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The tumor suppressor gene, RASSF1A, is essential for protection against inflammation -induced injury
PloS one, 2013-10, Vol.8 (10), p.e75483
2013
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Autor(en) / Beteiligte
Titel
The tumor suppressor gene, RASSF1A, is essential for protection against inflammation -induced injury
Ist Teil von
  • PloS one, 2013-10, Vol.8 (10), p.e75483
Ort / Verlag
United States: Public Library of Science
Erscheinungsjahr
2013
Quelle
MEDLINE
Beschreibungen/Notizen
  • Ras association domain family protein 1A (RASSF1A) is a tumor suppressor gene silenced in cancer. Here we report that RASSF1A is a novel regulator of intestinal inflammation as Rassf1a(+/-) , Rassf1a(-/-) and an intestinal epithelial cell specific knockout mouse (Rassf1a (IEC-KO) ) rapidly became sick following dextran sulphate sodium (DSS) administration, a chemical inducer of colitis. Rassf1a knockout mice displayed clinical symptoms of inflammatory bowel disease including: increased intestinal permeability, enhanced cytokine/chemokine production, elevated nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) activity, elevated colonic cell death and epithelial cell injury. Furthermore, epithelial restitution/repair was inhibited in DSS-treated Rassf1a(-/-) mice with reduction of several makers of proliferation including Yes associated protein (YAP)-driven proliferation. Surprisingly, tyrosine phosphorylation of YAP was detected which coincided with increased nuclear p73 association, Bax-driven epithelial cell death and p53 accumulation resulting in enhanced apoptosis and poor survival of DSS-treated Rassf1a knockout mice. We can inhibit these events and promote the survival of DSS-treated Rassf1a knockout mice with intraperitoneal injection of the c-Abl and c-Abl related protein tyrosine kinase inhibitor, imatinib/gleevec. However, p53 accumulation was not inhibited by imatinib/gleevec in the Rassf1a(-/-) background which revealed the importance of p53-dependent cell death during intestinal inflammation. These observations suggest that tyrosine phosphorylation of YAP (to drive p73 association and up-regulation of pro-apoptotic genes such as Bax) and accumulation of p53 are consequences of inflammation-induced injury in DSS-treated Rassf1a(-/-) mice. Mechanistically, we can detect robust associations of RASSF1A with membrane proximal Toll-like receptor (TLR) components to suggest that RASSF1A may function to interfere and restrict TLR-driven activation of NFκB. Failure to restrict NFκB resulted in the inflammation-induced DNA damage driven tyrosine phosphorylation of YAP, subsequent p53 accumulation and loss of intestinal epithelial homeostasis.
Sprache
Englisch
Identifikatoren
ISSN: 1932-6203
eISSN: 1932-6203
DOI: 10.1371/journal.pone.0075483
Titel-ID: cdi_plos_journals_1442465901
Format
–
Schlagworte
Accumulation, Adaptor Proteins, Signal Transducing - genetics, Adaptor Proteins, Signal Transducing - metabolism, Animals, Apoptosis, Apoptosis - drug effects, BAX protein, bcl-2-Associated X Protein - genetics, bcl-2-Associated X Protein - metabolism, Benzamides - pharmacology, Biochemistry, Cancer, Cancer genetics, Cell cycle, Cell Cycle Proteins, Cell death, Cell injury, Cell Proliferation - drug effects, Cell survival, Colitis, Colitis, Ulcerative - chemically induced, Colitis, Ulcerative - drug therapy, Colitis, Ulcerative - genetics, Colitis, Ulcerative - pathology, Colon - drug effects, Colon - metabolism, Colon - pathology, Damage accumulation, Dentistry, Deoxyribonucleic acid, Dextran, Dextran Sulfate, Dextrans, Diabetes, DNA, DNA damage, DNA methylation, DNA-Binding Proteins - genetics, DNA-Binding Proteins - metabolism, Enzyme inhibitors, Epigenetics, Epithelial cells, Epithelial Cells - drug effects, Epithelial Cells - metabolism, Epithelial Cells - pathology, Gastrointestinal diseases, Gene expression, Gene Expression Regulation, Gene regulation, Genes, Genetic aspects, Genetic engineering, Gordon, Marilyn, Homeostasis, Imatinib, Imatinib Mesylate, Immune system, Inflammation, Inflammation - chemically induced, Inflammation - drug therapy, Inflammation - genetics, Inflammation - pathology, Inflammatory bowel disease, Inflammatory bowel diseases, Injuries, Intestinal Mucosa - drug effects, Intestinal Mucosa - metabolism, Intestinal Mucosa - pathology, Intestine, Kidney diseases, Kinases, Lymphocytes B, Medicine, Mice, Mice, Knockout, Mortality, NF-kappa B - genetics, NF-kappa B - metabolism, NF-κB protein, Nuclear Proteins - genetics, Nuclear Proteins - metabolism, Oxidative stress, p53 Protein, Pediatrics, Permeability, Pharmaceutical sciences, Pharmacy, Phosphoproteins - genetics, Phosphoproteins - metabolism, Phosphorylation, Physiology, Piperazines - pharmacology, Protein-tyrosine kinase, Proteins, Proto-Oncogene Proteins c-abl - pharmacology, Pyrimidines - pharmacology, Rodents, Signal Transduction, Sodium, Survival, TNF inhibitors, Toll-like receptors, Toll-Like Receptors - genetics, Toll-Like Receptors - metabolism, Tumor Protein p73, Tumor proteins, Tumor suppressor genes, Tumor Suppressor Protein p53 - genetics, Tumor Suppressor Protein p53 - metabolism, Tumor Suppressor Proteins - deficiency, Tumor Suppressor Proteins - genetics, Tumor Suppressor Proteins - metabolism, Tumorigenesis, Tumors, Tyrosine, Yes-associated protein

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