Notch signaling pathway consists of three parts: Notch receptor, Notch ligand and intracellular effector. Notch is a family of transmembrane proteins that function both as cell surface receptors and transcription regulators. As the first human gene of this family, Notch1 was discovered in 1991 through the analysis of the chromosomal translocation t(7;9) (q34;q34.3) observed in patients with T-cell acute lymphoblastic leukemia (T-ALL). Since then Notch signaling has been implicated in multiple processes that govern normal morphogenesis, differentiation, cell proliferation and apoptosis. At the same time a role of Notch in the pathogenesis of hematologic and solid malignancies has become apparent. The identification of activating mutations in Notch1 were discovered in over 50% of T-ALL patients. However, whether the mutation in Notch1 is an early event or an secondary event is still unknown. It is becoming increasingly evident that Notch signaling can be both oncogenic and tumor suppressive. This review focuses on the recent findings regarding the Notch signaling during the development and progression of different kinds of hematologic malignancies, the types of mutations in Notch1 in T-ALL and the relationship between Notch signaling pathway and other signaling pathways.In addition, the clinical prospects of Notch inhibitors also are discussed.
Humans ; Neoplasms ; Receptor, Notch1 ; Signal Transduction

T-cell acute lymphoblastic leukemia (T-ALL) is the hematological malignancy of bone marrow characterized by the rapid proliferation and subsequent accumulation of immature T lymphocyte and mainly occurs in children and adolescents. In 1991, a kind of activating mutation of Notch 1 was found in a subset of T-ALL with chromosomal translocation t(7;9) for the first time. During the past 20 years since then, understanding of the relationship between Notch 1 activating mutation and T-ALL has been deepened and widened. This review briefly discusses the four main subtypes of Notch 1 activating mutations, also focuses on how these mutations change the normal signaling pathways and genes expression during their participation in the pathogenesis of T-ALL, and how these insights will promote the development of newly targeting therapies for patients with this aggressive form of leukemia.
Humans ; Mutation ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; etiology ; genetics ; Receptor, Notch1 ; genetics

Notch1 (EC Notch1) and tumoral miR-34a as prognostic markers in patients with TNBC.METHODS: The expression of miR-34a was analyzed using archival tumor tissues from 114 patients with TNBC. Simultaneously, archival tumor tissues were also checked for the expression of CD34 and Notch1 by immunostaining. The ratio of Notch1-microvascular density (MVD) to CD34-MVD was defined as EC Notch1. The association between the expression of miR-34a or EC Notch1 and clinicopathological characteristics was analyzed.RESULTS: In the overall patient population, patients with low expression of EC Notch1 was associated with better overall survival (OS, p = 0.041) than those with high expression of EC Notch1. In lymph node-positive TNBC patients, high levels of miR-34a and low levels of EC Notch1 correlated significantly with higher survival benefits in terms of OS (p = 0.026), disease-free survival (p = 0.009), and metastasis-free survival (p = 0.038) relative to that in other patients. Decreased expression of EC Notch1 and increased expression of miR-34a also showed a survival benefit in locally advanced TNBC.CONCLUSION: The fact that miR-34a and EC Notch1 are associated with the angiogenesis suggests that angiogenesis may play a role in the development and progression of TNBC.]]>
Disease-Free Survival ; Endothelial Cells ; Humans ; Prognosis ; Receptor, Notch1 ; Triple Negative Breast Neoplasms

OBJECTIVE: To investigate the effects and mechanisms of irbesartan on myocardial injury in diabetic rats, and to analyze the changes of Notch1 signaling pathway in it. METHODS: Thirty rats were randomly divided into four groups:normal control group (CON, =6), high calorie group (HC, =6) and diabetes mellitus group (DM, =9), irbesartan + diabetes group (Ir + DM, =9). After modeling 8 weeks later, the body weight ratio and left ventricular weight index were measured and the serum levels of triglyceride (TG) and total cholesterol (TC) were measured by automatic biochemical analyzer. The changes of superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in myocardium of rats were determined by the kit and the expressions of B-cell lymphoma-2 (Bcl-2) and Bcl-2 assaciated X protein (Bax) protein in myocardium were detected by immunohistochemistry. The expressions of Notch1, Hes-1 and jagged-1 in myocardium of rats were detected by Western blot. RESULTS: Compared with CON group, the levels of heart weight/body weight (H/B), left ventricular weight index(LVWI) and fasting blood glucose(FBG) in HC group were not significantly changed, while the levels of blood lipids, MDA and Bax were increased significantly, and the expressions of SOD, Bcl-2 and Notch1, Hes-1 and Jagged-1 were decreased. Compared with HC group, the levels of H/B, LVWI, FBG, MDA and Bax in DM group were increased significantly, and the levels of SOD, Bcl-2 and Notch1, Hes-1 and Jagged-1 were decreased. The expression of H/B, LVWI, Notch1, Hes-1 and Jagged-1 in Ir+DM group were increased, but there was no significant difference between the other indexes. The H/B and LVWI in Ir + DM group were significantly lower than those in DM group, the levels of blood lipid and blood glucose did not change significantly, but the incidence of oxidative stress and apoptosis was reduced. While Notch1, Hes-1, Jagged -1 protein expressions were increased. CONCLUSIONS Diabetes can induce myocardial injury, and irbesartan has myocardial protective effects through activation of Notch1.
Animals ; Diabetes Mellitus, Experimental ; Irbesartan ; Myocardium ; Rats ; Rats, Sprague-Dawley ; Receptor, Notch1 ; Signal Transduction

