Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0075483
Title: The Tumor Suppressor Gene, RASSF1A, Is Essential for Protection against Inflammation -Induced Injury
Authors: Gordon, M.
El-Kalla, M.
Zhao, Y.
Fiteih, Y.
Law, J.
Volodko, N.
Mohamed, A.
El-Kadi, A.O.S.
Liu, L.
Odenbach, J.
Thiesen, A.
Onyskiw, C.
Ghazaleh, H.A.
Park, J.
Lee, S.B.
Yu, V.C. 
Fernandez-Patron, C.
Alexander, R.T.
Wine, E.
Baksh, S.
Issue Date: 16-Oct-2013
Source: Gordon, M., El-Kalla, M., Zhao, Y., Fiteih, Y., Law, J., Volodko, N., Mohamed, A., El-Kadi, A.O.S., Liu, L., Odenbach, J., Thiesen, A., Onyskiw, C., Ghazaleh, H.A., Park, J., Lee, S.B., Yu, V.C., Fernandez-Patron, C., Alexander, R.T., Wine, E., Baksh, S. (2013-10-16). The Tumor Suppressor Gene, RASSF1A, Is Essential for Protection against Inflammation -Induced Injury. PLoS ONE 8 (10) : -. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0075483
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 (Rassf1aIEC-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. © 2013 Gordon et al.
Source Title: PLoS ONE
URI: http://scholarbank.nus.edu.sg/handle/10635/106453
ISSN: 19326203
DOI: 10.1371/journal.pone.0075483
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