Coupling cellular mitogenesis to apoptosis by designed biomolecules
Weis Center for Research, Geisinger Clinic, Danville, PA 17822, United States.Cellular Signalling (Impact Factor: 4.32). 09/2009; 22(2):190-6. DOI: 10.1016/j.cellsig.2009.09.005
Cellular signal transduction pathways transduce input signals to produce corresponding output effects, ensuring correct response to extracellular signals. Manipulation of components in signaling pathways will alter correlation of input signals to output effects. Here we report that by reconstructing the components in mitogenic and apoptotic signaling pathways, Ras, Raf, and caspase-3, we manipulated the cells to couple mitogenic signal input to apoptotic output. The reconstructed biomolecules that couple mitogenesis to apoptosis are designated as "mitogenesis coupled-apoptosis molecular device" (MCAMD). As mitogenesis in cancer cells is constitutively active, MCAMD may have potential applications for cancer gene therapy.
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ABSTRACT: JAG1, the gene for the Jagged-1 ligand (Jag1) in the Notch signaling pathway, is variably mutated in Alagille Syndrome (ALGS). ALGS patients have skeletal defects, and additionally JAG1 has been shown to be associated with low bone mass through genome-wide association studies. Plating human osteoblast precursors (human mesenchymal stem cells—hMSCs) on Jag1 is sufficient to induce osteoblast differentiation; however, exposure of mouse MSC (mMSC) to Jag1 actually inhibits osteoblastogenesis. Overexpression of the notch-2 intracellular domain (NICD2) is sufficient to mimic the effect of Jag1 on hMSC osteoblastogenesis, while blocking Notch signaling with a γ-secretase inhibitor or with dominant-negative mastermind inhibits Jag1-induced hMSC osteoblastogenesis. In pursuit of interacting signaling pathways, we discovered that treatment with a protein kinase C δ (PKCδ) inhibitor abrogates Jag1-induced hMSC osteoblastogenesis. Jag1 results in rapid PKCδ nuclear translocation and kinase activation. Furthermore, Jag1 stimulates the physical interaction of PKCδ with NICD. Collectively, these results suggest that Jag1 induces hMSC osteoblast differentiation through canonical Notch signaling and requires concomitant PKCδ signaling. This research also demonstrates potential deficiencies in using mouse models to study ALGS bone abnormalities. STEM Cells 2013;31:1181–1192Stem Cells 06/2013; 31(6). DOI:10.1002/stem.1353 · 6.52 Impact Factor
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