OBJECTIVE: To evaluated the effect of curcumin on the bortezomib-resistant myeloma cells and the expression of Notch1 signaling pathway, in order to further explore its potential mechanism. METHODS: Curcumin, bortezomib, and curcumin combined bortezomib were added into RPMI 8266, U266, 5 nmol/L bortezomib-resistant RPMI 8266 (RPMI 8226-V5R), 5 nmol/L bortezomib-resistant U 266 (U266-V5R) and CD138+ plasma cells respectively. The cell proliferation was measured by MTT assay. the apoptotic rate was determined by flow cytometry, and the Western blot was used to detect the expression of apoptosis-related proteins. Then, the expression of Notch1 in cells was inhibited by notch1 inhibitor DAPT and RNA interference, the above-motioned experiments should be repeated. RESULTS: Compared with single drug-treated groups, the treatment with 2 drugs could further inhibit cell proliferation, induce apoptosis and enhance the inhibition effect on notch1 signaling pathway (P<0.05), while the inhibiting Notch1 signaling pathway could reduce cell proliferation and increase the expression of cleaved caspase-3. CONCLUSION Curcumin can increase chemosensitivity of myeloma cells to bortezomib, this effect may be related to the inhibition of Notch1.
Apoptosis ; Bortezomib ; Cell Line, Tumor ; Cell Proliferation ; Curcumin ; Humans ; Multiple Myeloma ; Receptor, Notch1 ; Signal Transduction

The aim of the present study was to observe the effects of Notch1 and autophagy on extracellular matrix deposition in renal tubulointerstitium of diabetes and to explore the mechanism. The mice were randomly divided into normal control group (db/m mice) and diabetes group (db/db mice). After 12 weeks of feeding, the mice were sacrificed and the corresponding biochemical indexes were measured. Rat renal tubular epithelial cells NRK52E were cultured under normal glucose (NG) and high glucose (HG) respectively, and the expression of Notch1 and LC3 proteins were detected by Western blotting. Autophagosomes in NRK52E cells with overexpressed and knockdown Notch1 under NG and HG conditions were observed by confocal microscope, and the expression changes of Notch1, Collagen-I and III protein were detected by immunofluorescence. The results showed that the Notch1 and Collagen-III expressions were increased (P < 0.01) and the LC3 expression was decreased (P < 0.05) in db/db mice compared with db/m mice. In vitro, the Notch1 was increased (P < 0.01) and the LC3 expression was decreased significantly (P < 0.01) in NRK52E cells of HG group compared with NG group. There was no significant change of Notch1 and LC3 expression between the mannitol (MA) group and the NG group. Autophagy was decreased and extracellular matrix deposition was aggravated when Notch1 was overexpressed. In contrast, autophagy was increased and extracellular matrix deposition was relieved by knockdown of Notch1 under HG conditions. In conclusion, Notch1 protein expression was increased and autophagy was reduced in renal tissue of diabetes and renal tubular epithelial cells under HG. The extracellular matrix deposition in the renal tubulointerstitium was relieved by regulating autophagy after the knockdown of Notch1.
Animals ; Autophagy/physiology* ; Diabetes Mellitus ; Extracellular Matrix ; Glucose/pharmacology* ; Kidney ; Mice ; Rats ; Receptor, Notch1/genetics*

OBJECTIVETo investigate the expressions and the role of Notch signaling-associated proteins in esophageal squamous cell carcinoma (ESCC).

METHODSFifty patients with ESCC were included in this study. The expressions of Notch signaling-associated protein (4 receptors: Notch1, Notch2, Notch3, Notch4; 5 ligands: Dll1, Dll3, Dll4, Jagged1, Jagged2) in cancer foci and adjacent normal tissues (5 cm distance to cancer) were examined by immunohistochemitry. Correlations of these proteins with cancer cell proliferation(Ki-67 index) and clinicopathologic features were investigated.

RESULTSHigher levels of Notch1 and Notch2 were measured in cancer foci compared with adjacent tissues (all P<0.05). There were no differences in the expressions of Notch3, Dll1 and Dll3 (all P>0.05). Notch4, Dll4 and Jagged2 were not detected in both cancer foci and adjacent tissues. Notch1 expression was negatively correlated with lymph node metastasis and TNM staging (all P<0.01). Jagged 1 expression was positively correlated with TNM staging (P<0.01). Ki-67 index was obviously higher in cancer foci, while it was negatively correlated with Notch1 and Notch3 (all P<0.01) and positively correlated with Dll1 and Jagged 1 (all P<0.01).

