Article

CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation.

Department of Biological Sciences and Biotechnology, State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, Tsinghua University, Beijing 100084, China.
The Journal of Cell Biology (Impact Factor: 10.82). 07/2008; 181(6):959-72. DOI: 10.1083/jcb.200711044
Source: PubMed

ABSTRACT Runx2, an essential transactivator for osteoblast differentiation, is tightly regulated at both the transcriptional and posttranslational levels. In this paper, we report that CHIP (C terminus of Hsc70-interacting protein)/STUB1 regulates Runx2 protein stability via a ubiquitination-degradation mechanism. CHIP interacts with Runx2 in vitro and in vivo. In the presence of increased Runx2 protein levels, CHIP expression decreases, whereas the expression of other E3 ligases involved in Runx2 degradation, such as Smurf1 or WWP1, remains constant or increases during osteoblast differentiation. Depletion of CHIP results in the stabilization of Runx2, enhances Runx2-mediated transcriptional activation, and promotes osteoblast differentiation in primary calvarial cells. In contrast, CHIP overexpression in preosteoblasts causes Runx2 degradation, inhibits osteoblast differentiation, and instead enhances adipogenesis. Our data suggest that negative regulation of the Runx2 protein by CHIP is critical in the commitment of precursor cells to differentiate into the osteoblast lineage.

0 Bookmarks
 · 
136 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Posttranslational modification by ubiquitin tagging is crucial for regulating the stability, activity and cellular localization of many target proteins involved in processes including DNA repair, cell cycle progression, protein quality control, and signal transduction. It has long been appreciated that ubiquitin-mediated events are important for certain signaling pathways leading to leukocyte activation and the stimulation of effector function. Now it is clear that the activities of molecules and pathways central to immune regulation are also modified and controlled by ubiquitin tagging. Among the mechanisms of immune control, regulatory T cells (or Tregs) are themselves particularly sensitive to such regulation. E3 ligases and deubiquitinases both influence Tregs through their effects on the signaling pathways pertinent to these cells or through the direct, posttranslational regulation of Foxp3. In this review, we will summarize and discuss several examples of ubiquitin-mediated control over multiple aspects of Treg biology including the generation, function and phenotypic fidelity of these cells. Fully explored and exploited, these potential opportunities for Treg modulation may lead to novel immunotherapies for both positive and negative fine-tuning of immune restraint.
    Journal of Molecular Medicine 04/2014; · 4.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The ubiquitin ligase Smad ubiquitination regulatory factor-1 (Smurf1) negatively regulates bone morphogenetic protein (BMP) pathway by ubiquitinating certain signal components for degradation. Thus, it can be an eligible pharmacological target for increasing BMP signal responsiveness. We established a strategy to discover small molecule compounds that block the WW1 domain of Smurf1 from interacting with Smad1/5 by structure based virtual screening, molecular experimental examination and cytological efficacy evaluation. Our selected hits could reserve the protein level of Smad1/5 from degradation by interrupting Smurf1-Smad1/5 interaction and inhibiting Smurf1 mediated ubiquitination of Smad1/5. Further, these compounds increased BMP-2 signal responsiveness and the expression of certain downstream genes, enhanced the osteoblastic activity of myoblasts and osteoblasts. Our work indicates targeting Smurf1 for inhibition could be an accessible strategy to discover BMP-sensitizers that might be applied in future clinical treatments of bone disorders such as osteopenia.
    Scientific Reports 01/2014; 4:4965. · 5.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Carboxy-terminus of Hsc70 Interacting Protein (CHIP) is a co-chaperone E3 ligase containing three tandem repeats of tetratricopeptide (TPR) motifs and a C-terminal U-box domain separated by a central charged coiled-coil region. CHIP is known to function as a central quality-control E3 ligase and regulates several proteins involved in a myriad of physiological and pathological processes. Recent studies have highlighted varied regulatory mechanisms operating on the activity of CHIP which is crucial for cellular homeostasis. In this review article, we give a concise account of our current knowledge on the biochemistry and regulation of CHIP.
    BioMed Research International 04/2014; · 2.71 Impact Factor

Full-text (2 Sources)

Download
85 Downloads
Available from
May 22, 2014