PLoS ONE (Jan 2013)

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,
  • 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 Wine,
  • Shairaz Baksh

DOI
https://doi.org/10.1371/journal.pone.0075483
Journal volume & issue
Vol. 8, no. 10
p. e75483

Abstract

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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.