 publications

(35 citation statements)

References 111 publications

(219 reference statements)

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“…In one study, the majority of the intracellular mutations were activating mutations [44]. However, the majority of mutations in the extracellular domain of NOTCH have been associated with a wide range of congenital disorders [26].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in the same studies, the authors demonstrated that the most common mutation in the intracellular domain was an activating mutation. However, the majority of mutations in the extracellular domain in NOTCH have been associated with a wide range of congenital disorders, such as bicuspid aortic valve, Alagille syndrome (a multisystemic disorder with cardiac, liver, ocular, and skeletal abnormalities), and cerebral arteriopathy [26].…”

Section: Plos Onementioning

confidence: 99%

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Association between tumor mutation profile and clinical outcomes among Hispanic Latina women with triple-negative breast cancer

et al. 2020

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Triple-negative breast cancer (TNBC) represents 15%-20% of all breast cancer types. It is more common among African American (AA) and Hispanic-Latina (HL) women. The biology of TNBC in HL women has been poorly characterized, but some data suggest that the molecular drivers of breast cancer might differ. There are no clinical tools to aid medical oncologists with decisions regarding appropriate individualized therapy, and no way to predict long-term outcomes. The aim of this study was to characterize individual patient gene mutation profiles and to identify the relationship with clinical outcomes. We collected formalin-fixed paraffin-embedded tumors (FFPE) from women with TNBC. We analyzed the gene mutation profiles of the collected tumors and compared the results with individual patient's clinical histories and outcomes. Of 25 patients with TNBC, 24 (96%) identified as HL. Twenty-one (84%) had stage III-IV disease. The most commonly mutated genes were TP53, NOTCH1, NOTCH2, NOTCH3, AKT, MEP3K, PIK3CA, and EGFR. Compared with other international cancer databases, our study demonstrated statistically significant higher frequencies of these genes among HL women. Additionally, a worse clinical course was observed among patients whose tumors had mutations in NOTCH genes and PIK3CA. This study is the first to identify the most common genetic alterations among HL women with TNBC. Our data strongly support the notion that molecular drivers of breast cancer could differ in HL women compared with other ethnic backgrounds. Therefore, a deeper understanding of the biological mechanisms behind NOTCH gene and PIK3CA mutations may lead to a new treatment approach.

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Section: Discussionmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Association between tumor mutation profile and clinical outcomes among Hispanic Latina women with triple-negative breast cancer

et al. 2020

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“…Online databases was applied to predict the target gene of miR-342-5p ( Fig. 4A-B) and it has been reported that the APLN, ZBTB39, PIK3R1, MEF2D and NOTCH2 genes may be associated with cardiovascular disease (8,(20)(21)(22)(23), therefore infer that APLN, ZBTB39, PIK3R1, MEF2D and NOTCH2 may were potential target genes of miR-342-5p. The role of miR-342-5p in the aforementioned target genes was examined using RT-qPCR.…”

Section: Mir-342-5p Promotes Cell Viability Migration and Invasionmentioning

confidence: 99%

MicroRNA‑342‑5p activates the Akt signaling pathway by downregulating PIK3R1 to modify the proliferation and differentiation of vascular smooth muscle cells

