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5. The tumor suppressor gene, RASSF1A, is essential for protection against inflammation -induced injury.

Author

Gordon M, El-Kalla M, Zhao Y, Fiteih Y, Law J, Volodko N, Anwar-Mohamed A, El-Kadi AO, Liu L, Odenbach J, Thiesen A, Onyskiw C, Ghazaleh HA, Park J, Lee SB, Yu VC, Fernandez-Patron C, Alexander RT, Wine E, and Baksh S

Subjects
Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Animals, Apoptosis drug effects, Benzamides pharmacology, Cell Cycle Proteins, Cell Proliferation drug effects, Colitis, Ulcerative chemically induced, Colitis, Ulcerative drug therapy, Colitis, Ulcerative pathology, Colon drug effects, Colon pathology, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Dextran Sulfate, Epithelial Cells drug effects, Epithelial Cells pathology, Gene Expression Regulation, Imatinib Mesylate, Inflammation chemically induced, Inflammation drug therapy, Inflammation genetics, Inflammation pathology, Intestinal Mucosa drug effects, Intestinal Mucosa pathology, Mice, Mice, Knockout, NF-kappa B metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism, Phosphoproteins genetics, Phosphoproteins metabolism, Piperazines pharmacology, Proto-Oncogene Proteins c-abl pharmacology, Pyrimidines pharmacology, Signal Transduction, Toll-Like Receptors metabolism, Tumor Protein p73, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Proteins deficiency, Tumor Suppressor Proteins metabolism, YAP-Signaling Proteins, bcl-2-Associated X Protein genetics, bcl-2-Associated X Protein metabolism, Colitis, Ulcerative genetics, Colon metabolism, Epithelial Cells metabolism, Intestinal Mucosa metabolism, NF-kappa B genetics, Toll-Like Receptors genetics, Tumor Suppressor Proteins genetics
Abstract

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.

Published
2013
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