ABSTRACT
DNA damage triggers Atm- and/or Atr-dependent signaling pathways to control cell cycle progression, apoptosis, and DNA repair. However, how Atm and Atr are activated is not fully understood. One of the downstream targets of Atm is non-receptor tyrosine kinase c-Abl, which is phosphorylated and activated by Atm. The current view is that c-Abl relays pro-apoptotic signals from Atm to p73 and p53. Here we show that c-Abl deficiency resulted in a broad spectrum of defects in cell response to genotoxic stress, including activation of Chk1 and Chk2, activation of p53, nuclear foci formation, apoptosis, and DNA repair, suggesting that c-Abl might also act upstream of the DNA damage-activated signaling cascades in addition to its role in p73 and p53 regulation. Indeed, we found that c-Abl is required for proper activation of both Atm and Atr. c-Abl is bound to the chromatin and shows enhanced interaction with Atm and Atr in response to DNA damage. c-Abl can phosphorylate Atr on Y291 and Y310 and this phosphorylation appears to have a positive role in Atr activation under genotoxic stress. These findings suggest that Atm-mediated c-Abl activation in cell response to double-stranded DNA breaks might facilitate the activation of both Atm and Atr to regulate their downstream cellular events.
Subject(s)
Cell Cycle Proteins/metabolism , DNA Damage , DNA-Binding Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-abl/physiology , Tumor Suppressor Proteins/metabolism , Animals , Antibiotics, Antineoplastic/pharmacology , Apoptosis , Ataxia Telangiectasia Mutated Proteins , Cell Line , Checkpoint Kinase 1 , Checkpoint Kinase 2 , DNA Breaks, Double-Stranded , DNA Repair , Doxorubicin/pharmacology , Fibroblasts/metabolism , Mice , Mice, Knockout , Nuclear Proteins/metabolism , Phosphorylation , Protein Kinases/metabolism , Proto-Oncogene Proteins c-abl/genetics , Proto-Oncogene Proteins c-abl/metabolism , Tumor Protein p73 , Tumor Suppressor Protein p53/metabolismABSTRACT
Osteoblasts are bone forming cells that are responsible for bone growth and remodeling. They are derived from bone marrow mesenchymal stem cells through a series of processes including commitment, osteoprogenitor expansion, terminal differentiation and cell death. Osteoblastogenesis and bone formation are regulated by hormones, growth factors, cytokines, mechanical loading and aging. Osteoblasts can sense these external cues, transduce the signals through various signaling pathways and regulate the expression of specific genes, to determine the cell fate. In this review, we aim to update our current understanding of the signaling pathways that control different steps of osteoblast homeostasis, with special focus on how signaling events control cell fate through regulating gene expression.
Subject(s)
Cell Differentiation/physiology , Cell Proliferation , Osteoblasts/metabolism , Osteoblasts/physiology , Signal Transduction/physiology , Animals , Bone Morphogenetic Proteins/metabolism , Bone and Bones/physiology , Gene Expression Regulation , Humans , Mitogen-Activated Protein Kinases/metabolism , Models, Biological , Osteoblasts/cytology , Parathyroid Hormone/metabolism , Wnt Proteins/metabolismABSTRACT
BACKGROUND: Previous findings have demonstrated increased expression of inducible heat shock protein 70 (iHSP70) in the gastric mucosa of rats exposed to partial sleep deprived (PSD). The purpose of this study was to investigate the functional role of iHSP70 and its relationship with acid secretion in the stomachs of PSD animals. METHODS: A slowly rotating drum was used to induce PSD in male Sprague-Dawley rats with or without omeprazole treatment. Gastric mucosal samples were harvested for iHSP70 mRNA and protein analysis with RT-PCR and Western blotting, respectively. Enzyme immunoassay was used to determine plasma gastrin level and gastric acidity was measured by titration. The modulating effect of PSD on 0.6 M hydrochloric acid (HCl)-induced gastric damage was also evaluated. RESULTS: PSD increased plasma gastrin, gastric acidity and expression of iHSP70, while significantly reducing HCl-induced gastric damage. Omeprazole administration decreased gastric acidity and reversed iHSP70 over-expression in PSD rats. CONCLUSIONS: PSD increases gastric acidity which enhances expression of mucosal iHSP70. Over-expression of iHSP70 may be a protective homeostatic response of the stomach to stress induced by PSD and acid secretion.
