The Notch signaling pathway regulates cell proliferation, apoptosis and cell fate decision. Recent preclinical and clinical evidence supports a pro-oncogenic function for Notch signaling in several solid tumors including breast and prostate cancer. Consequently, there is increasing interest in targeting Notch signaling therapeutically in cancer patients. Notch inhibitors, particularly gamma-secretase inhibitors, are being investigated as candidate cancer therapeutic agents. However, rational targeting of Notch signaling in cancer will require a systematic exploration of several areas that remain incompletely understood. Therefore, a clear understanding of the Notch signaling and its cross-talk with other signaling cascade will increase our ability to design rational combination regimens for cancer therapy.

Major characteristics of embryonic stem cells (ESCs) are sustaining of stemness and pluripotency by self-renewal. In this report, transcriptional profiles of the molecules in the developmentally important signaling pathways including Wnt, BMP4, TGF-β, RTK, Hh, Notch, and JAK/STAT signaling pathways were investigated to understand the self- renewal of mouse ESCs (mESCs), J1 line, and compared with the NIH3T3 cell line and mouse embryonic fibroblast (MEF) cells as controls. In the Wnt signaling pathway, the expression of Wnt3 was seen widely in mESCs, suggesting that the ligand may be an important regulator for self-renewal in mESCs. In the Hh signaling pathway, the expression of Gli and N-myc were observed extensively in mESCs, whereas the expression levels of in a Shh was low, suggesting that intracellular molecules may be essential for the self-renewal of mESCs. IGF-I, IGF-II, IGF-IR and IGF-IIR of RTK signaling showed a lower expression in mESCs, these molecules related to embryo development may be restrained in mESCs. The expression levels of the Delta and HES5 in Notch signaling were enriched in mESCs. The expression of the molecules related to BMP and JAK-STAT signaling pathways were similar or at a slightly lower level in mESCs compared to those in MEF and NIH3T3 cells. It is suggested that the observed differences in gene expression profiles among the signaling pathways may contribute to the self-renewal and differentiation of mESCs in a signaling-specific manner.

Endocytosis of the Notch ligand, DeltaD, by mind bomb1 is indispensable for activation of Notch in cell fate determination, proliferation, and differentiation during zebrafish neurogenesis. Loss of mind bomb1 activity as an E3 Ubiquitin ligase causes the accumulation of deltaD at the plasma membrane and results in the ectopic neurogenic phenotype by activation of Notch in early zebrafish embryogenesis. However, the regulatory mechanism of deltaD during neurogenesis is not identified yet. This study aims to analyze the pathway of mib1 and deltaD after endocytosis in vivo during zebrafish embryogenesis. Mind bomb1 and deltaD are co-localized into autophagosome and mutant form of mind bomb1 fails to cargo deltaD into autophagosomes. These findings suggest that mind bomb I mediates deltaD regulation by autophagy in an ubiquitin-dependent manner during zebrafish embryogenesis.