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1.
PLoS One ; 6(8): e23571, 2011.
Article in English | MEDLINE | ID: mdl-21887275

ABSTRACT

The tumor suppressor p53 controls multiple cellular functions including DNA repair, cell cycle arrest and apoptosis. MDM2-mediated p53 ubiquitination affects both degradation and cytoplasmic localization of p53. Several cofactors are known to modulate MDM2-mediated p53 ubiquitination and proteasomal degradation. Here we show that IRTKS, a novel IRSp53-like protein inhibited p53-induced apoptosis and depressed its transcription activity. IRTKS bound directly to p53 and increased p53 ubiquitination and cytoplasmic localization. Further studies revealed that IRTKS interacted with MDM2 and promoted low levels of MDM2-mediated p53 ubiquitination in vitro and in vivo. In unstressed cells with low levels of MDM2, IRTKS was found to stabilize the interaction of p53 and MDM2. In stressed cells, IRTKS dissociated from p53, and high levels of MDM2 induced by p53 activation mediate IRTKS poly-ubiquitination and subsequent proteasomal degradation. These data suggest that IRTKS is a novel regulator of p53, modulating low level of MDM2-mediated p53 ubiquitination in unstressed cells.


Subject(s)
Microfilament Proteins/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/metabolism , Ubiquitination , Apoptosis , Cell Line , Cell Nucleus/enzymology , Humans , Protein Binding , Protein Transport , Proteolysis , Transcription, Genetic , Transcriptional Activation/genetics , Tumor Suppressor Protein p53/genetics , Ubiquitin-Protein Ligases/metabolism
2.
J Immunol ; 183(10): 6646-56, 2009 Nov 15.
Article in English | MEDLINE | ID: mdl-19864597

ABSTRACT

LPS is an immunostimulatory component of Gram-negative bacteria. Acting on the immune system in a systemic fashion, LPS exposes the body to the hazard of septic shock. In this study we report that cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2/Crispld2; human and mouse/rat versions, respectively), expressed by multitissues and leukocytes, is a novel LPS-binding protein. As a serum protein, median CRISPLD2 concentrations in health volunteers and umbilical cord blood samples are 607 microg/ml and 290 microg/ml, respectively. Human peripheral blood granulocytes and mononuclear cells including monocytes, NK cells, and T cells spontaneously release CRISPLD2 (range, 0.2-0.9 microg/ml) and enhance CRISPLD2 secretion (range, 1.5-4.2 microg/ml) in response to stimulation of both LPS and humanized anti-human TLR4-IgA Ab in vitro. CRISPLD2 exhibits significant LPS binding affinity similar to that of soluble CD14, prevents LPS binding to target cells, reduces LPS-induced TNF-alpha and IL-6 production, and protects mice against endotoxin shock. In in vivo experiments, serum Crispld2 concentrations increased in response to a nontoxic dose of LPS and correlated negatively with LPS lethality, suggesting that CRISPLD2 serum concentrations not only are indicators of the degree of a body's exposure to LPS but also reflect an individual's LPS sensitivity.


Subject(s)
Cell Adhesion Molecules/immunology , Interferon Regulatory Factors/immunology , Lipopolysaccharides/immunology , Recombinant Proteins/immunology , Shock, Septic/immunology , Animals , Antibodies, Monoclonal/pharmacology , Cell Adhesion Molecules/blood , Cell Adhesion Molecules/drug effects , Cell Adhesion Molecules/metabolism , Female , Granulocytes/immunology , Granulocytes/metabolism , Humans , Immunologic Factors/pharmacology , Interferon Regulatory Factors/blood , Interferon Regulatory Factors/drug effects , Interferon Regulatory Factors/metabolism , Interleukin-6/immunology , Interleukin-6/metabolism , Kaplan-Meier Estimate , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lipopolysaccharides/metabolism , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred BALB C , Monocytes/immunology , Monocytes/metabolism , Recombinant Proteins/pharmacology , Shock, Septic/prevention & control , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Toll-Like Receptor 4/immunology , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolism
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