Disease relevance of NOTCH2

• NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway [1].
• NOTCH2 is the a major cause of Hajdu-Cheney syndrome [2].
• Epstein-Barr virus immortalization: Notch2 interacts with CBF1 and blocks differentiation [3].
• Our results show that there are aberrant levels of Notch-1 and Notch-2 in breast cancer tissues compared with normal breast tissue [4].
• Notch1 and notch2 have opposite effects on embryonal brain tumor growth [5].
• We found that the expression of Notch-1 and Notch-2, as well as Notch ligands, was upregulated in 'dysplastic nevi' and melanomas as compared with common melanocytic nevi [6].
• Our results demonstrate that Notch2 signaling is a potent inhibitory signal in human breast cancer xenografts [7].

High impact information on NOTCH2

• Increased Notch1 signaling, but not Notch2, causes a dramatic down-modulation of HPV-driven transcription of the E6/E7 viral genes, through suppression of AP-1 activity by up-regulation of the Fra-1 family member and decreased c-Fos expression [8].
• We previously reported the isolation from a thymic tumor of a feline leukemia virus that had transduced a fragment of the Notch2 gene [9].
• Here we present evidence that a nuclear form of Notch2 corresponding to the biologically active intracellular domain (N2ICD) is expressed from this recombinant retrovirus through internal ribosome entry [9].
• In addition, new evidence points to a requirement for Notch2 in the development of marginal zone B cells [10].
• Furthermore, ectopic expression of DVL1, LRP8 and Notch2 in malignant lung tissue validates the biological impact of these genetic alterations [11].

Chemical compound and disease context of NOTCH2

• It is assumed that such interactions might modulate the physiological functions of Notch2 and epithelin/granulin, thereby affecting various pathologies associated with CAEV [12].
• The Tat protein of the caprine arthritis encephalitis virus interacts with the Notch2 EGF-like repeats and the epithelin/granulin precursor [12].

Biological context of NOTCH2

• Gonadotropes complete their differentiation program eventually, although expression of LH and FSH is mutually exclusive with NOTCH2 transgene expression [13].
• These clones were used as probes in fluorescence in situ hybridization to human metaphase chromosomes, and the results, combined with data from somatic cell hybrid panels, show that the NOTCH2 and 3 genes are located at positions 1p13-p11 and 19p13.2-p13.1, respectively, which are regions of neoplasia-associated translocation [14].
• However, activation of only Notch-1, but not Notch-2, resulted in protection of tumor cells from melphalan- and mitoxantrone-induced apoptosis [15].
• Exposure of B-CLL cells to PI led to induction of apoptosis, a time- and dose-dependent downregulation of CD23 expression and a decline in DNA binding of transcriptionally active Notch2 [16].
• A prominent feature of B-CLL cells is the high expression of CD23, which is closely related to cell survival and is regulated by Notch2 [16].

Anatomical context of NOTCH2

• Notch-1 and Notch-2 showed a transient induction after 2 days and a decrease after 7 days in osteoblasts and after 28 days in SaOS-2 cells [17].
• Notch-2 was only seen occasionally within the developing cortex and spinal cord [18].
• RESULTS: Notch2 and Notch4 were expressed in limited areas in a few samples or in small blood vessels, respectively [19].
• Transforming growth factor beta-1, which stimulates odontoblast differentiation and hard tissue formation after dental injury, downregulated Notch2 expression in cultured human dental slices, in vitro [20].
• During the earlier stages of tooth development, the Notch2 protein was expressed in the epithelium, but was absent from proliferating cells of the inner enamel epithelium [20].

Associations of NOTCH2 with chemical compounds

• Supershift assays revealed that the nuclear form of Notch2 is a component of C1 in B-CLL cells, supporting a model in which NotchIC activates transcription by binding to CBF1 tethered to DNA [21].
• Here we report that Notch2 acts non-redundantly to control the processes of nephron segmentation through an Rbp-J-dependent process [22].
• We identify three specific phosphorylation sites in the Notch2 serine/threonine-rich domain that are dependent on GSK-3 beta activity [23].
• It is thus suggested that the cysteine-rich domain of Tat plays a role in the interaction between the Tat and either Notch2 or the epithelin/granulin domains, both of which exhibit EGF-like-repeat-imposed spatial conformation [12].
• Positive staining for Notch1, Notch 2 in hyperoxia group was much lower than those in room air group at all time points (P < 0. 01, P < 0.05), but compared with the controls, the hyperoxia group showed higher expression of Notch3 (P > 0.05) [24].

Physical interactions of NOTCH2

• Coimmunoprecipitation experiments show that full-length Notch2 binds more efficiently than intracellular Notch2 to GSK-3 beta [23].

Enzymatic interactions of NOTCH2

• In this study, we show that GSK-3 beta is able to bind and phosphorylate Notch2 in vitro and in vivo [23].

Regulatory relationships of NOTCH2

• However, the decrease in Jagged1-triggered Notch2 signaling by mFng was again greater than that by lFng [25].
• Genetic analysis reveals that only Notch2 is required for the differentiation of proximal nephron structures (podocytes and proximal convoluted tubules) despite the presence of activated Notch1 in the nuclei of putative proximal progenitors [22].
• Activation of Notch2 was down-regulated by CHSY1 siRNA treatment [26].
• Overexpression of active Notch2 inhibited TGF-beta1-induced expression of alpha-SMA and collagen I [27].
• Furthermore, we found Notch3 was counter-regulated by Notch2 in C2C12 cells [27].

Other interactions of NOTCH2

• Although both manic fringe (mFng) and lunatic fringe (lFng) decreased the binding of Jagged1 to Notch2 and not that of Delta1, the decrease by mFng was greater in degree than that by lFng [25].
• Therefore, Notch-1 may possess tumour-promoting functions, while Notch-2 could play a tumour-suppressive role in human breast cancer [4].
• Neither Notch-2, nor -3 showed overlap with either PS1 or PS2 immunoreactivity [18].
• The AP-1 transcription factors c-jun, junD, junB, and c-fos as well as Notch2 were found to be specifically up-regulated [28].
• Notch3 mRNA was increased significantly, while Notch1 mRNA was decreased compared to controls, and expression of Notch2 was similar to that of control [29].

Analytical, diagnostic and therapeutic context of NOTCH2

• We used qualitative and quantitative RT-PCR analysis, along with immunohistochemical staining to examine Notch-1 and Notch-2 expression in association with the patients clinical parameters (median follow-up 72 months) [4].
• Shortly after co-culture with osteoclasts, we found that the Notch2 receptor was activated in myeloma cells but Notch1 was not [26].
• Cell proliferation, soft agar colony formation, and xenograft growth were all promoted by Notch2 and inhibited by Notch1 [5].
• We report here novel Notch2 mutant alleles generated by gene targeting in embryonic stem cells, including a conditional null allele in which exon 3 of the Notch2 gene is flanked by loxP sequences [30].
• Three genes (Notch2, H2AFY2, and CDC5L) showed similar expression differences between microsatellite instability and chromosomal instability cell lines as observed between the young and old cell cultures suggesting that they may play a role in tumorigenesis [31].

References