Glycoprotein130 (gp130) and Notch signaling are thought to participate in neural stem cell (NSC) self-renewal. We asked whether gp130 regulates Notch activity in forebrain epidermal growth factor (EGF)-responsive NSCs. Disruption of Notch1 using antisense or a gamma-secretase inhibitor demonstrated a requirement for Notch1 in the maintenance and proliferation of NSCs. Ciliary neurotrophic facto...

The mechanisms by which transcription factor haploinsufficiency alters the epigenetic and transcriptional landscape in human cells to cause disease are unknown. Here, we utilized human induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) to show that heterozygous nonsense mutations in NOTCH1 that cause aortic valve calcification disrupt the epigenetic architecture, resulting in ...

Two recent studies reported whole-genome sequencing of chronic lymphocytic leukemia (CLL) samples and found repeated mutations in the XPO1 and NOTCH1 genes. XPO1 was found mutated in 2.4% of cases, while NOTCH1 was found mutated in 12.2% or 15.1% of CLL samples. Here we report the results of sequencing of XPO1 and NOTCH1 in 186 CLL cases. Our results confirmed frequency of XPO1 mutations. Howev...

An ascending aortic aneurysm (AscAA) is a life-threatening disease whose molecular basis is poorly understood. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV), which is associated with AscAA. Here, we describe a potentially novel role for Notch1 in AscAA. We found that Notch1 haploinsufficiency exacerbated the aneurysmal aortic root dilation seen in the Marfan syndrome mouse...

Oncogenic activating mutations in NOTCH1 occur in more than 50% of T-cell acute lymphoblastic leukemias (T-ALLs). In the present study, we describe a novel mechanism of NOTCH1 activation in T-ALL in which a deletion removing the 5' portion of NOTCH1 abolishes the negative regulatory control of the extracellular domain and leads to constitutively active NOTCH1 signaling. Polypeptides translated ...

The Notch signalling pathway regulates proliferation, cell death and cell type specification that is critical for organogenesis. Mouse models carrying mutations in the Notch signalling pathway display defects in development of the placenta, suggesting that this pathway is required for placental development. In particular, Notch1 mutant embryos exhibit abnormal placental morphogenesis and arrest...

Enhanced Notch signaling contributes to uncontrolled cell growth and cell death resistance in cancer. Here, we demonstrate that in colorectal carcinoma cells the Notch1-dependent activation of cell cycle and proliferation is mediated by repression of the cyclin-dependent kinase inhibitor (CDKI) p27. The half-life of p27 significantly increased after siRNA‑mediated knockdown of Notch1. Notch1 de...

Notch1 protein is a transmembrane receptor that directs various cell fate decisions. Active forms of Notch1 consisting of a transmembrane domain and an intracellular domain (Notch1TM) or only an intracellular domain (Notch1IC) function as oncoproteins. To elucidate the effect of Notch1 abnormalities in radiation-induced lymphomagenesis, we determined the structure of the Notch1 gene and examine...

Tumor invasion and metastasis are the main causes of mortality in patients with hepatocellular carcinoma (HCC). Thus, the effective inhibition of these tumorigenic processes is critical in order for HCC therapy to be effective. Previous studies have demonstrated that Notch1 is associated with metastasis in several human malignancies. However, the exact molecular mechanisms underlying the Notch1...

Recently, the human gene NOTCH1 has been found to be implicated in cancer cell metastasis and the maintenance of cancer stem cells. However, for breast cancer in particular, an association between NOTCH1 levels and metastasis has not been determined. In this study, we investigated the expression status and correlation of NOTCH1 with clinically important factors related to metastasis and the can...