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

Marilyn Gordon, Mohamed El-Kalla, Yuewen Zhao, Yahya Fiteih, Jennifer Law, Natalia Volodko, Anwar Anwar-Mohamed, Anwar Mohamed, Ayman O S El-Kadi, Lei Liu, Jeff Odenbach, Aducio Thiesen, Christina Onyskiw, Haya Abu Ghazaleh, Jikyoung Park, Sean Bong Lee, Victor C Yu, Carlos Fernandez-Patron, R Todd Alexander, Eytan WineShairaz Baksh

    Research output: Contribution to journalArticlepeer-review

    39 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)e75483
    JournalPLOS One
    Volume8
    Issue number10
    DOIs
    Publication statusPublished - 16 Oct 2013

    Keywords

    • Adaptor Proteins, Signal Transducing
    • Animals
    • Apoptosis
    • Benzamides
    • Cell Proliferation
    • Colitis, Ulcerative
    • Colon
    • DNA-Binding Proteins
    • Dextran Sulfate
    • Epithelial Cells
    • Gene Expression Regulation
    • Imatinib Mesylate
    • Inflammation
    • Intestinal Mucosa
    • Mice
    • Mice, Knockout
    • NF-kappa B
    • Nuclear Proteins
    • Phosphoproteins
    • Piperazines
    • Proto-Oncogene Proteins c-abl
    • Pyrimidines
    • Signal Transduction
    • Toll-Like Receptors
    • Tumor Protein p73
    • Tumor Suppressor Protein p53
    • Tumor Suppressor Proteins
    • bcl-2-Associated X Protein
    • Journal Article
    • Research Support, Non-U.S. Gov't

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