Biological role of the tumor suppressor protein, RASSF1A in Inflammation and Cancer

  • Author / Creator
    El-Kalla, Mohamed
  • Inflammatory bowel disease (IBD) such as Crohn’s disease (CD) and ulcerative colitis (UC) are chronic intestinal diseases characterized by inflammation of the gastrointestinal area resulting in abdominal pain, chronic diarrhoea, and weight loss. IBD affects 1 in 1000 individuals and between 10% and 15% of CD patients are children (with northern Alberta having one of the highest rates of CD in the world). Molecularly, it is characterized by hyperactivation of the transcription factor, nuclear factor κ B (NFκB), and elevated production of pro-inflammatory cytokines. RASSF1A is a tumor suppressor protein required for death receptor dependent cell death (apoptosis) originating from the tumor necrosis factor alpha (TNFα) receptor (TNF-R1). It is one of the most methylated genes identified in human cancers and one of the earliest detectable loss in cancer. Loss of RASSF1A expression arises by methylation of the promoter for exon 1Aα (encoding the N-terminal 119 amino acids) without epigenetic loss of the other isoforms of RASSF1, suggesting selective pressure to silence isoform RASSF1A. We have defined apoptotic regulation by RASSF1A involving death receptors (such as TNF-R1) and its downstream target modulator of apoptosis, MOAP-1. We now define a novel role for RASSF1A in modulating innate immunity. Rassf1a-/- mice rapidly become sick following challenge with LPS or dextran sulphate in comparison to wild type animals and cytokine analysis of the peripheral blood reveal an elevated production of NFκB regulated cytokines (IL-6, IL-12, IL-8 and IL-10) Rassf1a-/- mice when compared to wild type animals. We propose that RASSF1A is an emerging novel negative regulator of inflammation and maybe a new susceptibility gene for inflammatory diseases.

  • Subjects / Keywords
  • Graduation date
    Spring 2010
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.