CONCLUSIONNotch signaling path may act as tumor suppressive gene in the pathogenesis of esophageal squamous cell cancer, in which Notch1 protein plays an important role.

Carcinoma, Squamous Cell ; metabolism ; Esophageal Neoplasms ; metabolism ; Genes, Tumor Suppressor ; Humans ; Lymphatic Metastasis ; Neoplasm Staging ; Receptor, Notch1 ; metabolism ; Receptor, Notch2 ; metabolism ; Receptor, Notch3 ; Receptors, Notch ; metabolism ; Signal Transduction

This study aimed to construct the dual expression vectors of wide type or N187D mutant P2X7 receptor and intracellular domain of Notch1 (ICN1) linked by 2A peptide to coexpress them in leukemia cells so as to lay a foundation for further investigating the role of P2X7 in development of leukemia. Overlap PCR was used to construct the dual expression vectors encoding wide type or N187D mutant type P2X7 receptor and ICN1 linked by the self-cleaving 2A sequence. The results showed that stable expressing cell lines were obtained by retroviral infection followed by cell sorting after DNA sequence analysis. RT-PCR, Western blot, intracellular free calcium concentration analysis were used to verify the functionally successful construction of K562 cell line expressing P2X7 receptor alone or with ICN1. DNA sequence analysis revealed that all construction were right. The infection efficiency of packaged constructed virus ranged from 40% to 70% for K562 cells. Stable infected cell line was obtained by cell sorting. RT-PCR analysis revealed that P2X7 receptor and/or ICN1 could be detected at high level in their stable infected cell lines, respectively. Western blot analysis also showed that P2X7 receptor was highly expressed in cell line infected by virus with P2X7 receptor. Sustained increase in intracellular free calcium concentration ([Ca(2+)]i) could be observed in K562 cells overexpressing either type of P2X7 receptor upon stimulation with BzATP. It is concluded that the wide type or N187D mutant P2X7 receptor and ICN1 are simultaneously and functionally over-express in leukemia cells, which lay a foundation for further studying the role of P2X7 receptor in the development of leukemia.
Gene Expression ; Genetic Vectors ; Humans ; K562 Cells ; RNA, Messenger ; genetics ; Receptor, Notch1 ; genetics ; Receptors, Purinergic P2X7 ; genetics ; Retroviridae ; genetics

The proliferation and apoptosis of multiple myeloma (MM) cells were regulated by bone marrow microenvironments in which Notch signal plays important role in mediating cell-cell communication. However, the regulatory effect of Notch signal on the proliferation and apoptosis of multiple myeloma cells remains unclear. In this study, regulatory effect of Notch signal on the apoptosis of MM cells induced by DMS (N, N-dimethylsphingosine) was investigated. RT-PCR was used to identify the expression of Notch receptor and related molecules such as Dll-1, Jagged-1, Deltex-1 in MM cell lines. The intracellular domain of Notch (ICN), active form of Notch, was transferred into MM cells by retrovirus. The apoptosis of MM cells was determined by trypan blue exclusion tests and TdT-mediated dUTP nick end labeling (TUNEL) assay. The results showed that multiple myeloma cells expressed the Notch-1 and its related molecules. Notch activated multiple myeloma cell lines were obtained. Activation of Notch protected the multiple myeloma cells from the apoptosis induced by DMS,which was determined by cell viability and TUNEL assay. In conclusion, Notch signal suppressed the apoptosis of multiple myeloma cells and would possibly be a novel therapeutic target.
Apoptosis ; Cell Division ; Humans ; Multiple Myeloma ; drug therapy ; pathology ; Receptor, Notch1 ; Receptors, Cell Surface ; physiology ; Signal Transduction ; Transcription Factors ; physiology

OBJECTIVETo investigate the correlation between the expressions of glypican-3 (GPC3) and Notch1 and their roles in the tumorigenesis and progression of hepatocellular carcinoma (HCC).

METHODSImmunohistochemistry and computerized image analysis were utilized to quantitatively detect the expressions of GPC3 and Notch1 in 30 HCC tissue specimens.

RESULTSIn the 30 HCC specimens, GPC3 expression decreased significantly as the grade of tumor differentiation increased (P<0.05 or P<0.01), while Notch1 expression presented with a reverse pattern of changes (P<0.05 or P<0.01). An obvious negative correlation was found between the expressions of GPC3 and Notch1 in HCC tissues (rp=-0.607, P=0.000; r=-0.692, P=0.000).

CONCLUSIONThe expressions of GPC3 and Notch1 show a negative correlation in HCC, suggesting a possible mechanism for mutual regulation between them to contribute to the tumorigenesis and progression of HCC.

Adult ; Aged ; Carcinoma, Hepatocellular ; metabolism ; pathology ; Female ; Glypicans ; metabolism ; Humans ; Liver Neoplasms ; metabolism ; pathology ; Male ; Middle Aged ; Receptor, Notch1 ; metabolism