Peng

Liu

et al. 2020

Exp Ther Med

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Abnormal cell proliferation and invasion of vascular smooth muscle cells are among the primary causes of cardiovascular disease. Studies have shown that microRNA(miR)-342-5p participates in the development of cardiovascular diseases. The current study aimed to explore the role of miR-342-5p in the proliferation and differentiation of mouse aortic vascular smooth muscle (MOVAS) cells. MOVAS cells were transfected with miR-342-5p mimics, miR-342-5p inhibitor or their respective negative controls, and co-transfected with small interfering (si)RNA targeting phosphatidylinositol 3-kinase regulatory subunit α (PIK3R1) and miR-342-5p inhibitor. The cell proliferation of MOVAS cells was detected using the Cell Counting Kit-8, while cell migration and cell invasion were investigated using a wound healing and Transwell assays, respectively. Target genes for miR-342-5p were confirmed using reverse transcription-quantitative PCR (RT-qPCR) and dual luciferase reporter assay. The relative mRNA and protein expression levels of miR-342-5p were measured using RT-qPCR and western blot analysis. MOVAS cells were treated with a PI3K inhibitor (LY294002) to explore the role of miR-342-5p on the Akt pathway. The results revealed that miR-342-5p mimics promoted cell viability, migration and invasion, and increased the expression of vimentin and phosphorylated-Akt but reduced a-smooth muscle actin (α-SMA) and PIK3R1 expression. However, miR-342-5p inhibitor produced the opposite effects. PIK3R1 was the target gene for miR-342-5p and the effect of siPIK3R1 on MOVAS cells was similar to that of miR-342-5p mimics, while siPIK3R1 partially reversed the effect of miR-342-5p inhibitor on MOVAS cells. The Akt signaling pathway was activated by miR-342-5p mimics or siPIK3R1. Moreover, miR-342-5p mimics partially activated the Akt signaling pathway inhibited by LY294002. MiR-342-5p could promote the proliferation and differentiation of MOVAS and phenotypic transformation. The mechanism behind these processes may be associated with the activation of the Akt signaling pathway induced by PIK3R1 inhibition.

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“…Many signaling pathways are involved in cardiac development, and genes in these pathways are frequently disrupted in patients with CHD. Notch signaling is important for cellular differentiation and is involved in the pathogenesis of both isolated and syndromic CHD (Li et al 1997b;McDaniell et al 2006;Kamath et al 2012;Stittrich et al 2014;Meester et al 2019). Mutations in NOTCH1 have been identified in autosomal dominantly inherited CHD consisting primarily of BAV and are associated with abnormalities of the outflow tracts and semilunar valves (Garg et al 2005;Kerstjens-Frederikse et al 2016;Preuss et al 2016).…”

Section: Cell Signaling and Adhesion Modelsmentioning

confidence: 99%

Genetic Basis of Human Congenital Heart Disease

Nees¹,

Chung

2019

Cold Spring Harb Perspect Biol

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Congenital heart disease (CHD) is the most common major congenital anomaly with an incidence of ∼1% of live births and is a significant cause of birth defect-related mortality. The genetic mechanisms underlying the development of CHD are complex and remain incompletely understood. Known genetic causes include all classes of genetic variation including chromosomal aneuploidies, copy number variants, and rare and common singlenucleotide variants, which can be either de novo or inherited. Among patients with CHD, ∼8%-12% have a chromosomal abnormality or aneuploidy, between 3% and 25% have a copy number variation, and 3%-5% have a single-gene defect in an established CHD gene with higher likelihood of identifying a genetic cause in patients with nonisolated CHD. These genetic variants disrupt or alter genes that play an important role in normal cardiac development and in some cases have pleiotropic effects on other organs. This work reviews some of the most common genetic causes of CHD as well as what is currently known about the underlying mechanisms. C ongenital heart disease (CHD) is the most common major congenital anomaly with an incidence of ∼1% of live births (Hoffman and Kaplan 2002; Calzolari et al. 2003). CHD is a significant cause of birth defect-related mortality (

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Overlapping but distinct roles for NOTCH receptors in human cardiovascular disease

Cited by 46 publications

References 111 publications

Association between tumor mutation profile and clinical outcomes among Hispanic Latina women with triple-negative breast cancer

Association between tumor mutation profile and clinical outcomes among Hispanic Latina women with triple-negative breast cancer

MicroRNA‑342‑5p activates the Akt signaling pathway by downregulating PIK3R1 to modify the proliferation and differentiation of vascular smooth muscle cells

Genetic Basis of Human Congenital Heart Disease

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