title: The tumor suppressor gene, RASSF1A, is essential for protection against inflammation -induced injury.
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.
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Gordon
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Kalla
authors.forename: Yuewen
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yahya
authors.initials: Y
authors.lastname: Fiteih
authors.forename: Jennifer
authors.initials: J
authors.lastname: Law
authors.forename: Natalia
authors.initials: N
authors.lastname: Volodko
authors.forename: Anwar
authors.initials: A
authors.lastname: Anwar-Mohamed
authors.forename: Anwar
authors.initials: A
authors.lastname: Mohamed
authors.forename: Ayman O S
authors.initials: AO
authors.lastname: El-Kadi
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Jeff
authors.initials: J
authors.lastname: Odenbach
authors.forename: Aducio
authors.initials: A
authors.lastname: Thiesen
authors.forename: Christina
authors.initials: C
authors.lastname: Onyskiw
authors.forename: Haya Abu
authors.initials: HA
authors.lastname: Ghazaleh
authors.forename: Jikyoung
authors.initials: J
authors.lastname: Park
authors.forename: Sean Bong
authors.initials: SB
authors.lastname: Lee
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yu
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Patron
authors.forename: R Todd
authors.initials: RT
authors.lastname: Alexander
authors.forename: Eytan
authors.initials: E
authors.lastname: Wine
authors.forename: Shairaz
authors.initials: S
authors.lastname: Baksh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D000068877:Imatinib Mesylate; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics* / Q000378:metabolism; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494827:Bax protein, mouse; D001549:Benzamides; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D010750:Phosphoproteins; D010879:Piperazines; D011743:Pyrimidines; C496882:RASSF1 protein, mouse; D051193:Toll-Like Receptors; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051028:bcl-2-Associated X Protein; D000068877:Imatinib Mesylate; D016264:Dextran Sulfate; D016315:Proto-Oncogene Proteins c-abl