The Tumor Suppressor Gene, RASSF1A, Is Essential for Protection against Inflammation -Induced Injury

摘要: Ras association domain family protein 1A (RASSF1A) is a tumor suppressor gene silenced in cancer. Here we report that RASSF1A novel regulator of intestinal inflammation as Rassf1a+/−, Rassf1a−/− and an epithelial cell specific knockout mouse (Rassf1a IEC-KO) rapidly became sick following dextran sulphate sodium (DSS) administration, chemical inducer colitis. Rassf1a mice displayed clinical symptoms inflammatory bowel disease including: increased permeability, enhanced cytokine/chemokine production, elevated nuclear factor kappa light polypeptide enhancer B-cells (NFκB) activity, colonic death injury. Furthermore, restitution/repair was inhibited DSS-treated with reduction several makers proliferation including Yes associated (YAP)-driven proliferation. Surprisingly, tyrosine phosphorylation YAP detected which coincided p73 association, Bax-driven p53 accumulation resulting apoptosis poor survival mice. We can inhibit these events promote the intraperitoneal injection c-Abl related kinase inhibitor, imatinib/gleevec. However, not by imatinib/gleevec background revealed importance p53-dependent during inflammation. These observations suggest (to drive up-regulation pro-apoptotic genes such Bax) are consequences inflammation-induced injury Mechanistically, detect robust associations membrane proximal Toll-like receptor (TLR) components to may function interfere restrict TLR-driven activation NFκB. Failure NFκB resulted DNA damage driven YAP, subsequent loss homeostasis.