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

PLoS One. 2013 Oct 16;8(10):e75483. doi: 10.1371/journal.pone.0075483. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Apoptosis / drug effects
  • Benzamides / pharmacology
  • Cell Cycle Proteins
  • Cell Proliferation / drug effects
  • Colitis, Ulcerative / chemically induced
  • Colitis, Ulcerative / drug therapy
  • Colitis, Ulcerative / genetics*
  • Colitis, Ulcerative / pathology
  • Colon / drug effects
  • Colon / metabolism*
  • Colon / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dextran Sulfate
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Gene Expression Regulation
  • Imatinib Mesylate
  • Inflammation / chemically induced
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Inflammation / pathology
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Mice
  • Mice, Knockout
  • NF-kappa B / genetics*
  • NF-kappa B / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-abl / pharmacology
  • Pyrimidines / pharmacology
  • Signal Transduction
  • Toll-Like Receptors / genetics*
  • Toll-Like Receptors / metabolism
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Bax protein, mouse
  • Benzamides
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • NF-kappa B
  • Nuclear Proteins
  • Phosphoproteins
  • Piperazines
  • Pyrimidines
  • RASSF1 protein, mouse
  • Toll-Like Receptors
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Yap1 protein, mouse
  • bcl-2-Associated X Protein
  • Imatinib Mesylate
  • Dextran Sulfate
  • Proto-Oncogene Proteins c-abl