Notch Signaling Activation Suppresses v-Src-Induced Transformation of Neural Cells by Restoring TGF-β-Mediated Differentiation

Amarir, Samira; Marx, Maria; Calothy, Georges

doi:10.1371/journal.pone.0013572

Cited by 4 publications

(2 citation statements)

References 42 publications

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“…The NICD translocates to the nucleus and activates the transcription of target genes, such as those belonging to the Hairy/enhancer of split and Hairy/enhancer of split-related with YRPW motif families [ 1 ]. In cancer, Notch crosstalks with numerous oncogenic pathways, such as Akt, TGF-β and src signaling [ 2 - 4 ]. In certain context, the interaction between Notch and other oncogenic pathway is independent of the canonical HEY and HES activation [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting notch pathway enhances rapamycin antitumor activity in pancreas cancers through PTEN phosphorylation

Amarasinghe

Washington

et al. 2011

Mol Cancer

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BackgroundPancreas cancer is one of most aggressive human cancers with the survival rate for patients with metastatic pancreas cancer at 5-6 months. The poor survival demonstrates a clear need for better target identification, drug development and new therapeutic strategies. Recent discoveries have shown that the role for Notch pathway is important in both development and cancer. Its contribution to oncogenesis also involves crosstalks with other growth factor pathways, such as Akt and its modulator, PTEN. The mounting evidence supporting a role for Notch in cancer promotion and survival suggests that targeting this pathway alone or in combination with other therapeutics represents a promising therapeutic strategy.ResultsUsing a pancreas cancer tissue microarray, we noted that Jagged1, Notch3 and Notch4 are overexpressed in pancreas tumors (26%, 84% and 31% respectively), whereas Notch1 is expressed in blood vessels. While there was no correlation between Notch receptor expression and survival, stage or tumor grade, Notch3 was associated with Jagged1 and EGFR expression, suggesting a unique relationship between Notch3 and Jagged1. Inhibition of the Notch pathway genetically and with gamma-secretase inhibitor (GSI) resulted in tumor suppression and enhanced cell death. The observed anti-tumor activity appeared to be through Akt and modulation of PTEN phosphorylation. We discovered that transcriptional regulation of RhoA by Notch is important for PTEN phosphorylation. Finally, the mTOR inhibitor Rapamycin enhanced the effect of GSI on RhoA expression, resulting in down regulation of phospho-Akt and increased in vitro tumor cytotoxity.ConclusionsNotch pathway plays an important role in maintaining pancreas tumor phenotype. Targeting this pathway represents a reasonable strategy for the treatment of pancreas cancers. Notch modulates the Akt pathway through regulation of PTEN phosphorylation, an observation that has not been made previously. Furthermore, we discovered that this regulation is dependent on RhoA/Rock1 activation. Enhanced phospho-Akt suppression when GSI is combined with rapamycin suggests that targeting both pathways will lead to a greater efficacy in the treatment of patients with pancreas cancer.

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Section: Introductionmentioning

confidence: 99%

Targeting notch pathway enhances rapamycin antitumor activity in pancreas cancers through PTEN phosphorylation

Amarasinghe

Washington

et al. 2011

Mol Cancer

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“…In certain context, Notch crosstalk with numerous pathways, such as Akt, TGF-β and src signaling [ 16 – 18 ]. Protein phosphorylation is one of the most important post-translational modifications regulating various signaling transduction.…”

Section: Introductionmentioning

confidence: 99%

Notch4 mediates vascular remodeling via ERK/JNK/P38 MAPK signaling pathways in hypoxic pulmonary hypertension

et al. 2022

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Background Hypoxic pulmonary hypertension (HPH) is a chronic progressive advanced disorder pathologically characterized by pulmonary vascular remodeling. Notch4 as a cell surface receptor is critical for vascular development. However, little is known about the role and mechanism of Notch4 in the development of hypoxic vascular remodeling. Methods Lung tissue samples were collected to detect the expression of Notch4 from patients with HPH and matched controls. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured in hypoxic and normoxic conditions. Real-time quantitative PCR and western blotting were used to examine the mRNA and protein levels of Notch4. HPASMCs were transfected with small interference RNA (siRNA) against Notch4 or Notch4 overexpression plasmid, respectively. Cell viability, cell proliferation, apoptosis, and migration were assessed using Cell Counting Kit-8, Edu, Annexin-V/PI, and Transwell assay. The interaction between Notch4 and ERK, JNK, P38 MAPK were analyzed by co-immunoprecipitation. Adeno-associated virus 1-mediated siRNA against Notch4 (AAV1-si-Notch4) was injected into the airways of hypoxic rats. Right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. Results In this study, we demonstrate that Notch4 is highly expressed in the media of pulmonary vascular and is upregulated in lung tissues from patients with HPH and HPH rats compared with control groups. In vitro, hypoxia induces the high expression of Delta-4 and Notch4 in HPASMCs. The increased expression of Notch4 promotes HPASMCs proliferation and migration and inhibits cells apoptosis via ERK, JNK, P38 signaling pathways. Furthermore, co-immunoprecipitation result elucidates the interaction between Notch4 and ERK/JNK/P38. In vivo, silencing Notch4 partly abolished the increase in RVSP and pulmonary vascular remodeling caused by hypoxia in HPH rats. Conclusions These findings reveal an important role of the Notch4-ERK/JNK/P38 MAPK axis in hypoxic pulmonary remodeling and provide a potential therapeutic target for patients with HPH.

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Down-regulation of miR-140-3p can alleviate neonatal repetitive pain in rats via inhibiting TGF-β3

Zhang

Yin

Chen

et al. 2019

Biochemical and Biophysical Research Communications

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Notch Signaling Activation Suppresses v-Src-Induced Transformation of Neural Cells by Restoring TGF-β-Mediated Differentiation

Cited by 4 publications

References 42 publications

Targeting notch pathway enhances rapamycin antitumor activity in pancreas cancers through PTEN phosphorylation

Targeting notch pathway enhances rapamycin antitumor activity in pancreas cancers through PTEN phosphorylation

Notch4 mediates vascular remodeling via ERK/JNK/P38 MAPK signaling pathways in hypoxic pulmonary hypertension

Down-regulation of miR-140-3p can alleviate neonatal repetitive pain in rats via inhibiting TGF-β3

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