Rabbit Anti-Human Jagged2 monoclonal antibody, clone U.695.5

The Notch signaling pathway has a crucial role in the differentiation of hair cells and supporting cells by mediating "lateral inhibition" via the ligands Delta-like1 (DII1) and Jagged2 (Jag2) and the effectors Hes1 and Hes5 during mammalian inner ear development. Recently, another Notch ligand, Jagged1 (Jag1)-dependent Notch activation, has been revealed to be important for the determination of the prosensory region in the earlier stage before cell differentiation. However, little is known about the effectors of the Notch pathway in this context. P27(Kip1), a cyclin-dependent kinase inhibitor, is also known to demarcate the prosensory region in the cochlear primordium, which consists of the sensory progenitors that have completed their terminal mitoses. Hes1 reportedly promotes precursor cell proliferation through the transcriptional down-regulation of p27(Kip1) in the thymus, liver, and brain. In this study, we observed Hes1 as a mediator between the Notch signaling pathway and the regulation of proliferation of sensory precursor cells by p27(Kip1) in the developing cochlea. We showed that Hes1, but not Hes5, was weakly expressed at the time of onset of p27(Kip1). The expression pattern of Hes1 prior to cell differentiation was similar to that of activated Notch1. P27(Kip1) was up-regulated and BrdU-positive S-phase cells were reduced in the developing cochlear epithelium of Hes1 null mice. These results suggest that the Notch-Hes1 pathway may contribute to the adequate proliferation of sensory precursor cells via the potential transcriptional down-regulation of p27(Kip1) expression and play a pivotal role in the correct prosensory determination. (C) 2009 Wiley-Liss, Inc.

Several studies have shown that tRNAs can be enzymatically cleaved to generate distinct classes of tRNA-derived fragments (tRF). Here, we report that tRF/miR-1280, a 17-bp fragment derived from tRNA(Leu) and pre-miRNA, influences Notch signaling pathways that support the function of cancer stem-like cells (CSC) in colorectal cancer progression. tRF/miR-1280 expression was decreased in human specimens of colorectal cancer. Ectopic expression of tRF/miR-1280 reduced cell proliferation and colony formation, whereas its suppression reversed these effects. Mechanistic investigations implicated the Notch ligand JAG2 as a direct target of tRF/miR-1280 binding through which it reduced tumor formation and metastasis. Notably, tRF/miR-1280-mediated inactivation of Notch signaling suppressed CSC phenotypes, including by direct transcriptional repression of the Gata1/3 and miR-200b genes. These results were consistent with findings of decreased levels of miR-200b and elevated levels of JAG2, Gata1, Gata3, Zeb1, and Suz12 in colorectal cancer tissue specimens. Taken together, our results established that tRF/miR-1280 suppresses colorectal cancer growth and metastasis by repressing Notch signaling pathways that support CSC phenotypes. Furthermore, they provide evidence that functionally active miRNA can be derived from tRNA, offering potential biomarker and therapeutic uses.